Bioactive Natural Products: Opportunities and Challenges in Medicinal ...

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called methionine aminopeptidase-2 (MetAP-2), and for this reason, the compound, together with semi-synthetic derivatives, are investigated as.
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Natural Products in Drug Discovery: Impacts and Opportunities — An Assessment

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Goutam Brahmachari*

Nature stands as an inexhaustible source of novel chemotypes and pharmacophores, and has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs find their origin in natural products. Natural product chemistry has experienced explosive and diversified growth, making natural products the subject of much interest and promise in the present day research directed towards drug design and discovery. It is noteworthy that natural products are a source of new compounds with diversified structural arrangements possessing interesting biological activities. Natural products, thus, have played and continue to play an invaluable role in the drug discovery process. Recently, there has been a renewed interest in natural products research due to the failure of alternative drug discovery methods to deliver many lead compounds in key therapeutic areas such as immunosuppression, anti-infective, and metabolic diseases. However, continuing improvements in natural products research are needed to continue to be competitive with other drug discovery methods, and also to keep pace with the ongoing changes in the drug discovery process. Faithful drives are needed in a more intensified fashion to explore “Nature” as a source of novel and active agents that may serve as the leads and scaffolds for elaboration into urgently needed efficacious drugs for a multitude of disease indications. Natural products have provided considerable value to the pharmaceutical industry over the past half century. In particular, the therapeutic

* Corresponding author. E-mail: [email protected]; [email protected] 1

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areas of infectious diseases and oncology have benefited much from numerous drug classes derived from the natural form and as templates for synthetic modification. About 40 new drugs launched on the market between 2000 and 2010, originating from terrestrial plants, terrestrial microorganisms, marine organisms, and terrestrial vertebrates and invertebrates are reported, and summarized categorically (as per disease area) in this article. In addition, this review incorporates natural products and natural product-derived compounds that are being presently evaluated in clinical trials or are in registration highlighting their mechanism of action. These drugs substances, representative of very wide chemical diversity, thus continue to demonstrate the importance of compounds from natural sources in modern drug discovery efforts. Hence, the proven natural product drug discovery track record, coupled with the continuing threat to biodiversity through the destruction of terrestrial and marine ecosystems, provides a compelling challenge for the global scientific community to undertake expanded exploration of “Nature” as a source of novel leads for the development of drugs and other valuable bioactive agents. A huge number of natural product-derived compounds in various stages of clinical development highlight the existing viability and significance of the use of natural products as sources of new drug candidates.

“Organic chemistry just now is enough to drive one mad. It gives the impression of a primeval tropic forest, full of the most remarkable things, a monstrous and boundless thicket, with no way to escape, into which one may well dread to enter.” Wöhler (1835)

1. Introduction Almost two centuries had elapsed after Wöhler’s historical comment cited in his letter to Berzelius in the year 1835 on the ongoing development of organic chemistry; his “monstrous and boundless thicket” is now sufficiently more dense and complex than ever and quite forbidding to strangers! Natural products chemistry, a vital section of organic chemistry,

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has also undergone an explosive growth in its own course and has already established itself as a distinct discipline. Mother Nature now stands as an inexhaustible source of novel chemotypes and pharmacophores.1 Nature’s terrestrial flora and fauna have formed the basis of sophisticated traditional medicine systems that have been in existence for thousands of years — such an intrinsic dependence of human beings on Nature has invoked tremendous interest in the scientific world, which ultimately led to the isolation of a vast number of chemical agents with the potential for multipurpose uses.2–9 Natural product chemists took up the challenge of determining the structures of ever more complicated natural products. From the late 19th century until today, generations of natural product chemists have applied their skills and intellect to many tens of thousands of molecules of natural origin, encouraged by a society that values many natural products for their life-giving or life-enhancing properties. Although ~200 000 natural compounds derived from natural sources such as plants, animals or microorganisms are currently known, this figure is with small variety regards to the widen of natural resources; only about 5–15% of nearly 250 000 higher plants and less than 1% of the microbial world have been explored so far chemically — the vast majority of these sources remains untapped.10–12 The future of natural products in drug discovery, thus, appears to be a tale of justifiable hope. The pragmatic optimism currently placed on natural products in search of new drugs and lead molecules has recently been aptly expressed as “The world of plants, and indeed all natural sources, represent a virtually untapped reservoir of novel drugs awaiting imaginative and progressive organizations”.1 By the 20th century, natural products began to provoke some biochemists interested in understanding the way in which compounds were made that eventually initiated the concepts of biosynthetic pathways for different kinds of natural products. In the early 20th century, very few researchers associated with the emerging departments of clinical biochemistry, pharmacology, toxicology, microbiology and cell biology became motivated to work with some specific natural products, but the study of natural products as a group was still largely confined to chemistry departments. By the mid 20th century, some cell biologists and physiologists screened a few natural products (viz. colchicine, atropine, nicotine, digoxin, etc.) as experimental tools that influenced or disrupted cell functions in specific

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ways. However, it was the discovery of antibiotics that offered the study of natural products a great boost in microbiology departments and ensured that natural products remained central to growing pharmaceutical companies.13,14 Due to multidirectional promising aspects, the interest in natural products continues to this very day.15–30 The last decade has seen a greater use of botanical products among members of the general public through self-medication than never before. The use of herbal drugs is once more escalating in the form of complementary and alternative medicine (CAM).31,32 This phenomenon has been mirrored by an increasing attention to phytomedicines as a form of alternative therapy by the health professions; in many developing countries of the world, there is still a major reliance on crude drug preparation of plants used in traditional medicines for their primary healthcare.33–36 The World Health Organization (WHO) estimates that approximately 80% of the world’s population relies mainly on traditional medicine, predominantly originated from plants, for their primary health care.37,38 The worldwide economic impact of herbal remedies is noteworthy; in the US alone, in 1997, it was estimated that 12.1% of the population spent $5.1 billion on herbal remedies.39 In the UK, sales of herbal remedies were worth of £75 million in 2002, an increase of 57% over the previous 5 years of herbal medicines.40 Studies carried out in other countries, such as Australia and Italy, also suggest an increasing prevalence of use of herbal medicines among the adult population.40,41 In India and China, the Ayurvedic and Chinese traditional medicine systems respectively are particularly well developed, and both have provided potential for the development of Western medicine. Throughout our evolution, the importance of natural products for medicine and health has been enormous; the past few years have seen a renewed interest in the use of natural compounds and, more importantly, their role as a basis for drug discovery. The modern tools of chemistry and biology — in particular, the various “-omics” technologies — now allow scientists to detail the exact nature of the biological effects of natural compounds on the human body, as well as to uncover possible synergies, which holds much promise for the discovery of new therapies against many devastating diseases.42–49 Natural products, thus, have been the major sources of chemical diversity as starting materials for driving pharmaceutical discovery over the past century.1,50,51 Many natural products and synthetically modified

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natural product derivatives have been successfully developed for clinical use to treat human diseases in almost all therapeutic areas.52 Natural product medicines have come from various source materials including terrestrial plants, terrestrial microorganisms, marine organisms, and terrestrial vertebrates and invertebrates.4,8,41,42 The importance of natural products in modern medicine has been described in a number of earlier reviews and reports.8,30,53–60 A comprehensive review of natural products in clinical trials, “Recent Natural Products Based Drug Development: A Pharmaceutical Industry Perspective”, was published in 1998 by Shu.61 Since then, a good number of discussions have been published that describe natural product-derived compounds in clinical trials by organism type, compound class and/or therapeutic area.48,53–71 In addition, there have been a number of reviews detailing marine-derived natural products in clinical trials.47,57,72–80 This present chapter is aimed, particularly, to highlight the impact and opportunities of natural products in modern drug discovery programs delineating the approved natural product-based drugs launched during the period 2000 to 2010, and also natural product-based drug candidates undergoing clinical evaluation.

2. Natural Products in Traditional Medicine: A Historical Perspective in Brief Natural products (including plants, animals and minerals) have been the basis of treatment of human diseases. History of medicine dates back practically to the existence of human civilization. Modern medicine system has gradually developed over the years by scientific and observational efforts of scientists; however, the basis of its development remains rooted in traditional medicine and therapies, prevailing throughout the world for thousands of years, which continue to provide mankind with new remedies. Plant-based medicines initially dispensed in the form of crude drugs such as tinctures, teas, poultices, powders, and other herbal formulations,6 now serve as the basis of novel drug discovery. The plant-based indigenous knowledge was passed down from generation to generation in various parts of the world throughout its history and has significantly contributed to the development of different traditional systems of medicine.

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The history of traditional medicine in India can be traced to the remote past. Multidirectional therapeutic uses of various plants in traditional way are known in India since the Vedic times as Ayurvedic and Unani systems of medicine. The lore of any country man is built upon the experience of generations, often of centuries and the data upon which it is based have often been obtained at a price in human lives which no modern research worker would ever dream of considering. The earliest mention of the medicinal use of plants is found in the Rig Veda, perhaps the oldest repository of human knowledge, having been written between 4500 and 1600 BC. “Susruta Samhita” which was written not later than 1000 BC contains a comprehensive chapter on therapeutics and “Charaka Samhita”, written about the same period, gives a remarkable description of the materia medica as it was known to the ancient Hindus. During the centuries that have gone by, the materia medica of the indigenous system of medicine has become explosive and heterogeneous. The “Nei Ching” is also one of the earliest health science anthologies, which dates back to 1300 BC.81 Some of the first records on the use of natural products in medicine were written in cuneiform in Mesopotamia on clay tablets and date to approximately 2600 BC.81,82 Indeed, many of these agents continue to exist in one form or another to this day as treatments for various ailments. Chinese herb guides document the use of herbaceous plants as far back in times as 2000 BC;22 in fact, “The Chinese Meteria Medica” has been repeatedly documented over centuries starting at about 1100 BC.82 Li Shih-Chen produced a Chinese drug encyclopedia during the Ming Dynasty entitled “Pen-ts’as kang mu” in AD 1596, which records 1898 herbal drugs and 8160 prescriptions.71 Egyptians have been found to have documented uses of various herbs in 1500 BC;22,82 the best known of these documents is the Ebers Papyrus, which documents nearly 1000 different substances and formulations, most of which are plant-based medicines.81 The Greek Botanist, Pedanius Dioscorides compiled a work entitled “De Materia Medica” in approximately AD 100, and this is still a very well-known European document on the use of herbs in medicine. However, it should not go unrecognized that it was the Arabs who were responsible for maintaining the documentation of much of the Greek and Roman knowledge of herbs and natural products and expanding that information with their own knowledge of Chinese and Indian herbal medicine.82

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Besides, various types of societies and botanical clubs held meetings and published different types of communications to educate the general people with regard to the availability of natural products and how they could be helpful to an individual’s health. Samuel Thompson’s “Thompson’s New Guide to Health” was also one very popular publication. For a variety of reasons, the interest in natural products continues to this very day.16,17,19,20–22,83,84 In many developing countries of the world, there is still a major reliance on crude drug preparation of plants used in traditional medicines for their primary health care.33–36 Pharmacognosists employed in the different institutions are aware of the changing trends of herbal medications and a number of useful texts on the analysis, uses, and potential toxicities of herbal remedies have appeared recently, which serves as useful guides in pharmacy practice. The history of medicine includes many ludicrous therapies. Nevertheless, ancient wisdom has been the basis of modern medicine and will remain as one important source of future medicine and therapeutics. The future of natural products drug discovery will be more holistic, personalized and involve the wise use of ancient and modern therapeutic skills in a complementary manner so that maximum benefits can be accrued to the patients and the community.85 The use of natural products as medicine has invoked the isolation of active compounds; the first commercial pure natural product introduced for therapeutic use is generally considered to be the narcotic morphine (1), marketed by Merck in 1826,8 and the first semi-synthetic pure drug aspirin (2), based on a natural product salicin (3) isolated from Salix alba, was introduced by Bayer in 1899. This success subsequently led to the isolation of early drugs such as cocaine, codeine, digitoxin (4), quinine (5), and pilocarpine (6), of which some are still in use.7,8,86–88 NCH3

HO

H

COOH

CH2OH

O

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OH OH HO

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O Morphine (1)

OH

OAc Aspirin (2)

Salicin (3)

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O

H H H O

O

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O

O

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OH

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OH

O

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Digitoxin (4)

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N O O

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N Quinine (5)

Pilocarpine (6)

3. Natural Products: The Inherent Potentiality The most striking feature of natural products in connection to their longlasting importance in drug discovery is their structural diversity that is still largely untapped. Most natural products are not only sterically more complex than synthetic compounds, but differ also with regards to the statistical distribution of functionalities.89 They occupy a much larger volume of the chemical space and display a broader dispersion of structural and physicochemical properties than compounds issued from combinatorial synthesis.90 It needs to be mentioned that in spite of massive endeavors adopted in recent times for synthesizing complex structures following “diversity oriented synthesis” (DOS) strategy,91 about 40% of the chemical scaffolds found in natural products are still absent in today’s medicinal chemistry.92 The chemical diversity and unique biological

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activities of a wide variety of natural products have propelled many discoveries in chemical and biological sciences, and provided therapeutic agents to treat various diseases as well as offered leads for the development of valuable medicines. The history of pharmacognosy is, in part, defined by the ever expanding catalog of naturally occurring, biologically active compounds that have been discovered and characterized. It has been estimated that about 40% of medicines have their origin in these natural products.52,93 The chemical potential of plants is however, still largely unexplored. Chemical diversity has only been analyzed in about 5–15% of all land plants, and even here only the most abundant compounds have been well characterized. Hence, there remains an unprecedented possibility for the discovery of novel chemicals that may find diverse uses from pharmaceuticals through fine chemicals. Natural products, thus, continue to be a major source of biologically active compounds that may serve as commercially significant entities themselves or may provide lead structures for the development of modified derivatives possessing enhanced activity and/or reduced toxicity. Even though combinatorial synthesis is now producing molecules that are drug-like in terms of size and property, these molecules, in contrast to natural products, have not evolved to interact with biomolecules.94 Natural compounds such as brefeldin A, camptothecin, forskolin and immunophilins often interfere with protein–protein interaction sites.95 Analysis of the properties of synthetic and natural compounds compared to drugs revealed the distinctiveness of natural compounds, especially concerning the diversity of scaffolds and the large number of chiral centres. This may be one reason why ~50% of the drugs introduced to the market during the last 20 years are derived directly or indirectly from natural compounds.97 In chemical biology, natural products play an important role to elucidate complex cellular mechanisms, including signal transduction and cell cycle regulation, leading to the identification of important targets for therapeutic intervention.56,98 There has been an increasing demand for new natural products, or new natural product-like small molecules in the fields of genomic and proteomics for the rapid identification of large numbers of gene products for which the small molecule modulators will

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be of both biological and medicinal interest.99–103 Besides, the combination of cell biology and high throughput technology has led to the development of various cellular assays in which small molecule libraries can be used to identify and study previously known targets.104 The reason for the lack of lead compounds from synthetic libraries in some therapeutic areas such as anti-infectives, immunosuppression, oncology, and metabolic diseases may be due to the different chemical space occupied by natural products and synthetic compounds.89,90,92,105 This difference in chemical space makes natural products an attractive alternative to synthetic libraries, especially in therapeutic areas that have a dearth of lead compounds. Natural products have been used also as starting templates in the synthesis of combinatorial libraries.92,106–110 Natural product pharmacophores are well represented in lists of “privileged structures”, which make them ideal candidates for building blocks for biologically relevant chemical libraries.111,112 Natural products still constitute a prolific source of novel lead compounds or pharmacophores for medicinal chemistry, and hence, natural products should be incorporated into a well-balanced drug discovery program. Besides their potential as lead structures in drug discovery, natural products also provide attractive scaffolds for combinatorial synthesis and act as indispensable tools for the validation of new drug targets.113

4. Natural Products in Drug Discovery: Success, Constrains and New Approaches for Remedies 4.1. A Success Story Mother Nature still continues to be a resource of novel chemotypes and pharmacophores, and an impressive number of modern drugs have been isolated from natural sources, many based on their uses in traditional medicine systems.33–35,114 To a large extent, the use of natural products in drug design represents the natural evolution of this old tradition. It has been extensively documented that the traditional medicine systems of many cultures worldwide are based on plants,38,113,115–118 for example in countries like China33 and India35 where plants have formed the basis for traditional systems of medicines. According to Kim and Park,119 natural

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products have been regarded as important sources that could produce potential chemotherapeutic agents. A comprehensive review of the history of medicine may be consulted, in this regard, on the homepage of the National Library of Medicine (NLM), History of Medicine at www.nlm.nih.gov/hmd/hmd.html. Large numbers of promising lead molecules have come out of Ayurvedic experimental base including Rauwolfia alkaloids for hypertension, psoralens in vitiligo, guggulsterons as hypolipidemic agents, Mucuna pruriens for Parkinson’s disease, bacosides in mental retention, phyllanthus as antivirals, picrosides in hepatic protection, curcumines in inflammations, withanolides and many others steroidal lactones and glycosides as immunomodulators;24,120 plants have thus, always been a rich source of natural product leads — a few more examples are: morphine, cocaine, digitalis, quinine, tubocurarine, nicotine, muscarine, paclitaxel (Taxol™) and artemisinin. There are growing evidences where the old molecules are finding new applications through better understanding of traditional knowledge and clinical observations. For instance, the alkaloid, forskolin isolated by Hoechest and coleonol by Central Drug Research Institute (CDRI), Lucknow, India a few decades ago from Coleus forskohlii121 and phytochemicals from Stephania glabra, which were shelved for a considerable time are now being rediscovered as adenylate cyclase and nitric oxide activators, which may help in preventing conditions including obesity and atherosclerosis.122 Natural products also provide a vast pool of pancreatic lipase inhibitors as potential candidates, which can be developed into new drugs for the treatment of conditions like obesity.123 A large number of promising leads for the development of newer anti-inflammatory drugs are also available in medicinal plants.124 The blossoming of natural product discovery efforts occurred after the large scale production of penicillin during World War II, when the pharmaceutical companies that contributed to the war-time efforts to build stocks of penicillin refocused their programs on the search for new antibiotics from microorganisms.50 Mining of the bacterial genome and identification of crucial targets followed by study of new bacterial or fungal strains have resulted in the discovery of significant antibacterial agents such as cephalosporins, streptomycin, gentamicin, tetracycline, chloramphenicol,

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aminoglycosides, rifamycins and many others that spurred the industry to develop large research and development programs around natural product discovery, particularly microbial fermentation-based technologies.125,126 All of the major pharmaceutical companies had programs on natural product discovery, and these programs focused not only on anti-bacterial and anti-fungal targets, but also on targets other than infectious diseases. In the 1970s for example, the discovery of cholesterol biosynthesis-inhibiting drugs compactin127,128 and mevinolin (a fungal metabolite isolated from cultures of Aspergillus terreus)129,130 led to the development of the hugely successful statin therapeutics, which even today represent successes in both medical treatment and in pharmaceutical business fortunes.131–134 Since the past five decades, marine sources (viz. coral, sponges, fish and marine microorganisms) have attracted scientists from different disciplines leading to the discovery of several marine natural products with promising biological activities; a few of them include curacin A, eleutherobin, discodermolide, bryostatins, dolostatins, and cephalostatins.78,135 Venoms and toxins (peptides and non-peptides) found in snakes, spiders, scorpions, insects, and other microorganisms are also significant in drug discovery due to their specific interactions with macromolecular targets in the body, and have been proven crucial while studying receptors, ion channels, and enzymes. Toxins like α-bungarotoxin (from the venom of the elapid snake Taiwanese banded krait (Bungarus multicinctus)),136,137 tetrodotoxin (from puffer fish and many other widely varying animals including certain bacteria)138–143 and teprotide (from Brazilian viper)144 etc. are in clinical trials for drug development. Similarly, neurotoxins obtained from Clostridium botulinum (responsible for botulism, a serious food poisoning), were been found to be significant in preventing muscle spasm.145 The impact of natural products on drug discovery has, thus, been enormous; natural products originating from microorganism, plant and animal sources have been the single most productive source of leads for the development of drugs to treat human diseases9,48,52 More than 80% of drug substances involved in drug discovery programs in “olden times” (i.e. before the advent of high-throughput screening (HTS) and the post-genomic era) were reported to be natural products or inspired by natural product structures.87,113 It is arguably still true; comparisons of the information

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presented on sources of new drugs from 1981 to 200751,72 indicate that almost half of the drugs approved since 1994 are based on natural products. In the areas of cancer and infectious diseases, 60% and 75% of new drugs, respectively, originated from natural sources between 1981 and 2002.52 Between 2001 and 2005, 23 new drugs derived from natural products were introduced for the treatment of disorders such as bacterial and fungal infections, cancer, diabetes, dyslipidemia, atopic dermatitis, Alzheimer’s disease and genetic diseases such as tyrosinaemia and Gaucher disease; two drugs have been approved as immunosuppressive agents and one for pain management. Thirteen natural product-related drugs were approved from 2005 to 2007 and, as pointed out by Butler, five of these represented the first members of new classes of drugs:72 the peptides exenatide and ziconotide, and the small molecules ixabepilone, retapamulin and trabectedin.146 Of the 90 antibacterial drugs that became commercially available in the US or were approved worldwide from 1982 to 2002, ~79% can be traced to a natural product origin.52 According to a study by Grifo and his colleagues,147 84 of a representative 150 prescription drugs (prescribed mainly as anti-allergy/ pulmonary/respiratory agents, analgesics, cardiovascular drugs, and for infectious diseases) in the US were natural products and related drugs. Another study found that natural products or related substances accounted for 40%, 24%, and 26% of the top 35 worldwide ethical drug sales in 2000, 2001, and 2002 respectively.9 Of these natural product-based drugs, paclitaxel (ranked at 25 in 2000), a plant-derived anticancer drug, had sales of $1.6 billion in 2000.148,149 The sales of two categories of plant-derived cancer chemotherapeutic agents were responsible for approximately one third of the total anticancer drug sales worldwide, or just under $3 billion dollars in 2002; namely, the taxanes, paclitaxel and docetaxel, and the camptothecin derivatives, irinotecan and topotecan.148,149 In addition to this historical success in drug discovery, natural products are likely to continue to be sources of new commercially viable drug leads. Combined with pharmacological screening, the chemistry of natural products has always provided highly useful leads for drug discovery. The search for new biologically active compounds are most often based on hints from ethnobotany but there are still a large number of unstudied plants, mushrooms, marine organisms, insects, and microorganisms. There is a wealth of molecular diversity out there, waiting to be discovered and utilized.

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4.2. Lacunae/Constrains After very successful drug discovery and development programs based on natural products, the pharmaceutical industry, in particular the large pharmaceutical companies, de-emphasized natural product discovery research in the 1990s and early 2000s.27,60,146,150,151 This was caused by the advent of alternative drug discovery methods such as rational drug design involving automated high-throughput screening (HTS) technology in combination with combinatorial chemistry152–159 with the belief and hope that newly developed technologies would result in the development of drugs within a short and affordable time scale of the so-called “blitz” screen (start to finish in 3 months). Thus, the promise of a ready supply of large synthetic compound libraries led many companies to eliminate or considerably scale down their natural product operations.160–164 The major causative points that directed the downfall of natural products in the pharmaceutical industry in the 1990s include difficulties in access and supply, complexities of natural product chemistry, the inherent slowness of working with natural products, and concerns about intellectual property rights. Rediscovery of known compounds is a major problem when screening natural product libraries. This is caused by a lack of efficient dereplication methodologies for both natural product sourcing and compounds in the natural product libraries. The time-consuming processes of dereplication and purification are not compatible with the present regime of “blitz” screening campaigns in which assay support is only available for a limited duration (3 months). Besides, natural products are often structurally complex; modification of complex natural products using organic chemistry is frequently challenging. Medicinal and combinatorial chemists prefer not to work with natural products because of the large size and complexity of the compounds, which have too many functional groups to protect. It is difficult to prepare as many natural product analogs as synthetic chemicals in the same amount of time.47 However, despite the promise of these alternative drug discovery methods, there is still a shortage of lead compounds progressing into clinical trials. This is especially the case in therapeutic areas such as oncology, immunosuppression and metabolic diseases where natural products have played a central role in lead discovery. Marketed drugs derived from natural products still account for significant revenues in many of the major pharmaceutical companies.165 Lipitor, zocor and pravachol, the cholesterol-regulating

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therapeutic agents derived from the natural product statin class of compounds, continue to generate multi-billion dollar revenues. Antibiotics, like zithromax and the generic penicillins, continue to be essential in medical care, however they contribute less to pharmaceutical revenues than nonantibiotics due to their relatively limited dosing intervals.

4.3. New Approaches for Possible Remedies Recent technological advances and the development of new methods have revolutionized the screening of natural products and offer a unique opportunity to re-establish natural products as major source of drug leads. The new methods and technologies can address the aforementioned limitations of the screening of natural products. Examples of recent advances in the application of these technologies that have immediate impact on the discovery of novel drugs are: (i) development of a streamlined screening process for natural products, (ii) improved natural product sourcing, (iii) advances in organic synthetic methodologies, (iv) combinatorial biosynthesis, and (v) microbial genomics. Each of these technologies was discussed in details by Kin S. Lam in his article “New aspects of natural products in drug discovery”.47 Approaches based on reverse pharmacology may also offer efficient platforms for herbal formulations; the impact of such approaches has recently been elaborately reviewed by Patwardhan and Vaidya.24 All these technologies at large have already shown an impact on the development of natural product leads arising out of varying natural sources inducing microbial and marine environments. The biosynthesis of natural products themselves can also be manipulated with the understanding of the genetics and biosynthesis pathways to yield new derivatives with possibly superior qualities and quantities.166,167 In addition to identifying new natural products, genome mining would certainly have an impact on the understanding and manipulation of the production of natural products. Natural product compounds not only serve as drugs or templates for drugs, but in many instances lead to the discovery and better understanding of targets and pathways involved in the disease process. Elucidation of the anti-inflammatory mechanism of aspirin action led to the discovery of the cyclooxygenase isozymes COX-1 and -2, which are being used in the development of novel anti-inflammatory drugs.168 Again natural products

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that interact with some other novel targets, such as the protein–protein complexes B-catenin in the WNT pathway and HIF-1/p300,169 have validated these anticancer targets and pathways. Natural products also create opportunities for additional drug targets to be identified and exploited in these pathways. Whereas synthetic drugs are typically the result of numerous structural modifications over the course of an extensive drug discovery program, a natural product can go straight from “hit” to drug in many situations. Microbial natural products are notable not only for their potential therapeutic activities, but also for the fact that they frequently have the desirable pharmacokinetic properties required for clinical development. Antibacterial agents erythromycin A, vancomycin, penicillin G, streptomycin and tetracycline, antifungal agents amphotericin B and griseofulvin, the cholesterol-lowering agent lovastatin, anticancer agents daunorubicin, mitomycin C and bleomycin, and immunosuppressants rapamycin, mycophenolic acid and cyclosporine A are just a few of the many microbial natural products that reached the market without requiring any chemical modifications. These examples clearly demonstrate the remarkable ability of microorganisms to produce drug-like small molecules.47

5. Drug Discovery, Development and Approval Processes The final launching of a natural product (NP)-based drug in the market is a multi-step phenomena starting from its discovery stage.170 Bioactivityguided screening followed by isolation and characterization of a NP-lead molecule is the first step; after that the NP-lead enters into the drug discovery stage involving target identification and lead optimization. Lead optimization is an outcome of various steps including analysis (also involves QSAR and molecular modeling), design, synthesis and screening. In the drug discovery and development stages, the pharmacokinetics and pharmacodynamics including absorption, distribution, metabolism, excretion, and toxicity (ADMET) for the test drug molecule are thoroughly investigated. After analyzing all these data, the drug molecule may enter into the final development stage for drug delivery that involves proper production formulation, which is eventually considered for clinical trials. The whole process may be summarized in the flowchart (Fig. 1).170 Lead identification and optimization (involving medicinal and combinatorial chemistry), lead

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Clinical Trial Stage

Approval Processes

Launching of the drug on the market, after successful clinical trials followed by proper approvals

Lead Optimization

Rational Drug DesignBased Analog Synthesis

Discovery of NP-Lead

Bioactivity-Guided Screening, Isolation and Characterization of Natural Products (NPs)

Fig. 1. Flowchart for drug discovery, development and approval of a natural productbased drug.

development (including pharmacology, toxicology, pharmacokinetics, absorption, distribution, metabolism, and excretion (ADME) and drug delivery), and clinical trials all take considerable time. It has been estimated that the process of drug discovery usually takes an average period of 10 years and costs more than $800 million.151 Much of this time and money is spent on the numerous leads that are discarded during the drug discovery process. It is also estimated that only 1 in 5000 lead compounds will successfully advance through clinical trials and be approved for use. For approval and marketing of a new drug, certain processes are to be followed: first, the Investigational New Drug (IND) application is submitted to the US Food and Drug Administration (FDA) or European Medicines Agency (EMEA) before commencement of clinical trials. Once clinical trials are successfully completed, the applicant files for a New Drug Application (NDA) in the US or Marketing Authorization Application (MAA) in Europe seeking the drug’s approval for marketing, to which the agency replies in the form of an “approval letter”, “non-approval letter” or “approvable letter”. An “approval letter” allows the applicant to begin marketing of product, while a “non-approval letter” rejects the application. An “approvable letter” informs the applicants that the agency have completed their scientific review and determined that the application can be approved pending resolution of minor deficiencies identified in the letter or during an inspection of the manufacturing facilities.

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6. Natural Product-Based Drugs Approved During 2000–2010 A total of about 38 natural product-based drugs were approved and launched in the market during the period 2000 to 2010. This section deals with these approved drugs as per categorized diseases areas such as infectious disease area (15 drugs), oncology (7 drugs), neurological disease area (7 drugs), cardiovascular and metabolic disease area (4 drugs), diabetes (1 drug), and some other diseases areas (4 drugs). In addition, all these approved drugs are summarized in Table 1.

6.1. Infectious Disease Area 6.1.1. Arteether Arteether (7; Artemotil®, Artecef ®), the semi-synthetic derivative of artemisinin (8), is a potent antimalarial drug. Artemisinin, a natural endoperoxide sesquiterpene lactone, is the active chemical constituent of Artemisia annua L. (Asteraceae), a plant used in traditional Chinese medicine.171–176 Arteether belongs to the first-generation of artemisinin analogs obtained by derivatization at C-10, and such semi-synthetic derivatives were proved to be extremely active and more potent than the parent compound, acting rapidly as blood schizontocidal agent against the parasite’s (Plasmodium falciparum) asexual erythrocytic (red blood cell) stage as well as against the parasite blood-stage gametocytes (sexual stage), which can potentially help to reduce the rate of malaria transmission.177,178 Other derivatives of artemisinin are in various stages of clinical development as antimalarial drugs in Europe.54,172 H

H

O

O

O

O

O

O H O

H O

O Arteether (7)

O Artemisinin (8)

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Table 1. Natural product (NP)-derived drugs launched since 2000 by year with reference to their lead compound, classification, therapeutic area and mechanism of action. Lead compound (Str. No.)

Compound class

Classification

Producing organism/ Origin

Disease area/ Indication

Mechanism of action

Reference

Endoperoxide sesquiterpene lactone

Semi-synthetic NP

Plant

Antimalarial

Acts as blood schizontocidal agent against the parasite’s asexual erythrocytic (red blood cell) stage and also against the parasite blood-stage gametocytes (sexual stage)

54, 171–179

2000

Gemtuzumab ozogamicin (30; Mylotarg®)

Calicheamicin (31)

Enediyne-type antibiotic

NP-derived

Microbial

Anticancer

DNA-cleaving

319–331

2000

Bivalirudin (55; Angiomax®)

Hirudin

Peptide

Synthetic congener

Animal

Antithrombotic

Specific and reversible direct thrombin inhibitor (DTI)

479–491

2001

Caspofungin acetate (9; Cancidas®)

Pneumocandin B0

Lipopeptide

Semi-synthetic NP

Microbial

Antifungal

Inhibits fungal cell wall synthesis

180–186

2001

Ertapenem (10; Invanz®)

Thienamycin (11)

Carbapenem antibiotic

NP-derived

Microbial

Antibacterial

Inhibits bacterial cell wall synthesis

187–197

2001

Cefditoren pivoxil Cephalosporin (12, Spectracef ®)

β-Lactum antibiotic

NP-derived

Microbial

Antibacterial

Inhibits bacterial cell wall synthesis

198–200

Bioactive Natural Products

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(Continued )

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Arteether (7; Artemotil®, Artecef®, E-Mal®)

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Year

Generic name (Str. No.; trade name)

Lead compound (Str. No.)

Compound class

Classification

Producing organism/ Origin

Disease area/ Indication

Mechanism of action

Reference

Microbial

Inflammatory skin diseases and atopic dermatitis

Blocks T-cell activation

505–517

2002

Biapenem (14; Omegacin®)

Thienamycin (11)

Carbapenemtype β-lactum

NP-derived

Microbial

Antibacterial

Inhibits bacterial cell wall synthesis

201–210

2002

Amrubicin hydrochloride (32; Calsed®)

Doxorubicin (33)

Anthraquinone

NP-derived

Microbial

Anticancer

Inhibits topoisomerase II

208–210, 332–336

2002

Nitisinone (59; Orfadin®)

Leptospermone

2-[2-Nitro-4(trifluoromethyl) benzoyl] cyclohexane1,3-dione

NP-derived

Plant

Antityrosinaemia

Inhibits p-hydroxyphenylpyruvate dioxygenase (HPPD) activity

208–210, 518–524

2002

Galantamine hydrobromide (43; Reminyl®)

Galantamine (42)

Alkaloid

NP

Plant

Alzheimer’s disease

Inhibits the activity of acetylcholinesterase (AChE)

393–402

2003

Daptomycin (15; CubicinTM)

Daptomycin (15)

Lipopeptide

NP

Microbial

Antibacterial

Disrupts multiple aspects of bacterial cell membrane function

211–225

(Continued )

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Semi-synthetic NP

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Macrolactum antibiotic

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Ascomycin

Bioactive Natural Products

Pimecrolimus (58; Elidel®)

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Year

Generic name (Str. No.; trade name)

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Table 1. (Continued )

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Table 1. (Continued )

Year

Generic name (Str. No.; trade name)

Lead compound (Str. No.)

Compound class

Classification

Producing organism/ Origin

Disease area/ Indication

Mechanism of action

Reference

Type 1 Gaucher disease (GD1)

Inhibits glucosylceramide synthase activity

215–217, 525–531

2003

Mycophenolate sodium (62; Myfortic®)

Mycophenolic acid (61)

Fatty acid antibiotic

NP

Microbial

Immunosuppression

Inhibits inosine monophosphate dehydrogenase (IMPDH) activity

215–217, 532–560

2003

Rosuvastatin calcium (56; Crestor®)

Mevastatin

Statin

NP-derived

Microbial

Dyslipidemia

Inhibits the rate-limiting step in the formation of endogenous cholesterol by HMGCoA reductase

215–217, 492–495

2004

Telithromycin (16; Ketek®)

Erythromycin A

14-Membered macrolide

Semi-synthetic NP

Microbial

Antibacterial

Blocks bacterial polypeptide chain growth

181, 182, 183, 226–230

2004

Apomorphine hydrochloride (44; Apokyn®)

Morphine (43)

Alkaloid

Semi-synthetic NP

Plant

Parkinson’s disease

Potent dopamine receptor agonist

403–416

2004

Ziconotide (45; PrialtTM)

Ziconotide (45)

Peptide

NP

Animal

Pain

Acts as a selective N-type voltage-gated calcium channel blocker

417–428

(Continued )

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Microbial

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Iminosugar

Bioactive Natural Products

1-Deoxynojirimycin (DNJ)

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Miglustat (60; Zavesca®)

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21

Compound class

Classification

Producing organism/ Origin

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Lead compound (Str. No.)

Disease area/ Indication

Mechanism of action

Reference

Tiotropium bromide (54; Spiriva®)

Atropine

Alkaloid

Semi-synthetic NP

Plant

Chronic obstructive pulmonary disease (COPD)

Inhibits M3 muscarinic receptors

475–478

2005

Tigecycline (19, Tygacil®)

Tetracycline (17)

Tetracyclines

Semi-synthetic NP

Microbial

Antibacterial

Inhibits bacterial protein translation

231–238

2005

Doripenem(20; Finibax®/ DoribaxTM)

Thienamycin (11)

Carbapenem-type β-lactum

NP-derived

Microbial

Antibacterial

Inhibits bacterial cell wall growth

239–247

2005

Micafungin (21; Mycamine®/ Funguard®)

FR901379

Macrocyclic lipopeptidolactone

Semi-synthetic NP

Microbial

Antifungal

Inhibits fungal cell wall synthesis

186, 208–210, 248–260

2005

Fumagillin (22; Flisint®)

Fumagillin (22)

Antibiotic

NP

Microbial

Antiparasitic

Inhibits intestinal microsporidiosis

261–278

2005

Dronabinol (46)/ Cannabidol (47) (Sativex®)

Dronabinol (46)/ Cannabidol (47)

Cannabinoids

NPs

Plant

Pain

Suppresses neurotransmitter release

429–438

Bioactive Natural Products

2005

Zotarolimus (53; EndeavorTM stent)

Sirolimus (33)

Macrolide antibiotic

Semi-synthetic NP

Microbial

Cardiovascular surgery

Inhibits cell 467–474 proliferation, preventing scar tissue formation and minimizes restenosis in angioplasty patients

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Year

Generic name (Str. No.; trade name)

22

Table 1. (Continued )

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Table 1. (Continued ) Lead compound (Str. No.)

Compound class

Classification

Producing organism/ Origin

Disease area/ Indication

Mechanism of action

Reference

Inhibits fungal cell wall synthesis

279–293

2006

Exenatide (57; ByettaTM)

Exenatide-4 (57)

A 39-amino-acid peptide

NP

Animal

Diabetes

Enhances glucosedependent insulin secretion by the pancreatic β-cells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying

496–504

2007

Retapamulin (26; AltabaxTM/ AltargoTM)

Pleuromutilin (25)

Antibiotic

Semi-synthetic NP

Microbial

Antibacterial (topical)

Inhibits bacterial protein synthesis

294–303

2007

Temsirolimus (35; ToriselTM)

Sirolimus (34)

Macrolide antibiotic

Semi-synthetic NP

Microbial

Anticancer

Leads to cell cycle 337–350 arrest in the G1 phase, and inhibits tumor angiogenesis by reducing synthesis of vascular endothelial growth factor (VEGF) (Continued )

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Semi-synthetic NP

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Generic name (Str. No.; trade name)

23

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Lead compound (Str. No.)

Compound class

Classification

Producing organism/ Origin

Disease area/ Indication

Mechanism of action

Reference

Tetrahydroisoquinoline alkaloid

NP

Ascidian (marine animal)

Anticancer

Inhibits cell proliferation by disrupting the cell cycle

351–362

2007

Ixabepilone (40; IxempraTM)

Epothilone B (38)

Macrolide antibiotic

NP-derived

Microbial

Anticancer

Binds directly to βtubulin subunits on microtubules, ultimately leading to cell death

363–374

2007

Lisdexamfetamine (48; Vyvanse®)

Amphetamine (49)

Amine

NP-derived

Plant

Attention deficit hyperactivity disorder (ADHD)

Increases the release of 439–448 amphetamine-type monoamines into the extraneuronal space, thereby improving the effect of ADHD

2008

Methylnaltrexone (50; Relistor®)

Naltrexone (51)

Alkaloid

NP-derived

Plant

Opioid-induced constipation and pain

Blocks peripheral opioid receptors, and acts as an antagonist

(Continued )

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Trabectedin (36)

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Trabectedin (36; YondelisTM)

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Generic name (Str. No.; trade name)

Brahmachari

Table 1. (Continued )

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Table 1. (Continued ) Compound class

Classification

Producing organism/ Origin

Disease area/ Indication

Mechanism of action

Reference

Vanilloid

NP

Plant

Pain

Binds to the ion channel receptor vanilloid receptor subtype 1 (VR 1)

460–466

2009

Telavancin (28; VibativTM)

Vancomycin (27)

Antibiotic

Semi-synthetic NP

Microbial

Antibacterial

Inhibits bacterial cell wall synthesis

304–311

2009

Everolimus (40; Afinitor®)

Sirolimus (34)

Macrolide antibiotic

Semi-synthetic NP

Microbial

Anticancer

Inhibits mTOR kinase activity

375–382

2009

Romidepsin (41; Istodax®)

Romidepsin (41)

Depsipeptide

NP

Microbial

Anticancer

Inhibits histone deacetylase (HDAC)

383–392

2010

Aztreonam lysine (29; CaystonTM)

Aztreonam (29)

Monobactam antibiotic

NP-derived

Microbial

Antibacterial

Inhibits bacterial cell wall synthesis

312–318

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Capsaicin (52)

Bioactive Natural Products

Capsaicin (52; Qutenza®)

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The central Drug Research Institute (CDRI) in collaboration with CIMAP (Central Institute of Medicinal and Aromatic Plants), Lucknow, India have also conducted extensive clinical trials with arteether that was found not only to be very safe but also proved to be a fast-acting blood schizontocidal agent. CDRI has licensed the drug to Themis Chemicals Ltd., Mumbai which is marketing it under the trade name “E-Mal®” as an injectable formulation. The Drugs Controller General (India) has allowed the use of the drug exclusively in hospitals and nursing homes. The drug is indicated for use only in severe P. falciparum-induced-malaria including cerebral malaria as a secondline treatment for chloroquine-resistant cases. It is not recommended to be used as a first-line treatment against malaria to avoid against overuse, which may lead to the emergence of resistance against this drug once again.179 6.1.2. Caspofungin acetate Caspofungin acetate (9; Cancidas®, Merck, 2001) is a semi-synthetic antifungal lipopeptide compound derived from pneumocandin B0, a fermentation product of Glarea lozoyensis. The drug inhibits the synthesis of the glucose homopolymer β-(1,3)-D-glucan, an essential component H2N

H N

OH O

O HO

N H

NH O

H2N

N

HN

O

Me

O

NH

HO

OH 2CH3COOH

N H N

O HO

OH OH

O

HO Caspofungin (9)

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of the cell wall of many fungi but absent in mammals. The noncompetitive inhibition of β-(1,3)-D-glucan synthase by caspofungin interferes with fungal cell wall synthesis, leading to osmotic instability and death of the fungal cell.180–184 6.1.3. Ertapenem Ertapenem (10; Invanz™, Merck, 2001) is a new 1β-methylcarbapenem antibiotic derived from thienamycin (11), isolated from Streptomyces cattleya.181,187–191 The drug shows promising broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria, such as clinically relevant Enterobacteriaceae including Escherichia coli, Klebsiella species, Citrobacter species, Enterobacter species, Morganella morganii, Proteus species, and Serratia marcescens.190,192–195 Ertapenam is licensed for use in adults and has been marketed by Merck as “Invanz™” since 2001; later in 2005, it was licensed for use in children of more than 3 months of age. The antibiotic inhibits bacterial cell wall synthesis by binding to specific penicillin-binding proteins (PBPs). It is highly stable against most β-lactamases including AmpC β-lactamases and extended-spectrum β-lactamases with the exception of metallo-β-lactamases.190,195–197 OH

O

OH

H H

+− Na O

H

NH2 H N

S N H O

O HO

S

O

O

NH N H

HO O

Thienamycin (11)

Ertapenem (10)

6.1.4. Cefditoren pivoxil Cefditoren pivoxil (12; Spectracef ®; TAP Pharmaceuticals, 2001) is an oral prodrug of cefditoren (13), a derivative of cephalosporin isolated from Cephalosporium species. The prodrug is readily hydrolyzed by intestinal esterases to the microbiologically active cephalosporin cefditoren (13)

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O

O

O

O O N O

3

H

S N H

H2N

H

S

S

N

N N

OMe

Cefditoren pivoxil (SpectracefTM) (12)

Esterase (hydrolysis) O

O

OH

O N O

3

H

S N H

H2N

H

S

S

N

N N

OMe

−HCHO

OH

O O N O

3

H

S H 2N

N H

H

N

S

S N

N

OMe Cefditoren (13)

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exhibiting a broad spectrum of activity against both Gram-positive and Gram-negative bacteria, and is stable to hydrolysis in the presence of a variety of β-lactamases. Cefditoren pivoxil is approved for use in the treatment of acute exacerbations of chronic bronchitis (AECB), mild-tomoderate community-acquired pneumonia (CAP), acute maxillary sinusitis, acute pharyngitis/tonsillitis, and uncomplicated skin and skin structure infections in adult and adolescent patients. Thus, cefditoren pivoxil is a good option for the treatment of adult and adolescent patients with specific respiratory tract or skin infections, particularly if there is concern about Streptococcus pneumoniae with decreased susceptibility to penicillin, or β-lactamase-mediated resistance among the common community-acquired pathogens.198–200 Cefditoren bears a 2-aminothiazole methoxime ring that has been found to be responsible for its Gram-negative activity, while the methylthiazolesubstituted vinyl group at C-3 offers antibacterial activity against Gram-positive bacteria. It has been observed that the hydrophilic carboxyl group of the parent drug makes cefditoren orally inactive due to poor permeation across the intestinal mucosa; hence, esterification of the polar carboxyl group increases lipophilicity and allows intestinal absorption to occur. That is, cefditoren pivaloyl methyl ester (12) is not biologically active, but after absorption, esterases readily hydrolyze the prodrug to the biologically active cefditoren (13).200 6.1.5. Biapenem Biapenem (14; Omegacin®; Wyeth Lederle Japan, 2002) is a new analog of carbapenem based on thienamycin, isolated from Streptomyces cattleya; the antibacterial drug is found to be effective against both Gram-negative and Gram-positive bacteria including the species that produce β-lactamases. The early carbapenems (e.g. imipenem) are unstable to hydrolysis by human renal dihydropeptidase (DHP)-I and require co-administration with a DHP-I inhibitor (e.g. cilastatin). On the contrary, biapenem (14) is found to be more stable to hydrolysis by human renal DHP-I than imipenem, meropenem, and panipenem, and can thus be administered as a single agent without a DHP-I inhibitor.201–210

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+ N

OH H

N

H

S N

O

COO− Biapenem (14)

6.1.6. Daptomycin Daptomycin (15; Cubicin™; Cubist Pharmaceuticals, 2003), a cyclic lipopeptide antibacterial agent derived from Streptomyces roseosporus, was approved for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus and right-sided S. aureus endocarditis. Daptomycin has a unique mechanism of action that results in the disruption of multiple aspects of bacterial cell membrane function. It appears to bind to the membrane and cause rapid depolarization, resulting in a loss of membrane potential, leading COOH O H N

O

H N

N H O

H2N

COOH

O

NH

NH

O HN

HOOC O H N

HN H N

O

O

CONH2

N H

NH2 Daptomycin (15)

O

OH

O

O

O

O O

HN

H

N H

HN

O

O

NH H COOH

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to the inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death. The rapid bactericidal activity of daptomycin makes it an attractive antibiotic for serious Gram-positive infections.211–225 6.1.7. Telithromycin Telithromycin (16; Ketek®; Aventis, 2004) is a semi-synthetic derivative of the 14-membered macrolide, erythromycin A, isolated from Saccharopolyspora erythraea, and retains the macrolactone ring as well as a D-desosamine sugar moiety. It is the first approved ketolide, developed by Sanofi-Aventis in Phases II/III trials in 1998, that received approval from the FDA in April 2004 against respiratory infections. The drug exhibits an antibacterial effect on respiratory tract pathogens resistant to other macrolides. Telithromycin (16) displays bactericidal activity by blocking the progression of the growing polypeptide chain by binding with the peptidyltransferase site of the bacterial 50S ribosomal subunit.180,181,183,226–230 O O N N

N O

O

O

O N MeO O O OH Me2N Telithromycin (16)

6.1.8. Tigecycline Tigecycline (19, Tygacil®; Wyeth, 2005) is the 9-tert-butyl-glycylamido derivative of minocycline (18), which is in turn semi-synthetically derived

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N

N

HO H

N

H

H

H

OH

OH NH2

NH2

R

OH OH

O

OH

OH O

Tetracycline (17)

O

OH

O

OH

O

O

Minocycline (18): R = H O

Tigecycline (19): R =

H N N H

from the natural product tetracycline (17) isolated from Streptomyces aureofaciens. It is among one of the new generation antibiotics known as glycylcyclines; it contains a centralized four-ring carbocyclic skeleton substituted at the D-9 position, thus conferring broad spectrum activity. Tigecycline exhibited antibacterial activity typical of other tetracyclines, but with more potent activity against tetracycline-resistant organisms. Tigecycline is only utilized in an injectable formulation for clinical use, unlike currently marketed tetracyclines that are available in oral dosage forms. The drug (19) connects with 30S ribosome and hinders amino-acyl tRNA molecules moving to the A site of the ribosome, thus inhibiting protein translation. Tigecycline (19) was developed by Wyeth and was approved in June 2005 by the FDA for use against intra-abdominal and complicated skin and skin structure infections (cSSSIs).231–238 Since May 2006, tigecycline (19) has been approved in Europe and later in October 2007, a supplemental NDA for community-acquired pneumonia (CAP) to the FDA was submitted.72 6.1.9. Doripenem Doripenem (20; Finibax®/Doribax™; Shionogi Co. Ltd., 2005; Johnson & Johnson, 2007), a synthetic carbapenem-type β-lactam, has appeared to be an ultra-broad spectrum injectable antibiotic. It was launched in Japan by Shionogi Co. Ltd. in the year 2005 as a broad antibacterial spectrum.239–243 In October 2007, Johnson & Johnson (J&J) (formerly Peninsula Pharmaceuticals) obtained formal FDA approval for the use of doripenem

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OH H

H

S N H

O

O HO

H N N H

H

NH2 S O

O

Doripenem (20)

(20) in intra-abdominal and urinary tract infections, including pyelonephritis.244,245 When doripenem is absorbed into the body, the drug takes effect by eliminating the initial bacteria causing the infection. Primarily, doripenem decreases the process of cell wall growth, which eventually leads to elimination of the infectious cell bacteria altogether. The use of doripenem (20) for treatment of hospital-acquired (nosocomial) pneumonia (HAP) is under FDA review, while in Europe, treatment of HAP and complicated urinary tract infections are under review.72,246,247 6.1.10. Micafungin Micafungin (21; Mycamine®/Funguard®; Astellas Pharma/Fujisawa, Japan, 2002, 2005), is a semi-synthetic derivative of FR901379 that was first launched by Fujisawa in Japan in 2002 as a potent antifungal agent.208–210 This echinocandin-type compound exhibited good antifungal activity against a broad range of Candida species, including azole-resistant strains, and Aspergillus species, during in vitro and animal studies.186 Micafungin is indicated for the treatment of candidemia, acute disseminated candidiasis, candida peritonitis, abscesses and esophageal candidiasis.248–251 It received final approval from the US Food and Drug Administration on March 2005 and gained approval in the European Union on April 25, 2008. The drug (21) inhibits the production of 1,3-β-D-glucan, an essential polysaccharide component of fungal cell wall; this decreased glucan production leads to osmotic instability and thus cellular lysis;248–260 since January 2008, micafungin has been approved for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation.

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Brahmachari OH HO O

O

OH

SO3Na H N

H2N

NH

OH H

O N

O

O

O

O

H

HO

OH N H

NH

HO

HN OH O

HO NH O O

N

O

Micafungin sodium (21; Mycamine®)

6.1.11. Fumagillin Fumagillin (22; Flisint®; Sanofi-Aventis, 2005) was first isolated in 1949 from Aspergillus fumigatus261 and used shortly thereafter to treat intestinal amoebiasis;262–264 this antimicrobial agent is capable of inhibiting the proliferation of endothelial cells. In September 2005, France approved the use of fumagillin (22) as a potent antibiotic against intestinal microsporidiosis; this is a disease caused by the spore-forming unicellular parasite Enterocytozoon bieneusi, which is of major concern to immunocompromised patients as it can cause chronic diarrhea.265–273 In addition, semi-synthetic derivatives of fumagillin (22) with anti-angiogenic activity have undergone clinical evaluation for the treatment of cancer.72 Fumagillin can block blood vessel formation by binding to an enzyme called methionine aminopeptidase-2 (MetAP-2), and for this reason, the compound, together with semi-synthetic derivatives, are investigated as

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H O OMe O

O

COOH Fumagillin (22)

an angiogenesis inhibitor in the treatment of cancer and related disease areas.274–278 6.1.12. Anidulafungin Anidulafungin (23; Eraxis™ in US/Ecalta™ in Europe, Pfizer, 2006), finds use against invasive and esophageal candidiasis and candidemia;279–281 the drug is a semi-synthetic derivative of the fungal metabolite echinocandin B (24).282 The drug was originally developed by Eli Lilly and licensed to Vicuron Pharmaceuticals, which was further purchased by

HO

OH

O

O

HO

R

N H

N H

N

(23) R = O

O HN

OH

NH

HO

O

O

O N

H N

HO

OH

O O

OH

(24) R =

HO

Anidulafungin (23); Echinocandin (24)

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Pfizer in June 2005; Pfizer gained FDA approval in February 21, 2006 (Eraxis™ in the US) and EMEA approval (Ecalta™ in Europe) in July 2007.283–291 Anidulafungin inhibits enzyme complex 1,3-β-D-glucan synthase, thereby inhibiting fungal 1,3-β-D-glucan synthesis; this leads to the lysis of the fungal cell wall, and cell death.292,293 Glucan synthase is not present in mammalian cell walls and therefore is an attractive target for antifungal activity. 6.1.13. Retapamulin Retapamulin (26; Altabax™ in the US and Altargo™ in Europe; GlaxoSmithKline, 2007) received FDA approval in April 2007 and the European Medicines Agency (EMEA) approval in June 2007 for its topical use as 1% retapamulin ointment against bacterial infections.294–297 The drug is a semi-synthetic derivative of the fungal metabolite pleuromutilin (25), the first among pleuromutilin antibiotics developed by GlaxoSmithKline for topical treatment of impetigo caused by Gram-positive Staphylococcus aureus or Streptococcus pyogenes.294–301 Pleuromutilin (25) was found to bind to peptidyl transferase and exhibits antibacterial activity by inhibiting protein synthesis in bacteria.302,303 Retapamulin (26) also exerts its antibacterial potential specifically as a protein synthesis inhibitor. The medication selectively inhibits bacterial protein synthesis by interacting at

OH O R

H O

O Pleuromutilin (25): R = OH Retapamulin (26): R =

S

NCH3

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a site on the 50S subunit of the bacterial ribosome through an interaction that differs from other antibiotics.296,297,301 6.1.14. Telavancin Telavancin (28; Vibativ™; Theravance/Astellas Pharmaceuticals, 2009), was discovered by Theravance as an antibacterial agent, and was developed in partnership with Astellas.304–307 Telavancin (28), a semi-synthetic derivative of vancomycin (27), inhibits bacterial growth by binding to R1

OH HN O

OH OH

O

O

Cl

OH

O

O Cl

OH O

H N

H N

HO

N H

N H

N H O

O

O

O

NH

O O

HO

NH2 OH O

OH

HO

R2

Vancomycin (27) R1 = R2 = H R1

H N

=

Telavancin (28): R2 =

N H

PO(OH)2

H N

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bacterial peptidoglycan precursors termini, D-Ala-D-Ala; it shows dual mode of action though disruption of plasma barrier membrane functions by depolarization in addition to inhibition of cell wall synthesis.308 Theravance submitted an NDA in December 2006 and an MAA in May 2007 for the use of telavancin (28) against Gram-positive complicated skin and skin structure infections (cSSSIs) and methicillin-resistant Staphylococcus aureus (MRSA) that was approved in September 2009 by the FDA.309–311 Theravance also submitted telavancin (28) to the FDA in a second indication against nosocomial pneumonia or hospital-acquired pneumonia (HAP). In November 2009, the FDA released a complete response letter to Theravance for telavancin (28) NDA against nosocomial pneumonia.311 6.1.15. Aztreonam lysine Aztreonam lysine (29; Cayston™; Gilead Sciences, 2010), an inhaled lysine salt formulation of monobactam aztreonam, has been evaluated by Gilead in various Phase III trials against cystic fibrosis (CF) patients having a pulmonary infection of the Gram-negative bacteria Pseudomonas aeruginosa.312–317 In February 2010, the FDA approved the use of Temsirolimus (35) in CF patients, however its safety and efficacy is yet to be established in pediatric patients or Burkholderia cepacia colonized

COOH

O N H N

N H2N

O

N

S O

S O

Aztreonam (29)

O OH

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patients.318 Aztreonam binds to penicillin-binding proteins of susceptible bacteria, leading to the inhibition of bacterial cell wall synthesis and cell death.

6.2. Oncology 6.2.1. Gemtuzumab ozogamicin Gemtuzumab ozogamicin (30; Mylotarg®; Wyeth, 2000), the first and approved antibody–anticancer conjugate, was co-developed by Wyeth and UCB Pharma and launched in 2000 for the treatment of refractory acute myeloid leukaemia.319–326 Gemtuzumab ozogamicin (30) consists of N-acetyl-calicheamicin dimethyl hydrazide (CalichDMH), a derivative of the enediyne natural product calicheamicin (31), linked through a pH-labile hydrazone moiety to a recombinant humanized IgG4 k antibody. Mylotarg®, a prodrug of calicheamicin bound to the anti-CD33 monoclonal antibody, is cleaved by lysosomes in the cells to release calicheamicin. Calicheamicin is a hydrophobic member of the enediyne family of DNA-cleaving antibiotics and is effective in the treatment of

O humanized IgG4 anti-CD33

N H O

O Me

Me O

HO N

N H

S

S

H N

Me

O H Me

O

O

OMe

OH

O

O Me

O

HO O

OMe Me

O

O N H

S O

N MeO

HO MeO

MeO

Me

Me

I

OH

Gemtuzumab ozogamicin (30)

O

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HO S

MeS

H N

S

O H

Me

O

O

I

OMe

O

O

HO O

OH

OMe Me

O N H

S O

MeO

Me

Me

Me

O

O

H N MeO

HO MeO

OH

Calicheamicin (31)

patients with acute myeloid lymphoma.327–331 The calicheamicins (also known as the LL-E3328 antibiotics) were discovered from fermentation products produced by Micromonospora echinospora ssp. calichensis;331 calicheamicin (32) is an extremely potent cytotoxin that binds in the minor groove of DNA causing double strand DNA breakage.330,331 In the US, the drug was approved by the FDA in 2001 for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML), or those who are not considered candidates for standard chemotherapy.320 6.2.2. Amrubicin hydrochloride Amrubicin hydrochloride (33; Calsed®, Sumitomo Pharmaceuticals Co, 2002, Japan), a derivative of doxorubicin (34), isolated from Streptomyces peucetius var caesius, showed activity comparable to that of doxorubicin on transplantable animal tumors, including P388 leukemia, sarcoma 180, and Lewis lung carcinoma, and exhibited more potent antitumor activity against human tumor xenografts of breast, lung, and gastric cancer.208–210,332 The drug converts to its active form in the body and acts as an inhibitor of topoisomerase II, thereby finding an application in the treatment of lung cancer.332–336 It has been marketed in Japan since 2002 by Sumitomo Pharmaceuticals under the brand name Calsed®.

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O

OH

O

OH

OH

O OH

NH2

O

OH

OMe

O

41

O

OH

O O

O Me OH

OH

OH

NH

Doxorubicin (33)

Amrubicin (32)

6.2.3. Temsirolimus Temsirolimus (35; Torisel™, CCI-779; Wyeth, 2007), a semi-synthetic derivative of sirolimus (34), is an intravenous drug for the treatment of renal cell carcinoma (RCC)337–340 developed by Wyeth Pharmaceuticals OR O N

OMe

O

O

O

O HO O OH O O MeO

MeO

O Sirolimus (34): R = H OH

Temsirolimus (35): R = OH

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and approved by the US Food and Drug Administration (FDA) in May 2007, and was also approved by the European Medicines Agency (EMEA) in November 2007. Sirolimus (34), a macrolide antibiotic, was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island.341 Temsirolimus (35) has been found to be a specific inhibitor of mTOR (mammalian target of rapamycin) and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells.342–345 Treatment with temsirolimus leads to cell cycle arrest in the G1 phase, and also inhibits tumor angiogenesis by reducing synthesis of vascular endothelial growth factor (VEGF).346–350 6.2.4. Trabectedin Trabectedin (36; Yondelis™, ecteinascidin-743, ET-743; Zeltia and Johnson and Johnson, 2007), a tetrahydroisoquinoline alkaloid produced by the ascidian Ecteinascidia turbinate,351–356 received approval for its sale in Europe, Russia and South Korea by Zeltia and Johnson and Johnson under the brand name Yondelis™ for the treatment of advanced soft tissue sarcoma (STS).357–358 Trabectedin (36) binds to the minor groove of DNA and inhibits cell proliferation by disrupting the cell cycle.359,360 The biological mechanism of action is believed to involve the production of superoxides near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from the reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes “activated” into its reactive oxazolidine form. In September 2007, the EMEA approved the use of trabectidin against ovarian cancer (OC) and STS. In November 2009, Yondelis™ received its second marketing authorization from the European Commission for its administration in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer; presently, trabectedin (36) is under Phase II trials for the treatment of paediatric sarcomas as well as breast and prostate cancers.72 The European Commission and the US Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and

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OMe HO

HO NH

H O

Me

O

OMe

MeO

Me

HO

O O

Me

Me NMe

S

N

O

MeO

H

Me

NMe

OH

O NH

N O

NH2

O O

OH Me

Trabectedin (36) Cyanosafracin (37)

ovarian cancer. Trabectedin (36) is produced commercially semi-synthetically from the eubacterium-derived cyanosafracin B (37).361,362 6.2.5. Ixabepilone Ixabepilone (38; Ixempra™, BMS-247550; Bristol-Myers Squibb, 2007), a semi-synthetic derivative of epothilone B (39) produced by Sorangium cellulosum, was developed by Bristol-Myers Squibb (BMS) as an anticancer drug (administered through injection) that binds directly to β-tubulin subunits on microtubules, leading to suppression of microtubule dynamics, blocking of cells in the mitotic phase and ultimately leading to

O Me

S

OH Me

N X O

OH

Ixabepilone (38): X = NH Epothilone B (39): X = O

O

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cell death.363–368 In October 2007, the FDA approved ixabepilone, for the treatment of aggressive metastatic or locally advanced breast cancers that no longer respond to currently available chemotherapies, to be used as a monotherapy and as combination therapy with Xeloda against breast cancer patients who are resistant to standard therapy.369–374

6.2.6. Everolimus Everolimus (40; Afinitor®; Novartis, 2009), a rapamycin analog, is the 42O-(2-hydroxyethyl) derivative of sirolimus (34), and is marketed as an immunosuppressant by Novartis under the tradename Afinitor® for use in advanced renal cell carcinoma.375–378 In March 2009, the FDA approved everolimus (40) for use against advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.379 The drug works similarly to sirolimus as an inhibitor of mTOR (mammalian target of rapamycin), a serine–threonine kinase, downstream of the PI3K/AKT pathway. Everolimus (40) binds to an intracellular protein, FKBP-12, resulting in an inhibitory

O O N

OMe

O

O

O

O HO O OH O O MeO

MeO

Everolimus (40)

OH

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complex formation and inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP), downstream effectors of mTOR, involved in protein synthesis. In addition, everolimus (40) inhibited the expression of hypoxia-inducible factor (e.g. HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by the drug has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in vitro and/or in vivo studies. The spectrum of kinase inhibition, therefore its mechanism of anticancer activity, is different from that of Pfizer’s Sutent (sunitinib malate) or Onyx Pharmaceuticals’ Nexavar (sorafenib). Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers. The FDA has recently approved everolimus for organ rejection prophylaxis on April 22, 2010.380 A Phase II trial reports it is effective in the treatment of subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis.381 In Oct 2010, the FDA approved its use in SEGA unsuitable for surgery.382 As of Oct 2010 Phase III trials are under way in breast cancer, gastric cancer, hepatocellular carcinoma, pancreatic neuroendocrine tumors (NET), and lymphoma.382 6.2.7. Romidepsin Romidepsin (41; Istodax®; Gloucester Pharmaceuticals, 2009), a naturally occurring histone deacetylase (HDAC) inhibitor obtained from the bacteria Chromobacterium violaceum,383–386 was developed and evaluated by Gloucester Pharmaceuticals in various Phase I/II trials sponsored by the National Cancer Institute (NCI) to use against cutaneous and peripheral T-cell lymphoma (TCL).387,388 In November 2009, romidepsin (41) was approved by the FDA under the trade name Istodax® against selective cutaneous TCL patients that have received a minimum of one prior systemic therapy,389 while three Phase II trials for multiple myeloma and peripheral TCL are still recruiting patients. Romidepsin acts as a histone deacetylase (HDAC) inhibitor; HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins,

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S HN

NH

O

O H

O

Romidepsin (41)

such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.383–391 In January 2010, Celgene Pharmaceuticals completed the acquisition of Gloucester Pharmaceuticals.392

6.3. Neurological Diseases 6.3.1. Galantamine hydrobromide Galantamine hydrobromide (42; Reminyl®; Janssen, 2002), is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, particularly those of vascular origin.208–210,393–397 It is an Amaryllidaceae alkaloid obtained from Galanthus nivalis that has been used traditionally in Bulgaria and Turkey for neurological conditions.398,399 Galantamine (42) is a competitive, reversible cholinesterase inhibitor. It reduces the action of acetylcholinesterase (AChE) and therefore tends to increase the concentration of acetylcholine in the brain. It is hypothesized that this action might relieve some of the symptoms of Alzheimer’s. It was launched onto the market as a selective acetylcholinesterase inhibitor for Alzheimer’s disease treatment, slowing the process of neurological degeneration by inhibiting acetylcholinesterase

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OH

O MeO N Me Galantamine (42)

as well as binding to and modulating the nicotinic acetylcholine receptor.54,401,402 Approximately 75% of a dose of galantamine is metabolized in the liver. In vitro studies have shown that hepatic CYP2D6 and CYP3A4 are involved in galantamine metabolism. Galantamine was launched in Austria as Nivalin® in 1996 and as Reminyl® in the rest of Europe and the US in 2002.72 6.3.2. Apomorphine hydrochloride Apomorphine hydrochloride (44; Apokyn®; Bertek, 2004), is a semisynthetic derivative of opium alkaloid morphine (43) isolated from poppy (Papaver somniferum), and it has long been known for its erectile activity at the effective dose of 2–6 mg; physicians discovered the effect over 100 years ago, but found the drug, at a much higher dose (ca. 200 mg), to be more suitable for poison victims as an emetic because it also causes serious nausea and vomiting.61 Apomorphine exerts its erectile effect at the central nervous system; the drug has been found to be a non-selective dopamine agonist which activates both D1-like and D2-like NCH3 N H H HO HO

O Morphine (43)

OH

HO Apomorphine (44)

CH3

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receptors, with some preference for the latter subtypes.403–407 This potent dopamine receptor agonist is used to treat Parkinson’s disease, a chronic neurodegenerative disease caused by the loss of pigmented mesostriatal dopaminergic neurons linking the substantia nigra (pars compacta) to the neostriatum (caudate nucleus and putamen); subcutaneous apomorphine is currently used for the management of sudden, unexpected and refractory levodopa-induced off states in fluctuating Parkinson’s disease.408–413 Apomorphine has been reported to be an inhibitor of β-amyloid fibril formation, and may thus have potential as a therapeutic for Alzheimer’s disease.414–416 6.3.3. Ziconotide Ziconotide (45; Prialt™; Elan, 2004), is a non-opioid and non-NSAID analgesic agent used for the amelioration of severe and chronic pain. It is a synthetic version of the N-type calcium channel blocker ω-conotoxin MVIIA, a peptide first isolated from the venom of cone snail (Conus magus) venom.417–420 In December 2004, the Food and Drug Administration approved ziconotide (45) when delivered as an infusion into the cerebrospinal fluid using an intrathecal pump system for the treatment of severe chronic pain, and is currently used in pain management.421–423 Ziconotide (45), the synthetic form of peptide ω-conotoxin, acts as a selective N-type voltage-gated calcium channel blocker.424–427 This action inhibits the release of pro-nociceptive neurochemicals like glutamate, calcitonin gene-related peptide (CGRP), and substance P in the brain and spinal cord, resulting in pain relief.423–426 In 2005, Elan launched ziconotide (45) in US and Europe for the treatment of patients suffering from chronic pain. Rights for marketing ziconotide (Prialt™) in Europe was obtained by Eisai in March 2006.428

H2N-CKGKGAKCSRLMYDCCTGSCRSGKC-CONH2

Ziconotide (45)

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6.3.4. Dronabinol and Cannabidol Dronabinol (46) and cannabidol (47) (Sativex®; GW Pharmaceuticals, 2005), as a mixture formulation named as Sativex (tradename), the world’s first pharmaceutical prescription medicine derived from the cannabis plant (Cannabis sativa L.).429,430 The drug (a mixture of dronabinol (46) and cannabidol (47)), was launched in Canada in April 2005 for neuropathic pain relief in multiple sclerosis,431–433 and was also approved by Health Canada in August 2007 as an adjunctive analgesic for severe pain in advanced cancer patients by reducing the use of breakthrough opioid medications. Sativex® has also been found to reduce pain efficiently in patients with advance cancer,434 and has been recommended by FDA to enter directly in Phase III trials. In November 2009, GW Pharmaceuticals disclosed that recruitment for Phase II/III cancer pain trial of Sativex® has been completed. In March 2010, GW Pharmaceuticals provided an update on the progress of regulatory submission for Sativex® oromucosal spray for the treatment of the symptoms of spasticity due to multiple sclerosis.435 Me

Me

OH

OH

HO

O

Dronabinol (46)

Cannabidol (47)

Mammalian tissues contain at least two types of cannabinoid receptors, CB1 and CB2. The active cannabinoid ingredients of Sativex® react with the cannabinoid receptors. A receptor on a brain cell can stick or “bind” certain substances for a while. If this happens, it has an effect on the cell and the nerve impulses it produces, which causes a “dimming down” of the symptoms of spasticity. In patients who respond to Sativex®, it is this effect that helps to improve their symptoms of spasticity and to help them cope better with their usual daily activities. It has been hypothesised that these endogenous cannabinoids function in the CNS as “retrograde synaptic messengers” being released from postsynaptic

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neurons and traveling backwards across synapses to activate presynaptic CB1 receptors and to suppress neurotransmitter release. The mechanisms, by which the biological actions of endogenous cannabinoids are terminated, have not been fully evaluated. However, it appears likely that they are removed from the extracellular space by tissue uptake and that intracellular metabolism via an enzyme system, fatty acid amide hydrolase (FAAH), is also involved.436–438 6.3.5. Lisdexamfetamine Lisdexamfetamine (48; L-lysine-D-amphetamine, NRP104; Vyvanse®; New River and Shire Pharmaceuticals, 2007), a psychostimulant prodrug (sold under the tradename Vyvanse®) of the phenethylamine and amphetamine chemical classes, consists of dextroamphetamine coupled with the essential amino acid L-lysine. Lisdexamfetamine (48) is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children 6–12 years and in adults (April 2008) as an integral part of a total treatment program that may include other measures (i.e. psychological, educational, and social). Attention-deficit hyperactivity disorder (ADHD), a neurodevelopmental disorder in which dopaminergic and noradrenergic neurotransmission are supposed to be dysregulated, is primarily characterized by the co-existence of attentional problems and hyperactivity.439–441 NH2 H N NH2

NH2

O Lisdexamfetamine (48)

Amphetamine (49)

Methylphenidate and amphetamines have been used for ADHD management for many years but due to abuse potentials, these drugs are controlled substances.442 Lisdexamfetamine itself is inactive and acts as a prodrug to dextroamphetamine upon cleavage of the lysine portion of the molecule. It was developed for the intention of creating a longer-lasting and more-difficult-to-abuse version of dextroamphetamine, as the requirement

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of conversion into dextroamphetamine in the gastrointestinal tract increases its duration and renders it ineffective upon any other ingestion routes than the oral route.443 Intravenously administered lisdexamfetamine initially produced effects similar to placebo, and therefore intravenous abuse is completely ineffective; there is no increased onset or effect as occurs with intravenous administration of dextroamphetamine compared to oral use of the same.444 In February 2007, New River and Shire Pharmaceuticals obtained FDA approval for use of lisdexamfetamine (48) to help ADHD, and in April 2007, Shire bought New River.72 Vyvanse®, the prodrug of dextroamphetamine, is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of such monoamines into the extra-neuronal space. Norepinephrine and dopamine contribute to maintaining alertness, increasing focus, and sustaining thought, effort, and motivation. However, the exact therapeutic action in ADHD is not known.445–448 6.3.6. Methylnaltrexone Methylnaltrexone (50; Relistor®; Wyeth, 2008), an N-methyl derivative of naltrexone (51), contains a charged tetravalent nitrogen atom and remains unable to cross the blood–brain barrier (BBB), and so has antagonist effects throughout the body.449,450 Methylnaltrexone (50) binds to the same receptors as opioid analgesics such as morphine, but it acts as an antagonist, blocking the effects of those analgesics, specifically the constipating effects on the gastrointestinal tract.451–455 Furthermore, as methylnaltrexone cannot cross the blood–brain barrier, it does not reverse HO

HO

O

O

+ N HO

H

N

Br −

HO

Me

H

O

O Methylnaltrexone (50)

Naltrexone (51)

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the pain-killing properties of opioid agonists or cause withdrawal symptoms. This is the primary difference that makes methylnaltrexone behave differently from naltrexone (51), an approved drug used in management of alcohol and opioid dependence.452–459 Methylnaltrexone (50), thus, blocks peripheral opioid receptors activated by opioids administered for pain relief that cause side effects such as constipation, urinary retention and severe itching. In May 2007, Wyeth and Progenics filed an NDA for subcutaneous doses of methylnaltrexone (50) for the treatment of opioid-induced constipation (OIC) and other pain indications. In March 2008, Wyeth and Progenics reported that methylnaltrexone (50) failed in two Phase III trials for intravenous use in the treatment of post-operative ileus. In April 2008, Progenics and Wyeth announced that Health Canada and the FDA have approved methylnaltrexone (50) for the treatment of OIC. Since May 2009, an oral formulation of methylnaltrexone (50) is under Phase II trials against OIC in chronic pain. After acquisition of Wyeth by Pfizer in October 2009, both decided for joint operations. 6.3.7. Capsaicin Capsaicin (52; Qutenza®, NeurogesX, 2009), an active component of chili peppers belonging to genus Capsicum, was first isolated in pure and crystalline form by John Clough Thresh in 1876.460 Capsaicin is currently used in topical ointments to relieve the pain of peripheral neuropathy; the burning and painful sensations associated with capsaicin (capsaicin does not actually cause a chemical burn, or any direct tissue damage at all) result from its chemical interaction with sensory neurons.461–463 Capsaicin, being a member of the vanilloid family, binds to the ion channel receptor vanilloid

HO H N MeO O Capsaicin (52)

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receptor subtype 1 (VR 1), thereby permitting cations to pass through the cell membrane and into the cell when activated. The resulting depolarization of the neuron stimulates it to signal the brain.464,465 In November 2009, NeurogesX gained FDA approval for Qutenza® (a transdermal 8% patch of capsaicin (52)) against neuropathic pain combined with postherpetic neuralgia. In April 2010, NeurogesX launched Qutenza in US and is planning to market it in Europe by Astellas Pharma Europe Ltd.466

6.4. Cardiovascular and Metabolic Disease Area 6.4.1. Zotarolimus Zotarolimus (53; Endeavor™ stent; ABT-578; Medtronic, 2005), a semisynthetic derivative of sirolimus (34), was designed for use in stents with phosphorylcholine as a carrier; coronary stents reduce early complications R O N

OMe

O

O

O

O HO O OH O O MeO

MeO

Sirolimus (34): R = Zotarolimus (53): R =

OH N

N N

N

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and improve late clinical outcomes in patients needing interventional cardiology. Sirolimus (34; Rapamune, Wyeth) was originally discovered from bacterium Steptomyces hygroscopicus with promising antifungal activity467,468 and is being used along with other coronary stents against restenosis of coronary arteries due to balloon angioplastyis. Zotarolimus (53) is an active principle of Endeavor™ (tradename) stent that inhibits cell proliferation, preventing scar tissue formation and minimizes restenosis in angioplasty patients [469]. In July 2005, Medtronic received European approval for the sale of the Endeavor drug-eluting coronary stent that consists of a cobalt-based alloy integrated with a biomimetic phosphorylcholine polymer.470–472 In February 2008, Medtronic received FDA approval for the use of Endeavor® against coronary artery disease,473 while Cypher® is being marketed by Cordis (Johnson & Johnson).474 6.4.2. Tiotropium bromide Tiotropium bromide (54; Spiriva®; Boehringer-Ingelheim/Pfizer, 2004) has been approved by the US Food and Drug Administration (FDA) for the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).475 Tiotropium, a derivative of atropine from Atropa belladonna (Solanaceae), is a potent reversible nonselective inhibitor of

Me

+ Me N Br−

O H O O OH S

S

Tiotropium bromide (54)

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muscarinic receptors. Tiotropium is structurally analogous to ipratropium, a commonly prescribed drug for COPD, but this anticholinergic bronchodilator has shown longer-lasting effects (24 hours). Although the drug does not display selectivity for specific muscarinic receptors, on topical application it acts mainly on M3 muscarinic receptors located on smooth muscle cells and submucosal glands not to produce smooth muscle contraction and mucus secretion, thus producing a bronchodilatory effect.476 Tiotropium bromide (54) capsules for inhalation are co-promoted by Boehringer-Ingelheim and Pfizer under the trade name Spiriva®.477,478 6.4.3. Bivalirudin Bivalirudin (55; Angiomax®; The Medicines Company [MDCO], 2000) is a leech antiplatelet protein that is an inhibitor of collagen-induced platelet aggregation.479 Chemically, it is a synthetic congener of the naturally occurring drug hirudin (found in the saliva of the medicinal leech Hirudo medicinalis). Bivalirudin (55) is a new, genetically engineered form of hirudin, the substance in the saliva of the leech (Haementeria officinalis), and stops blood clotting, acting as a specific and reversible direct thrombin inhibitor (DTI).479,480 Bivalirudin is used to reduce the risk of blood clotting in adults with severe chest pain (unstable angina) who are undergoing a procedure to open blocked arteries in the heart.481 Bivalirudin overcomes many limitations seen with indirect thrombin inhibitors, such as heparin; bivalirudin is a short, synthetic peptide that is potent, highly specific, and a reversible inhibitor of thrombin.480–483 It inhibits both circulating and clotbound thrombin,483 while also inhibiting thrombin-mediated platelet activation and aggregation.484 Bivalirudin has a quick onset of action and a short half-life,480 and does not bind to plasma proteins (other than thrombin) or to red blood cells, thereby offering a predictable antithrombotic response. D-Phe-L-Pro-L-Arg-L-Pro-Gly-Gly-Gly-Gly-L-Asn-Gly-L-Asp-L-Phe-L-Glu-L-Glu-L-Ile-LPro-L-Glu-L-Glu-L-Tyr-L-Leu

Bivalirudin (55)

Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central

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role in the thrombotic process. It cleaves fibrinogen into fibrin monomers, and activates Factors V, VIII, and XIII, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus. Thrombin also promotes further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3Pro4 bond, resulting in the recovery of thrombin active site functions.480–491 6.4.4. Rosuvastatin calcium Rosuvastatin calcium (56; Crestor®; AstraZeneca, 2003), an inhibitor of 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and a derivative of mevastatin isolated from Penicillium citrinum and P. brevicompactum, is an effective lipid-lowering agent approved internationally (in most of Europe, the US, and Canada) for the management of dyslipidemias.215–217,492,493 Like other available HMG-CoA reductase inhibitors (atrovastatin, fluvastatin, lovastatin, pravastatin, and simvastatin), rosuvastatin competitively inhibits the rate-limiting step in the formation of endogenous cholesterol by HMG-CoA reductase. Consequently, hepatic intracellular stores of cholesterol are reduced, which results in reduced serum levels of low-density lipoprotein-cholesterol (LDL-C) and triglycerides, and increased serum levels of high-density lipoprotein-cholesterol (HDL-C), and thus improves the overall lipid profile of patients.494 Pitavastatin (Livalo, HO COOH OH

F

N

Me

Me

S O

O Rosuvastatin (56)

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57

Sankyo/Kowa, 2003), an analog of mevastatin-like rosuvastatin, has been approved for the treatment of dyslipidemia in Japan.495

6.5. Diabetes 6.5.1. Exenatide Exenatide (57; Byetta™; Amylin and Eli Lilly, 2005), originally named exenatide-4, is a 39-amino acid peptide isolated from the oral secretions of the Gila monster (Heloderma suspectum), a poisonous lizard found in the southwestern US and northern Mexico, and the first insulin mimetic found to improve glycemic control.496–498 Subcutaneous exenatide (57) was launched in the US for use in patients with type 2 diabetes who have failed in glycemic control by treatment with metformin and/or a sulfonylurea.499,500 Exenatide (57) has a structure similar to glucagon-like peptide-1 (GLP-1), a human hormone that helps the pancreas to regulate glucose-induced insulin secretion when the blood glucose levels are elevated, and is the first compound in a new class of drugs called “incretin mimetics”;501,502 it enhances glucose-dependent insulin secretion by the pancreatic β-cells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying, although the mechanism of action is still under study. Eli Lilly obtained FDA in April 2005 while Amylin Pharmaceuticals gained EMEA approval in November 2006 for the use of a synthetic version of exenatide (57) as an adjunctive therapy in type 2 diabetes mellitus.503,504 Amylin Pharmaceuticals, Eli Lilly and Alkermes in May 2009 submitted a NDA for subcutaneous dosing of exenatide (57) once weekly to the FDA, which was accepted in July 2009. L-His-Gly-L-Glu-Gly-L-Thr-L-Phe-L-Thr-L-Ser-L-Asp-L-Leu-L-Ser-L-Lys-L-Gln-L-MetL-Glu-L-Glu-L-Glu-L-Ala-L-Val-L-Arg-L-Leu-L-Phe-L-Ile-L-Glu-L-Trp-l-Leu-L-Lys-L-AsnGly-Gly-L-Pro-L-Ser-L-Ser-Gly-L-Ala-L-Pro-L-Pro-l-Pro-L-ser-NH2

Exenatide (57)

6.6. Few Other Disease Areas 6.6.1. Pimecrolimus Pimecrolimus (58; Elidel®; Novartis, 2001) is a novel macrolactum derivative of ascomycin, isolated as a fermentation product of Streptomyces

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Brahmachari Cl

MeO O OH

O

N

O

O

O

OH O

OMe

OMe

Pimaecrolimus (58)

hygroscopicus var ascomyceticus. Pimecrolimus (58) is an immunomodulating agent used in the treatment of atopic dermatitis (eczema). It is currently available as a topical cream, once marketed by Novartis (however Galderma Pharmaceuticals is promoting the compound in Canada since early 2007) under the tradename Elidel®. Its mechanism of action involves blocking T cell activation via the pimecrolimus–macrophilin complex that prevents the dephosphorylation of the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells. This drug was approved for the treatment of inflammatory skin diseases such as allergic contact dermatitis and atopic dermatitis.180,181,505–517 6.6.2. Nitisinone Nitisinone (59; Orfadin®; Swedish Orphan, 2002) is a derivative of leptospermone,518 an important new class of herbicides from the bottlebrush plant (Callistemon citrinus), and exerts an inhibitory effect for p-hydroxyphenylpyruvate dioxygenase (HPPD) involved in plastoquinone synthesis; the

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F3C

O

59

O

O Nitisinone (59)

drug (59) originally developed as an herbicide is now used successfully in the treatment of hereditary tyrosinemia type 1 (HT-1), a severe inherited disease of humans caused by a deficiency of fumaryl acetoacetate hydrolase (FAH), leading to accumulation of fumaryl and maleyl acetoacetate, and progressive liver and kidney damage.208–210,519–522 The mechanism of action of nitrisinone involves reversible inhibition of 4-hydroxyphenylpyruvate oxidase,519,523 thus preventing the formation of maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys.524 6.6.3. Miglustat Miglustat (60; Zavesca®; Actelion, 2003) has been approved for patients unable to receive enzyme replacement therapy as a therapeutic drug for type 1 Gaucher disease (GD1). Miglustat (OGT 918, N-butyl-1-deoxynojirimycin), a semi-synthetic derivative of 1-deoxynojirimycin isolated from the broth filtrate of Streptomyces lavendulae, is an analog of D-glucose and a white to off-white crystalline solid that has a bitter taste. Type 1 Gaucher disease is an autosomal recessive disorder one gets from both parents. Gaucher disease is a progressive lysosomal storage disorder associated with pathological accumulation of glucosylceramide in cells of the monocyte/macrophage lineage. People with type 1 Gaucher have a defect in the enzyme called glucocerebrosidase (also known as glucosylceramide synthase) that acts on a fatty substance glucocerebroside (also known as glucosylceramide). Accumulation of glucosylceramide causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease. Miglustat (60) reversibly inhibits the activity of glucosylceramide synthase, the ceramide-specific glucosyltransferase that catalyzes the formation of glucocerebroside (i.e. glycosphingolipids) and thereby decreases

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OH

N

N

HO

CH3

HO HO

HO

OH

HO

OH (N-Butyl-deoxynojirimycin) Miglustat (60)

tissue storage of glucosylceramide. Miglustat is, thus, a glucosylceramide synthase inhibitor.215–217,525–527 Treatment with miglustat (60) is known as substrate reduction therapy (SRT). Unlike enzyme replacement therapy (ERT), which has a direct effect on the breakdown of glycosphingolipids, the concept of SRT in Gaucher disease involves reduction of the delivery of potential storage material to the macrophage system. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. Miglustat was effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years. Miglustat is used to treat adults with mild to moderate type 1 Gaucher disease and it is the first treatment to be approved for patients with Niemann-Pick type C disease. Miglustat may only be used in the treatment of type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable; it has been approved by both the European Union and FDA for the treatment of progressive neurological manifestations in adult or pediatric patients with Niemann-Pick type C disease (NPC). It has also been approved for NPC treatment in Canada, Switzerland, Brazil, Australia, Turkey and Israel.528–531 6.6.4. Mycophenolate sodium Mycophenolate sodium (62; Myfortic®; Norvatis, 2003) is an immunosuppressant drug used to prevent rejection in organ transplantation. It is a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo pathway of guanosine nucleotide synthesis. Thus, mycophenolic acid (61), originally

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61

O

HO O O MeO Me

OH

Mycophenolic acid (61)

O

O N

OH

O O

NaO

O

O MeO Me

O O

Mycophenolate mofetil (63)

MeO Me

Mycophenolate sodium (62)

purified from Penicillium brevicompactum, has a selective antiproliferative effect on B- and T-lymphocytes that rely on the de novo synthesis of purine, and is used for the prophylaxis of organ rejection in patients receiving allogeneic renal transplants treated with cyclosporin (cyclosporin A) and corticosteroids. Mycophenolate sodium is particularly indicated for the prevention of renal transplant rejection in adults; besides, the drug has also been used to prevent rejection in liver, heart, and/or lung transplants in children over 2 years. Mycophenolic acid was initially marketed as the prodrug mycophenolate mofetil (63; MMF) to improve oral bioavailability. More recently, the salt mycophenolate sodium has been introduced. Mycophenolic acid (63) is commonly marketed under the tradenames CellCept® (63; mycophenolate mofetil; Roche) and Myfortic® (62; mycophenolate sodium; Novartis).215–217,532–560

7. Natural Product-Based Drugs in Clinical Developments Natural products (NP) or natural product-derived compounds undergoing clinical developments in various disease areas are summarized in this section. Drug candidates are categorized (Tables 2–5) according the natural sources of their corresponding leads, viz. plant (Table 2 and Fig. 2), microorganism (Table 3 and Fig. 3), marine (Table 4 and Fig. 4) and animal (Table 5 and Fig. 5) sources. Each drug candidate is also supplemented with its structure, code name, disease indication, mechanism of action, development status and name of the developer including respective references.

Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Antiparasitic (antimalarial)

Under study (on interation of peroxide moiety with parasite targets)

Betunilic acid (65)

Triterpenoid

Bevirimat (PA-457) (66)

Antiviral (antiHIV)

561–565

Inhibits the final step of Phase IIb the HIV Gag protein processing and thus blocks HIV maturation

Panacos Pharmaceuticals

566–573

Inhibits transcription factor specificity protein-1 (Sp1), Sp3, and Sp4 activation

Phase I

Advanced Life Sciences (UIC)

574–576

Indolizine alkaloid MX-3253 (formerly MBI-3253; Celgosivir; 6-Obutanoyl castanospermine) (68)

Antiviral [Hepatitis C virus (HCV)]

Inhibits α-glucosidase I

Phase II

MIGENIX (received license from Virogen Ltd., UK)

577–581

Promotes bile discharge, Phase II and inhibits hyaluronan biosynthesis

4-Methylumbelliferone Coumarin (Hymecromone) (69)

Heparvit® (dietary supplement)

Antiviral (antiHBV and anti-HCV)

1,5-Di-caffeoylquinic acid (70)

1,5-DCQA (70)

Antiviral (AntiInhibits HIV-1 integrase HIV HIV/AIDS and hepatitis B)

Cyclic polyolic derivative

Phase I/II

MTmedical Institute 582 of Health and BioMonde Chinese Academy 583–585 of Military Medical Sciences (Continued )

Bioactive Natural Products

Castanospermine (67)

Page 62

Ranbaxy

Betunilic acid (ALS- Oncology 357) (65)

Phase III

4:23 PM

Arterolane (RBX11160, OZ-277) (64)

References

9/7/2011

Endoperoxide sesquiterpene lactone

Developer

b1214

Artemisinin (8)

Development status

Brahmachari

Lead compound (Str. No.)

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Table 2. Plant-derived natural product-based drug candidates under clinical evaluation.

b1214_Chapter-01.qxd

Table 2. (Continued ) Lead compound (Str. No.)

Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References 586–591

Morphine (43)

Alkaloid

Morphine-6glucuronide (M6G) (72)

Neurological (pain; analgesic)

Mediates its effects by activating the microopioid receptor; it shows equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression.

Phase III

CeNeS Pharmaceuticals/ PAION Pharmaceuticals

592, 593

Lobeline (73)

Piperidine alkaloid

Lobeline (73)

Neurological (treatment of methamphetamine addiction and ADHD)

Reduces the methamphetamine induced dopamine release

Phase II

Yaupon Therapeutics and NIH

594–599

(Continued )

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Clinical Chinese scientists development Phase II NIA, a division of NIH

4:23 PM

Acetylcholinesterase (AChE) inhibitor

9/7/2011

Neurological (Alzheimer’s Disease)

Bioactive Natural Products

Huperzine-A (71)

b1214

Sesquiterpene alkaloid

Natural Products in Drug Discovery

Huperzine-A (71)

63

Capsaicinoid

Name (synonym)

Mechanism of action

Development status

Developer

References

Anesiva

461, 600

Phase III

Winston 601 Laboratories, Inc.

Phase III

Bristol-Myers Squibb (BMS)

602–607

Sirtris Pharmaceuticals

608–614

Polyphenolic glycoside

Dapagliflozin (BMS-512148) (75)

Antidiabetic

Sodium glucose co-transporters (SGLTs) inhibitor that lowers glucose plasma level and improves insulin resistance.

Resveratrol (76)

Triphenolic stilbene

SRT-501 (a formulation)

Against diabetes and obesity

Activates sirtuins.by Phase II working indirectly, via the energy sensor AMP-activated protein kinase (AMPK)

(Continued )

Bioactive Natural Products

Phlorizin (74)

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Phase III

4:23 PM

Neurological Binds to vanilloid (pain receptor subtype 1 indications (VR1) such as severe post-surgical pain, posttraumatic neuropathic pain and musculoskeletal diseases) Osteoarthritis -dopain

b1214

Capsaicin (Coded 4975; ALGRX 4975;AdleaTM) (52) Civanex® (zucapsaicin cream 0.075%; WL-1001)

Disease area/ Indication

9/7/2011

Capsaicin (52)

Compound class

Brahmachari

Lead compound (Str. No.)

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Table 2. (Continued )

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Table 2. (Continued ) Lead compound (Str. No.)

Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Suppresses IL-1β and Phase I matrix metalloproteinases (MMPs) through a peroxisome proliferator-activated receptor (PPAR) γ-mediated mechanism

Cervelo Pharmaceuticals

615–618

1-Deoxynojirimycin (Moranoline; 78)

Aza-sugar-type

Isofagomine (PliceraTM, AT2101) (79)

Gaucher’s disease, a lysosomal storage disorder caused by βglucocerebrosidase deficiency

Mimics the carbocation Phase II transition state used by glycosidases

Amicus Therapeutics in collaboration with Shire Pharmaceuticals

619–622

Himbacine (80)

Alkaloid

SCH 530348 (TRA) (81)

Cardiovascular diseases (antiplatelet agent)

Thrombin receptor antagonist

Schering-Plough

623–626

Eupatilin (82)

Flavone

DA-6034 (83)

Dry eye systems

Suppresses MMP-9 and Phase I inflammatory cytokines and activates MAPK Signaling pathway

Dong-A Pharmaceuticals

627–629

Bioactive Natural Products

65

(Continued )

Natural Products in Drug Discovery

Phase III (acute coronary syndromes)

Page 65

Neurological (neuropathic pain)

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CP 7075 (IP 751, ajulemic acid, CT-3) (synthetic version)

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Cannabinoid

b1214

Ajulemic acid (77)

Name (synonym)

Development status

Developer

References

Phase II

Inhibits topoisomerase I

Phase II

Novartis/Sigma-Tau 637–639

Inhibits topoisomerase I

Phase I

Ipsen

640

Inhibits topoisomerase I

Phase II/III

Dr Reddy/ClinTec International

641, 642

SN2310 141 (90)

Oncology

Inhibits topoisomerase I

Phase I

Combretastatin A-4 phosphate (ZybrestatTM, CA4P) (92) Ombrabulin (AVE-8062; AC-7700) (93)

Oncology (vascular disrupting agent) Oncology

Tubulin binding

Phase I/II/III

OXiGENE (Arizona State)

644–650

Tubulin binding

Phase III

Sanofi-Aventis

644, 645, 651

149, 630–634 635, 636

643

(Continued )

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Inhibits topoisomerase I

BioNumerik and ASKA Pharmaceutical Ipsen

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Phase III

9/7/2011

Inhibits topoisomerase I

Gimatecan (ST-1481) (87) Elomotecan (BN-80927, LBQ707, R-1559) (88) DRF 1042 (89)

Oncology (ovarian cancer) Oncology (advance metastatic cancers) Oncology (solid tumor) Oncology (advanced metastatic cancers) Oncology

Bioactive Natural Products

Phase II

b1214

Stimulates endogenous prostaglandin E2 (PGE2) synthesis as well as mucus secretion

Quinoline alkaloid Karenitecin® (BNP-1350) (85)

Stilbenoid phenol

Mechanism of action

Gastritis

Diflomotecan (BN-80915) (86)

Combretastatin A-4 (91)

Disease area/ Indication

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Camptothecin (84)

Compound class

Brahmachari

Lead compound (Str. No.)

66

Table 2. (Continued )

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Table 2. (Continued ) Lead compound (Str. No.)

Disease area/ Indication Oncology (advancedstage solid tumors)

Tubulin binding

Phase I/II

OXiGENE (Arizona State)

652–657

Paclitaxel (96)

Diterpene taxoid

Cabazitaxel (XRP-6258) (97)

Oncology (pancreatic and hormonerefractory prostate cancers) Oncology (pancreatic and hormonerefractory prostate cancers) Oncology (metastatic melanoma) Oncology (solid tumors)

Tubulin binding

Phase III

Sanofi-Aventis

658–662

Tubulin binding

Phase III

Sanofi-Aventis

658, 659, 661–664

Tubulin binding

Phase III

Luitpold Pharmaceuticals

665, 666

Tubulin binding

Phase I/II

Spectrum (Indena)

667–669

Tubulin binding

Phase II

Wyeth Pharmaceuticals

670, 671

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Natural Products in Drug Discovery 67

(Continued )

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OXi4503 (Combretastatin A-1 diphosphate) (95)

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Stilbenoid phenol

Oncology (colorectal neoplasm)

References

9/7/2011

Combretastatin A-1 (94)

DHA-paclitaxel (Taxoprexin®) (99) Ortataxel (IDN-5109, BAY-59-8862) (100) Milataxel (MAC-321, TL-00139) (101)

Developer

b1214

Name (synonym)

Larotaxel (XRP-9881) (98)

Mechanism of action

Development status

Compound class

Compound class

Name (synonym)

TPI-287 (103)

Development status

Developer

References

Daiichi Sankyo/ Genta

673–677

Tubulin binding

Phase II

Tapestry Pharmaceuticals

678

Tubulin binding

Phase II

Bristol-Myers Squibb (BMS)

679–681

Vinca alkaloid

Vinflunine (Javlor®) Oncology (106) (bladder cancer)

Tubulin binding

Phase III

Pierre Fabre Laboratories

682–687

Noscapine (107)

Benzylisoquinoline alkaloid

CB3304 (Noscapine) (107)

Oncology (multiple myeloma)

Tubulin binding

Phase I/II

Cougar Biotechnology

682–684, 688, 689

Curcumin (108)

Polyphenol

Curcumin (108)

Inflammation; oncology (matastatic colon cancer)

Various antiinflammatory and antioxidative properties

Phase I/II Phase II (MCC)

Being conducted by 690–692 various concerns worldwide

Oleanolic acid (109)

Triterpenoid

RTA-402 (CDDO-Me) (110)

Oncology (prostate cancer)

Inhibits IκB alpha kinase Phase I/II activation

Reata Pharmaceuticals

693, 694

(Continued )

Bioactive Natural Products

Vinblastine (105)

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Phase I/II

4:23 PM

Tubulin binding

b1214

BMS-188797 (104)

Oncology (advanced gastric and breast cancer) Oncology (advanced pancreatic cancer) Oncology (advanced malignancies)

Mechanism of action

9/7/2011

Tesetaxel (DJ-927) (102)

Disease area/ Indication

Brahmachari

Lead compound (Str. No.)

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Table 2. (Continued )

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Table 2. (Continued ) Lead compound (Str. No.)

Compound class

Name (synonym)

Disease area/ Indication

Regulates transcription factor Nrf2

Development status

Developer

References

Phase II

Reata Pharmaceuticals

695

9/7/2011

Chronic kidney disease (CKD) in type 2 diabetes mellitus patients

Mechanism of action

ArQule

696–699

Rohitukine (112)

Flavone

Alvocidib (flavopiridol, HMR 1275) (113)

Oncology

Cyclin-dependent kinase inhibition

Phase III (NSCLC) Phase IIb (CLL)

Sanofi-Aventis

700–702

Daidzein (114)

Isoflavone

Phenoxodiol (115)

Oncology

NADH oxidase (tNOX) and sphingosine-1phosphate inhibition

Phase III Marshall Edwards (ovarian (Novogen) cancer) Phase II (castrate and non-castrate prostate cancer)

703–707

Genistein (116)

Isoflavone

Genistein (116)

Oncology (antitumor)

Protein-tyrosine kinase inhibition, antioxidative

Phase I/II

708

Astellas, Bausch & Lomb

69

(Continued )

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Phase II

4:23 PM

Oncology Increases pro-apoptic (pancreatic and protein E2F1, as well ovarian cancer) as induces expression of cyclin dependent kinase inhibitor 1A (CDKN1A or P21)

Bioactive Natural Products

β-Lapachone (ARQ-501) (111)

b1214

Naphthaquinone

Natural Products in Drug Discovery

β-Lapachone (111)

Name (synonym)

Disease area/ Indication

Mechanism of action

b1214_Chapter-01.qxd

Compound class

Development status

Developer

References

Vascular targeting and Phase III angiogenesis inhibition

Antisoma (University of Auckland)/ Novartis

709–713

Silybin (119)

Flavonolignoid

Antioxidant and anti-inflammatory

Phase II (cancer chemoprevention)

American College of Gastroenterology/ Indena

714–719

3′-O-Methyl Lignoid nordihydroguaiaretic acid (NDGA; 120)

Terameprocol (EM-1421, tetraO-methyl nordihydroguaiaretic acid) (121)

Oncology (solid Transcription inhibitor tumors, glioma and leukemia)

Phase I/II

Erimos (John Hopkins)

720–726

Epipodophyllotoxin (122)

Alkaloid

Tafluposide (123)

Oncology

Topoisomerase I and II inhibitor

Phase I

Pierre Fabre

727–729

Ingenol (124)

Tetracyclic diterpene

Ingenol 3-angelate (PEP005) (125)/ Ingenol mebutate

Oncology

Protein kinase C activation

Phase II

Peplin

730–733

Acronycine (126)

Alkaloid

S23906-1 (127)

Oncology (solid tumors)

DNA binding

Phase I

Laboratoires Servier 734–737 (CNRS)

Homoharringtonine (128)

Alkaloid

Homoharringtonine (Omacetaxine mepesuccinate; Ceflatonin®) (128)

Oncology

Protein synthesis inhibition

Phase II/III

ChemGenex

Bioactive Natural Products

738, 739

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Oncology

b1214

IdB 1016 (Silipide; Silybin and phosphatidylcholine complex; Silophos®)

4:23 PM

Flavone derivative ASA404 (DMXAA, Oncology ASA1404) (118)

9/7/2011

Flavone-8-acetic acid (117)

Brahmachari

Lead compound (Str. No.)

70

Table 2. (Continued )

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Table 3. Microorganism-derived natural product-based drug candidates under clinical evaluation. Compound class

Cephalosporins

β-Lactum antibiotics

Mechanism of action

Development status

Developer

Inhibits bacterial cell wall synthesis

Phase III (cSSSIs)

Ceftaroline acetate (PPI-0903, TAK-599) (130)

Antibacterial

-do-

Phase II (cSSSIs; CAP)

Tebipenem pivoxil (ME-1211, L-084) (131)

Antibacterial (otolaryngological/ respiratory infections) Antibacterial (common nosocomial infections) Antibacterial

-do-

Phase III

Meiji Seika

749–751

-do-

Phase II

Daiichi Sankyo

752–754

-do-

Phase II

755, 756

Antibacterial

-do-

Phase I

Antibacterial

-do-

Phase I

Protez, licensed from Dainippon Sumitomo Forest and Meiji Seika Pfizer

Antibacterial

-do-

Phase III

Replidyne

762–764

745–748

757,758 759–761

71

(Continued )

Natural Products in Drug Discovery

ME-1036 (CP5609) (134) Sulopenem (CP70429) (135) Faropenem daloxate (SUN-208, BAY56-6824) (136)

740–744

Page 71

Antibacterial

4:23 PM

Ceftobiprole medocaril (BAL-5788) (129)

Tomopenem (CS-023, RO4908463, R1558) (132) PZ601 (SM216601) (133)

Basilea Pharmaceutica and J&J affiliated Cilag GmbH International Forest Laboratories

References

Bioactive Natural Products

β-Lactum antibiotics

Disease area/ Indication

b1214

Carbapenems

Name (synonym)

9/7/2011

Lead compound (Str. No.)

b1214_Chapter-01.qxd

72

Disease area/ Indication

Lipoglycopeptide antibiotic

Dalbavancin (Zeven®, BI-397) (138)

Antibacterial (cSSSIs)

Inhibits bacterial cell Phase III wall biosynthesis via formation of a complex with the C-terminal Dalanyl-D-alanine of growing peptidoglycan chains; in addition, it appears to have the unique ability to dimerise and anchor its lipophilic side chain in the bacterial membranes.

Pfizer

765–769

Chloroeremomycin (139)

Glycopeptide antibiotic

Oritavancin (NuvocidTM, LY333328) (140)

Antibacterial (cSSSIs including MRSA)

Inhibits bacterial cell wall biosynthesis

Phase III

Eli Lilly/Targanta

770

Vancomycin; Cephalosporin

Glycopeptide and βlactum antibiotics

TD-1792 (a VancomycinCephalosporin heterodimer) (141)

Antibacterial (cSSSIs including MRSA)

Inhibits bacterial cell wall synthesis

Phase II

Theravance

771

Mechanism of action

Development status

Developer

References

b1214 Bioactive Natural Products

(Continued )

Page 72

Teicoplanin analog A40926 (137)

Name (synonym)

4:23 PM

Compound class

9/7/2011

Lead compound (Str. No.)

Brahmachari

Table 3. (Continued )

b1214_Chapter-01.qxd

Table 3. (Continued ) Lead compound (Str. No.)

Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Oscient Pharmaceuticals

772–777

Semi-synthetic Streptogramins

Macrolide peptide antibiotcs

NXL-103 (XRP2868) — a 70:30 mixture of Flopristin (RPR132552A, Streptogramin A-type) (143) and Linopristin (RPR202698, Streptogramin B-type) (144)

Antibacterial (CAP and cSSSIs including MRSA)

Inhibits bacterial protein synthesis

Phase II

Sanofi-Aventis

778–783

Friulimicin B (145)

Lipopeptide antibiotic

Friulimicin B (145)

Antibacterial

Through complex formation with bactoprenolphosphate, leading to the interruption of peptidoglycan and teichoic acid biosynthesis.

Phase I

MerLion Pharmaceuticals

224, 784–786

(Continued )

Page 73

Phase II

4:23 PM

Inhibits bacterial cell wall synthesis

9/7/2011

Antibacterial [Clostridium difficile associated diarrhoea (CDAD)]

Bioactive Natural Products

Ramoplanin factor A2 (Ramoplanin) (142)

b1214

Lipopeptide antibiotic

Natural Products in Drug Discovery

Ramoplanin (142)

73

b1214_Chapter-01.qxd

74

Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Antibacterial (cystic fibrosis)

Increases chloride permeability in the nasal epithelium of healthy individuals and subjects with cystic fibrosis

Phase II

AOP Orphan in collaboration with Lantibio

787–789

Erythromycin (147)

Macrolide antibiotic

Cethromycin (RestanzaTM (ABT-773) (148)

Antibacterial (CAP, other respiratory tract infections, and anthrax)

Phase III

Advanced Life Sciences

790–795

EP-420 (EP-013420) (149)

Antibacterial (CAP)

Inhibits bacterial protein synthesis by interacting close to the peptidyl transferase site of the 50S ribosomal subunit. The main binding sites are within domains II and V of the 23S rRNA. -do-

Phase II

Enanta Pharmaceuticals and Shionogi & Co.

796–798

Bioactive Natural Products

(Continued )

Page 74

Moli1901 (duramycin, 2262U90) (146)

4:23 PM

Polycyclic peptide

b1214

Duramycin (146)

9/7/2011

Lead compound (Str. No.)

Brahmachari

Table 3. (Continued )

b1214_Chapter-01.qxd

Table 3. (Continued ) Lead compound (Str. No.)

Disease area/ Indication

Tiacumicin B (OPT-80, PAR101; identical to Lipiarmycin A3184 and Clostomicin B1) (152)

Antibacterial [Clostridium difficile-associated diarrhea (CDAD)]

Shows strong Pre-clinical/ suppression of the Phase I inflammatory response of human neutrophils, the white blood cells contributing to the inflammatory aspects of the disease. Inhibits bacterial Phase II/III protein synthesis by blocking the progression of the growing polypeptide chain through binding with the 50S subunit of ribosome

Basilea 799–801 Pharmaceutica AG

Sanofi-Aventis

802

Inhibits bacterial RNA synthesis

Optimer Pharmaceuticals

803–809

Phase III

75

(Continued )

Page 75

Antibacterial (respiratory infections)

References

4:23 PM

Telithromycin (Ketek®) (151)

Developer

9/7/2011

Antibacterial (acne)

Development status

Bioactive Natural Products

BAL-19403 (150)

Mechanism of action

b1214

Macrolactone

Name (synonym)

Natural Products in Drug Discovery

Tiacumicin B (152)

Compound class

b1214_Chapter-01.qxd

76

Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Antibacterial (broad spectrum antibiotic against MRSA, MDR Streptococcus pneumoniae and vancomycinresistant enterococci)

Inhibits bacterial protein synthesis

Phase III (treatment of hospital infections in both oral and i.v. injectable formulations)

Paratek/Novartis

810

Rs-DPLA (154)

Lipid-A analog

Eritoran (E5564) (155)

Antibacterial (acts against sepsis by Gram-negative bacteria)

Inhibits endotoxin response through antagonism of the Toll-like receptor 4 (TLR4)

Phase III

Eisai

811–818

Rifamycinquinolone heterodimer

Antibiotics

CBR-2092 (156)

Antibacterial

Exerts antimicrobial activity through combined effects on RNA polymerase, DNA topoisomerase IV and DNA gyrase

Phase IIa (treatment of infections caused by Gram-positive cocci)

Cumbre Pharmaceuticals

819, 820

Bioactive Natural Products

(Continued )

Page 76

MK-2764 (PTK0796; BAY 73-7388) (153)

4:23 PM

Aminomethylcycline

b1214

Aminomethylcyclines

9/7/2011

Lead compound (Str. No.)

Brahmachari

Table 3. (Continued )

b1214_Chapter-01.qxd

Table 3. (Continued ) Compound class

Development status

Developer

References

Various Phase I/II trials (gel, cream, injectable form)

aRigen Pharmaceuticals

821–824

Echinocandin- Aminocandin type (NXL-201, antifungal IP960, HMRantibiotic 3270) (159)

Antifungal (Candida sp. infections)

Targets the glucan in fungal cell walls

Phase I

Novexel

825–827

Patrician A (160)

Polyene antibiotic

SPK-843 (161)

Antifungal (systemic mycosis)

Destabilizes fungal cell membrane

Phase II

Kaken Pharmaceuticals

828–834

Cyclosporin (162)

Cyclic peptide

NIM 811 (SDZ NIM 811, Cyclosporin 29, MeIle4cyclosporin) (163)

Antiviral (anti-HCV)

Inhibits mitochondrial Phase I permeability transition

Sandoz (now Novartis)

835–840

(Continued )

Page 77

Interacts selectively to membrane phospholipids, causing sever damage to bacterial membrane

4:23 PM

Antibacterial (MRSA infections and acne)

Bioactive Natural Products

Deoxymulundocandin (158)

WAP-8294A2 (157)

Mechanism of action

b1214

Antibiotic

Disease area/ Indication

Natural Products in Drug Discovery

WAP-8294A2 (JA-002) (157)

Name (synonym)

9/7/2011

Lead compound (Str. No.)

77

Name (synonym)

Disease area/ Indication

Mechanism of action

b1214_Chapter-01.qxd

Compound class

Development status

Developer

References

Inhibits protein synthesis by interfering with endoplasmic reticulum and Golgi apparatus functions; it also induces cell differentiation and caspase-dependent apoptosis

Phase IIa

DARA Therapeutics, Inc.

841–844

Galactonojirimycin (Galactostatin) (165)

Aza-sugar type

Migalastat (AmigalTM, AT1001, 1Deoxygalactonojirimycin, 1Deoxygalactostatin) (166)

Fabry disease

Stabilizes protein structures and restores correct folding through binding with them

Phase III

Amicus Therapeutics in collaboration with Shire Pharmaceuticals

845, 846

Staurosporine (167)

Bis-indole alkaloid antibiotic

Ruboxistaurin (LY333531) (168)

Diabetes (diabetic peripheral retinopathy)

Protein kinase C (PKC) inhibitor

Phase III

Eli Lilly

847–853

Cyclosporine-A (162)

Macrocyclic peptide antibiotic

Voclosporin (ISA247, R1524) (169)

Immunosuppressive

Calcineurin inhibitor

Phase IIb (prevention of the rejection of kidney graft)

Lux Biosciences

854–856

Bioactive Natural Products

(Continued )

Page 78

Neurology (neuropathic pain in cancer patients, in particular, chemotherapyinduced peripheral neuropathy)

4:23 PM

KRN5500 (164)

9/7/2011

Antibiotic

b1214

Spicamycin

Brahmachari

Lead compound (Str. No.)

78

Table 3. (Continued )

b1214_Chapter-01.qxd

Table 3. (Continued )

Pladienolide D (170)

Macrolide antibiotic

E7107 (171)

Oncology

Binds with spliceosomeassociated protein 130 (SAP130) and inhibits the splicing of premRNA resulting cell cycle arrest

Phase I

Eisai

857–860

Elsamicin A (172)

Antibiotic

Elsamicin A (Elsamitrucin) (172)

Oncology

Inhibits topoisomerase I and II

Phase II

Spectrum Pharmaceuticals

861

Doxorubicin (173)

Antibiotic

L-Annamycin (174)

Oncology

Inhibits topoisomerase II

Phase I/IIa

862

Berubicin (RTA744, WP744) (175) Sabarubicin (MEN10755) (176)

Oncology

Inhibits topoisomerase II Inhibits topoisomerase II

Phase II

Callisto (M.D. Anderson Cancer Center) Reata Pharmaceuticals Menarini Pharmaceuticals

Nemorubicin (MMDX, PNU152243A) (177)

Oncology

Nerviano Medical Sciences

868, 869

Name (synonym)

Disease area/ Indication

Developer

References

9/7/2011 b1214

Phase II (smallcell lung cancer; SCLC) Phase I/II

863, 864 865–867

(Continued )

Bioactive Natural Products

Inhibits topoisomerase II

Development status

Natural Products in Drug Discovery

Oncology

Mechanism of action

Page 79

Compound class

4:23 PM

Lead compound (Str. No.)

79

b1214_Chapter-01.qxd

80

Lead compound (Str. No.)

Antibiotic

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Phase II (monotherapy against STS of metastatic or advanced stage)

Cell Therapeutics (Nerviano Medical Sciences)

870–877

Geldanamycin (180) Benzoquinone Tanespimycin (17ansamycin AAG, KOS-953, antibiotic NSC-330507) (181) Alvespimycin (17DMAG, KOS1022, NSC707545) (182)

Oncology

Inhibits HSP90 and interrupts MAPK pathway

Phase II/III (antimelanoma)

Kosan (NIH)

878–882

Oncology

HSP90 inhibitor

Kosan (NIH)

88, 884

Oncology

HSP90 inhibition

Phase I (solid tumors) Phase II (monotherapy against HER2positive metastatic breast cancer) Phase I/II (breast cancer)

Infinity Pharmaceuticals

885, 886

(Continued )

Bioactive Natural Products

Retaspimycin (IPI504, 17-AAG hydroquinone salt) (183)

Page 80

DNA minor groove binder

4:23 PM

Oncology

b1214

Brostallicin (PNU166196) (179)

9/7/2011

Distamycin A (178)

Compound class

Brahmachari

Table 3. (Continued )

b1214_Chapter-01.qxd

Table 3. (Continued ) Lead compound (Str. No.)

Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Macrolide antibiotic

Deforolimus (Ridaforolimus; MK-8669, AP23573) (184)

Oncology

mTOR inhibition

Phase I/II/III (various tumor types including metastatic STS and bone sarcomas)

Merck and ARIAD

887–890

Salinosporamide A (185)

Antibiotic

Salinosporamide A (NPI-0052) (185)

Oncology

Proteasome inhibition

Phase Ib (solid tumor malignancies)

Nereus

891–893

Staurosporine (167)

Bis-indole alkaloid antibiotic

Enzastaurin (LY317615) (186)

Oncology

Serine–threonine kinase inhibition

Eli Lilly

894–898

Midostaurin (PKC412, CGP 41251, 4′-N-Benzoylstaurosporine) (187)

Oncology

Inhibits protein kinases including FLT3 inhibition

Phase II (NSCLC) Phase III (DLBCL; diffuse large B-cell lymphoma) Phase I/II

Novartis

899

Lestaurtinib (CEP701, KT-5555) (189)

Oncology

Inhibition of FLT3 and tyrosine phosphorylation of TrkA

Phase II/III

Cephalon

900, 901

4:23 PM Page 81

Bioactive Natural Products

81

(Continued )

b1214

Alkaloidal antibiotic

Natural Products in Drug Discovery

K252a (Staurosporine analog) (188)

9/7/2011

Sirolimus (34)

b1214_Chapter-01.qxd

82

Table 3. (Continued ) Disease area/ Indication

Development status

KRX-0601 (UCN01, KW-2401) (190)

Oncology

Inhibition of CDKs

Phase II (melanoma, TCL, SCLC)

Keryx (Kyowa Hakko/NCI)

902–905

Diazepinomicin (ECO-4601) (191)

Dibenzodiazepine alkaloid

Diazepinomicin (ECO-4601) (191)

Oncology

RAS-mitogenactivated phosphokinase (MAPK) pathway inhibitor and inhibition of the peripheral benzodiazepine receptor

Phase I/II

Thallion (Ecopia)

906–910

Prodigiosin (Streptorubin B) (192)

Tri-pyrrole antibiotic

Obatoclax (GX15070) (193)

Oncology

Bcl-2 inhibition

Phase I/II

Gemin X

911, 912

Epothilone B (38)

Polyketide macrolactone (with a methylthiazole group) antibiotic

Patupilone (Epothilone B, EPO-906) (38) Sagopilone (ZKEPO, ZK219477) (194)

Oncology

Microtubulin stabilization

Novartis

913, 914

Oncology

Microtubulin stabilization

Phase III (ovarian cancer) Phase II (lung, ovarian and prostate cancers)

Schering AG

368, 915–918

Developer

References

b1214 Bioactive Natural Products

(Continued )

Page 82

Alkaloidal antibiotic

Mechanism of action

4:23 PM

UCN-01 201 (staurosporine analog) (190)

Name (synonym)

9/7/2011

Compound class

Brahmachari

Lead compound (Str. No.)

b1214_Chapter-01.qxd 9/7/2011

Table 3. (Continued ) Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Tubulin stabilization

Phase I/II

Kosan (Memorial Sloan-Kettering)

919

NPI-2350 (halimide, phenylahistin) (197)

Diketopiperazine

NPI-2358 (198)

Oncology

Tubulin binding

Phase II (NSCLC)

Nereus

920–922

Illudin S (199)

Sesquiterpenoid

Irofulven (MGI114, HMAF) (200)

Oncology

DNA synthesis inhibition

Phase II/III (advancedstage PC and advanced GI solid tumors)

Eisai (MGI Pharma)

923–926

Page 83

Oncology

Bioactive Natural Products

9,10-Didehydroepothilone D (KOS-1584) (196)

b1214

-do-

Natural Products in Drug Discovery

Epothilone D (195)

4:23 PM

Lead compound (Str. No.)

83

b1214_Chapter-01.qxd

84

Lead compound (Str. No.)

Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Enhances cognition; it acts as a partial agonist at neural nicotinic acetylcholine receptors. It binds to both the α4β2 and α7 subtypes, but activates only the α7 to a significant extent

Phase I/II

CoMentis

927–933

Plitidepsin (Aplidin) (203)

Cyclic depsipeptide

Plitidepsin (Aplidin®) (203)

Oncology

Inhibitor to VEGF, VEGFR1, and G1/ G2 phase cell cycle

Phase II

PharmaMar

934–936

Halichondrin B (204)

Macrocyclic polyether

Eribulin (E7389, NSC-707389) (205)

Oncology

Tubulin assembly inhibition

Phase II/III (advanced or metastatic breast cancer)

Eisai

937–943

Hemiasterlin (206)

Oligopeptide

E7974 (207)

Oncology

Tubulin assembly inhibition

Phase I (against a variety of human tumor xenografts)

Eisai

944

Bioactive Natural Products

(Continued )

Page 84

Neurology (Alzheimer’s disease)

4:23 PM

3-(2,4-Dimethoxy benzylidene)anabaseine (DMXBA; GTS21) (202)

9/7/2011

Tetrahydropyridinyl pyridine derivative (a nicotinic compound)

b1214

Anabaseine (201)

Brahmachari

Table 4. Marine-derived natural product-based drug candidates under clinical evaluation.

b1214_Chapter-01.qxd

Table 4. (Continued ) Compound class

Name (synonym)

Disease area/ Indication

Mechanism of action

Development status

Developer

References

Phase I/II/III

Novartis

945,946

Bryostatin 1 (210)

Macrolide lactone

Bryostatin 1 (210)

Oncology

Protein kinase C inhibition

Phase I/II

NCI

947–949

Jorumycin (211)

Dimeric isoquinoline alkaloid

Zalypsis® (PM00104/50) (212)

Oncology

DNA binding and transcriptional activity

Phase I (solid tumors or lymphoma)

PharmaMar

950, 951

Dolastatin 15 (213)

Depsipeptide

Tasidotin (Synthadotin, ILX-651) (214)

Oncology

Induces G2/M phase cell cycle arrest by inhibiting tubulin assembly

Phase II

Genzyme

952–954

Dolastatin 10 (215)

Depsipeptide

Soblidotin (YHI-501, TZT-1027, Auristatin PE) (216)

Oncology

Tubulin assembly inhibition

Phase II

Yakult Honsha (ASKA Pharmaceutical)

955

Kahalalide F (217)

Depsipeptide

Kahalalide F (217)

Oncology

Phase II

PharmaMar

956–961

PM02734 (Irvalec®; 218)

Oncology

Alters lysosomal membrane function Alters lysosomal membrane function

Phase I

PharmaMar

962–965

Page 85

Inhibits histone deacetylase (HDAC)

4:23 PM

Oncology

Bioactive Natural Products

Panobinostat (LBH589) (209)

b1214

Symmetrical bromotyrosinederived disulfide

Natural Products in Drug Discovery

Psammaplin A (208)

9/7/2011

Lead compound (Str. No.)

85

Disease area/ Indication

Development status

Quinazoline heterocycle

Tetrodotoxin (TectinTM/ TetrodinTM) (219)

Neurology (Pain)

Blocks the action potentials in nerves through binding to sodium channels in cell membrane

Phase III (TectinTM against neuropathic pain in cancer chemotherapy) Phase I (TetrodinTM in the management of opiate withdrawal symptoms)

Wex Pharmaceuticals (in conjunction with Chinese Medical Institutes)

139, 966–969

Xen-2174 (220) (isolated from the snail Conus marmoreus)

13-Amino-acid peptide (a conotoxin)

Xen-2174 (220)

Neurology (Pain)

Inhibits norepinephrine transporter (NET)

Phase II (against acute postoperative pain and chronic pain in cancer patient)

Xenome

970–973

Trodusquemine (221) (isolated from the liver of the dogfish shark, Squalus acanthias)

Sulfated aminosterol

Trodusquemine (MSI-1436) (221)

Diabetes

Suppresses mammalian appetite through inhibition of protein tyrosine phosphatase 1B (PTP-1B)

Phase I (against type 2 diabetes and related symptoms)

Genaera Corporation

974–978

Developer

References

b1214 Bioactive Natural Products

(Continued )

Page 86

Tetrodotoxin (TTX; isolated from Pufferfish) (219)

Mechanism of action

4:23 PM

Name (synonym)

9/7/2011

Compound class

Brahmachari

Lead compound (Str. No.)

b1214_Chapter-01.qxd

86

Table 5. Animal-derived natural product-based drug candidates under clinical evaluation

b1214_Chapter-01.qxd

Table 5. (Continued ) Lead compound (Str. No.)

Peptide

Name (synonym)

Disease area/ Indication

Omiganan (223)

Antibacterial

Mechanism of action Through bacterial cytoplasmic membrane interaction

Development status Phase III

Developer

979–983

Page 87

Bioactive Natural Products

4:23 PM

b1214

Natural Products in Drug Discovery 87

Developed by MIGENIX; licensed to Cadence Pharmaceuticals and Cutanea Life Sciences for catheter-related infections (coded OmigardTM, CPI-226, MBI-226) and dermatological diseases (coded as CLS001, MX-594AN), respectively. Primary end point was not achieved in a Phase III trial and additional Phase III trials using a gel-based formulation by Cadence Pharmaceuticals are underway. Cutanea Life Sciences have successfully evaluated 222 in Phase II trials (2007) and the Phase III trials for treatment of rosacea, a chronic inflammatory skin disorder are underway.

References

9/7/2011

Indolicidin (222) (isolated from neutrophils of bovine)

Compound class

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

88

Page 88

Bioactive Natural Products

Brahmachari

H H

O

COOH

H

O RO

Betunilic acid (65): R = H

H

O

N H

NH2

O

O

Bevirimat (66): R =

Arterolane (64)

COOH

OR N CH3

OH HO

H OH

O

Castanospermine (67): R = H

O

HO

MBI-3253 (Celgosivir) (68): R =

O

Hymecromone (69) HO

HO O

O

Me

HO

N O

H

H

HOOC

HO

OH O

OH

HO

O

1,5-DCQA (70)

Morphine (43): R = H HOOC

H2N

O

H

RO

N

M6G (72): R =

Huperzine-A (71)

O HO HO

OH

HO OH HO O

OH

O

HO

N

O

OH

OH O

Me

Lobeline (73)

Fig. 2.

Phlorizin (74)

Plant-derived drug candidates under clinical evaluation.

OH

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 89

Bioactive Natural Products

Natural Products in Drug Discovery HO HO O HO OH

OH Cl

HO OH

O

Dapagliflozin (75)

Resveratrol (76)

COOH

H N

H N

OH

HO OH HO

OH

HO

O

OH

OH

O O

H

Isofagomine (79)

1-Deoxynojirimycin (78)

Ajulemic acid (77) H

H

H N

H

O

O O

O

Me

Me

H

H

H

H

N

Me N Me

Himbacine (80) F

SCH 53048 (81) OMe O

OMe

O

O

OMe

HO

O

HO

OMe MeO

OMe OH

O

O

DA-6034 (83)

Eupatilin (82)

Fig. 2.

(Continued )

89

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 90

Bioactive Natural Products

Brahmachari

90

R O N N O

H3 C

OH

F

O

O N

Camptothecin (84): R = H N

F

O

Karenitecin (85): R =

Si

Gimatecan (87): R =

H3 C

N

O

HO

Diflomotecan (86)

O

CH3 OH

N O

H3C

O N

F

O

(90)

N

N

N

O

O

H3C

HO

O H3C

Elomotecan (88)

OH

O

DRF 1042 (89)

CH3 CH3

O

O CH3

O

CH3 O

O

SN2310 (90)

N N O

H3C

Fig. 2.

(Continued )

OH

O

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 91

Bioactive Natural Products

Natural Products in Drug Discovery

91

R

OMe MeO

OR OR

OMe OMe

Combretastatin A-4 (91): R = OH

OMe

Combretastatin A-4 phosphate (92): R = OPO3Na2

MeO

O

H N

OMe OMe

Ombrabulin (AVE-8062) (93): R =

OH

Combretastatin A-1 (94): R = H OXi4503 (95): R = PO3Na2

H2N

O O

O OH

O

H N O

MeO

O H N

H

O

OMe

O

O

H

O O OR2

O

O

HO

OH O

O

R1

O

O

HO

O

O

O O

Paclitaxel (96): R1= CH3, R2 = H BMS-188797 (104): R1 = OCH3, R2 = H

Cabazitaxel (97) O

DHA-paclitaxel (99): R1 = CH3, R2 =

O O

O H N

O

HO

O

O

H N

O

O

O

O

O

H

H

O

O

OH

O

O

HO O

O

OH

O

O

HO O

O

O

O

O

Larotaxel (98)

Fig. 2.

Milataxel (101)

(Continued )

O

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92

N

O O

O

O

OH

O

O

O

O

H N

H

O

O

O

H

N

OH

O

O

O

O

OH

O

O

O

HO

F

O

O

O

H N

O

O

O

O

O

O

Tesetaxel (102)

Ortataxel (100)

O O

O

O

O

O

H N

OH

O

H

N

O OH

O

O HO

H O

O

N

N H

O

OH

H3CO2C

OAc

N

CH3O

H CH3

Vinblastine (105)

TPI-287 (103) F F

H N

O H H

N

O

N

CH3 OMe

N H

O OH

H3CO2C

OAc

N

CH3O

O

H CH3

MeO

CO2CH3

Noscapine (107)

Vinflunine (106)

O

O OMe

MeO

HO

OMe

OH

Curcumin (108)

Fig. 2.

(Continued )

CO2CH3

O

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93

O H N H

H

COOH

CO2CH3

H

O

HO

H

H

RTA-402 (110)

Oleanolic acid (109) O

OH

O

OH

Cl

O O

HO

O

CH3

O

HO

OH

O

OH

N

N

CH3

β-Lapachone (111)

CH3

Rohitukine (112)

Alvocidib (113)

OH R

O

O OH O

O

O

HO

HOOC

O

HO

Daidzein (114): R = H Genistein (116): R = OH

Phenoxodiol (115)

Flavone-8-acetic acid (117)

O

O OH OMe

O

HO

O O HOOC

CH3

OH

CH3

OH

O

ASA-404 (118)

Silybin (119)

Fig. 2.

(Continued )

OH

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94

OH O O O H

O

OR

MeO

MeO

OR

OR

OMe

NDGA (120): R = H Terameprocol (121): R = CH3

F

OMe

Epipodophyllotoxin (122)

F

F

O F F

F

F

F

O

O

O O

O

O O

F F

O

O O O H

MeO

O

O

OMe O P

RO HO OH

OH

O

Ingenol (124): R = H

OH O

Ingenol mebutate (125): R =

Tafluposide (123)

O O

OH

OMe

O

OMe

HO OMe O MeO

O

N N

O

O H

Me

Me

O

AcO

N

O

OAc

Acronycine (126)

S23906-1 (127)

Fig. 2.

(Continued )

Homoharringtonine (128)

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95

OH N H2 N

O

H N

N

CH3

H S O

N S

O

N

O

N

O

N O

O

O HO

O

Ceftobiprole medocaril (129) CH3 +

CH3

N

O

OH

N HO

H N

P

H N

N

H

H

H S S

N

HO S

O

N

O

N

N

S

S

O

O O

N O

O

HO

S

O

O

N

Ceftaroline acetate (130)

Tebipenem pivoxil (131)

OH H

H S O

N

H N

N

O HO

N

O

NH2

N H NH

O

Tomopenem (132) OH H

OH

H

H

O

H N

N +

S

N

N

N

O

N O

S HO

NH

O

PZ601 (133)

Fig. 3.

S

HO

O

O

ME-1036 (134)

Microorganism-derived drug evaluation.

NH2

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H

H O OH

S H

N

H

O

O S N

O

O

O

O

O HO

O

O

Faropenem daloxate (136)

Sulopenem (135) O OH O

N H

OH COOH

O

O

O

HO Cl O

O

H N

H N

O N H HN

H N

N H

CH3

O

O

N H

Cl

R HO O

O

OH

O OH

OH

O

HO

HO OH

OH

Teicoplanin analog (137): R = OH H N

Dalbavancin (138): R =

Fig. 3.

(Continued )

O

N

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Bioactive Natural Products

Natural Products in Drug Discovery R HN OH O

HO

OH OH O

H2N

O

O

HO

Cl

O

O

O

O

OH

Cl

O

O

O

H N

H N

O

H N

N H

N H HN

N H

O

O O

HO

NH2 O OH OH HO

Chloroeremomycin (139): R = H Cl

Oritavancin (140): R = OH NH 2 OH O

OH OH O

O

O

Cl

O

O

HO

OH

Cl

O

O

O

H N

H N

O HN

O

O O

O

NH2 NH

OH OH

O N H N

N

H2N S

N

O

HO H S +

N

N

O HO

O

Fig. 3.

H N

N H

N H

TD-1792 (141)

(Continued )

N H

97

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OH

OH

O

H2N O

OH H N

H N

H N

NH N H

N H

N H

O

O

HN

NH2

O

O

O

N H

O

O

O

OH

O

O

H2 N OH

O

O

OH

HN

Cl

N H

N H

N H

O

O

O

OH

H N

H N

H N

NH

O

O

O

NH2 OH

O OH O OH

OH

O

HO HO HO

Ramoplanin factor A2 (142)

O OH

N

N

O

N N

N

O

O N

O

O

N

O

O

O

O

F

HN

O H N

O O

OH

HN

HO

O O

N H N

Flopristin (143) Linopristin (144)

Fig. 3.

(Continued )

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Bioactive Natural Products

Natural Products in Drug Discovery COOH O H N H 2N

N

O

O

N H

O O

HN

O

N H

COOH

NH

HN

O

HOOC O O H N

N

O

O NH

N H O

NH2

Friulimicin (145)

NH H-Ala-Lys-Gin-Ala-Ala-Ala-Phe-Gly-Pro-Phe-Abu-Phe-Val-Ala-HOAsp-Gl y-Asn-Abu-LysOH S S S

Duramycin (Moli 901) (146) N

O

O

OH HO

OH N

H N

O

HO O

O

O

O O

O

N HO

OMe

O

O

OH

O

Erythromycin (147)

O

O

O

Cethromycin (148)

Fig. 3.

(Continued )

99

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N

N

N

N

N

O

O

N O O

O

S OMe

O

N

O

H N

HO

HO

N O

HO O

O

O

O

O

OMe

O O

EP-420 (149)

BAL-19403 (150)

N N

O

N

O

N OMe O N HO O

O

O

O

O

Telithromycin (151)

OH

OH O

HO

H O O

OMe O

O O

O

O

OH O

O

OH Cl

O O OH

OH Cl

Tiacumicin (152)

Fig. 3.

(Continued )

OH

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101

N

N H

H OH

H N CONH2

OH O

OH

OH

O

MK-2764 (153) OH H2O3PO

OMe

O

O O

HO

O

N H

H2O3PO

O O

HO N H

O O

HN OPO3H2 O

HO HO

O

O O

O O

O

HN OPO3H2 O

MeO

O O

O

O

Rs-DPLA (154)

Eritoran (155)

O O MeO

OH

OH

OH

OH

O NH

N

O OH

O

O

N

COOH

F

N

N

O N

N

CBR-2092 (156)

Fig. 3.

(Continued )

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102

NH2

HO O

H N

NH2

O

O

O

O

O

N H

OH

O

O H N

H OH N H

N H

O

O

N

NH

O

O

O O

H2N

N

N H

H N

HN

H N

H N

O

O

HO

O

NH2

WAP-829A2 (157) HO

OH

O

O

HO

N H N

O

O

HO

N H

O O

O N H

OH

HN

N

HO

NH

NH2

H N

N H

O O

O N

HO

O

NH

OH

HN O N

O

OH O

OH O

OH OH

Deoxymulundocandin (158) HO

Aminocandin (159) HO

Fig. 3.

(Continued )

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103

H N O OH OH

OH

HO OH

OH

OH

OH

O

O

R1

O

O

O

O

O

OH

Patrician A (160): R1 = OH, R2 = H N O N

R2 =

HO O

O H N

H N

R

N N

N

N

O

O

O O O

O H N

N

N

N H

N H

O

Cyclosporin (162): R =

O

O

NIM-811 (163): R =

OH N

HO

N

O H N N H

O HO

O

KRN5500 (164)

Fig. 3.

(Continued )

N H

NH N

OH

NH

R2

H N

SPK-843 (161): R1 =

OH

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O

H N

R

HO

N

HO

N

O

OH OMe

OH NHCH3

Galactonojirimycin (165): R = OH Migalastat (166): R = H

Staurosporine (167)

HO O

O

O

H N

H

H N

N

O

N N

N

N

O

O

O O N

N

O

O H N

N

N

N H

O

N H

O

O

O

N

Voclosporin (169)

Ruboxistaurin (168)

H3 C OR OH

O O OH

OH

O

O

O

CH3

O

O O O

OH

OH

HO O

OH

CH3

Pladienolide D (170): R = Ac E7107 (171): R =

O N

N

H 2N

O

CH3

MeO OH

Elsamicin A (172)

Fig. 3.

(Continued )

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Bioactive Natural Products

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105

O

OH

OH

O

OH

OMe

O

OH

OH OH

O O

O

OH

NH2

O

O O

R

HO

Doxorubicin (173): R = H

I

HO

L-Annamycin (174)

Berubicin (175): R =

O

O

OH

O

OH

OH OH

O

O

OH

OH

O

OH

O

OH

O OMe

O

O

OH

OH

O O OMe

N

O

OH O

Sabarubicin (176)

NH2 OH

Nemorubicin (177)

H H N O

H N N H N

O N

H N

O

NH2

N

Distamycin (178)

Fig. 3.

O

(Continued )

NH

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106

Br H N O

H N N H N

O N

NH H N

O

NH2

N O

NH

Brostallicin (179)

O R O

Geldanamycin (180): R = OCH3

N H O

Tanespimycin (181): R =

N H

OH MeO MeO

Alvespimycin (182): R =

N

O

N H

O NH2

OR O N

OMe

O

O

O

O HO O H + H N Cl

OH

OH O O



O MeO

MeO

N H OH OH MeO MeO O

O

O

Sirolimus (34): R = H Deforolimus (Ridaforolimus) (184): R =

NH2

Retaspimycin (183)

Fig. 3.

(Continued )

OH P OH

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Bioactive Natural Products

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O

O

H N

O

OH N

N

O O

N

O

N

CH3

O

OMe N

N Me O

Cl

N

Salinosporamide A (185)

Enzastaurin (186)

H N

O

H N

O

N

N

O

N

O

Midostaurin (187)

OH

N

OH OMe

R NHCH3

K252a (188): R = COOCH3 Lestaurtinib (KT-5555) (189): R = CH2OH

KRX-0601 (190) OMe

O

N H

N

N

HN HO

OH

N H HO

Prodigiosin (192)

Diazepinomicin (191) OMe

O S

N H

Me

N

OH

N

HN

Me

O O

Me

Obatoclax (193)

OH

O

Sagopilone (194)

Fig. 3.

(Continued )

107

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S Me

O

O

Me

O

N

O

N

OH

OH

O

O

OH

OH

KOS-1574 (196)

Epothilone (195)

O

O NH

NH

N HN

HN

O

O

NPI-2350 (Phenylahistin) (197)

NPI-2358 (Plinabulin) (198) OH

OH

OH HO

N NH

NH

HO

O

O

Irofulven (200)

Illudin S (199)

Fig. 3.

(Continued )

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109

N

N

Anabaseine (201) OMe

O

N

OMe

O

N O

O

NH

O O

OMe

N

O

O

N

N H

OH

O

O

NH O

O O

N N

Plitidepsin (203)

DMXBA (GTS-21) (202)

H

H

H

H

H O

O

O

H

OH

H

O O H

H

O

O

O

O

H

H

H

H

O

H

HO

O

O

O OH

O O

Halichondrin B (204)

Fig. 4.

Marine-derived drug candidates under clinical evaluation.

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H

H O

H O

O

HO

O O H

H

O

NH2

O

O

O

COOH

N N H

O

O

HN

N

Eribulin (205)

Hemiasterlin (206) OH Br OH O

N H N

S N H

O N

N

S

N

COOH

O

HO

N H O

Br

E7974 (207)

Psammaplin A (208)

OH

OAc HO O O O

O

O

O

HO OMe

HO

O

OH

OH H N

N H

OMe O

N H

O

CH3

O

Bryostatin 1 (210)

Panobinostat (209)

Fig. 4.

(Continued )

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111

OMe O HO Me

OMe

Me

O H

O

Me

Me

Me N

O

N

H Me

O

O Me

OH

O

N

NH

N MeO

CF3

O

O

OH OAc

Jorumycin (211)

Zalypsis (212)

N

N N O

R

N

N H

O

O

O

O

O O

N

Dolastatin 15 (213): R =

OMe O H N

Tasidotin (214): R =

H N

N N

N

N H O

R

O

OMe

O

OMe

O

Dolastatin 10 (215): R =

S

N

Soblidotin (216): R =

Fig. 4.

(Continued )

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O

H2N

O

O N H

N O H

NH

O

O

N HN

NH O O

O

NH NH

O NH

O N H HO

O

H N

O

O

NH R

Kahalalide F (217): R = O

PM02734 (218): R =

Fig. 4.

O

(Continued )

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O

113



HO +

H2 N

OH

O O

N H N H HO

OH OH

Tetrodotoxin (219)

OSO3H

H N

H N H

NH2

H H

N H

NGVCCGYKLCHOC

H OH

H

Trodusquemine (221)

Xen-2174 (220)

ILPWKWPWWPWRR-NH2 Indolicidin (222)

Fig. 5.

N H

ILRWPWWPWRRK-NH2 Omiganan (223)

Animal-derived drug candidates under clinical evaluation.

8. Concluding Remarks Natural products continue to play a dominant role in the discovery of leads for the development of drugs to treat human diseases. Such chemical agents have traditionally also played a major role in drug discovery and still constitute a prolific source of novel chemotypes or pharmacophores for medicinal chemistry. Natural product-based scaffolds find key importance in drug discovery as well as in optimizing chemical diversity

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for human use. The impact of natural products on the development pipelines of the pharmaceutical industry is unabated. Despite increasing competition from combinatorial and classical compound libraries, there has been a steady introduction of natural product-derived drugs in the past years. Substances like taxol, cyclosporines and the “statins” are cornerstones of modern pharmacotherapy. We should think of the real scenario that the vast majority of different natural sources remain virtually untapped. It is estimated that only 5–15% of the approximately 250 000 species of higher plants (terrestrial flora) have been investigated chemically and pharmacologically so far; hence, the large areas of tropical rainforests demands for thorough investigation that would unearth tremendous potential at large. The marine kingdom stands as an enormous resource for the discovery of potential chemotherapeutics, and is waiting for its proper exploration. Another vast unexplored area is the microbial world; it has been reported that “less than 1% of bacterial species and less than 5% of fungal species are currently known, and recent evidences indicate that millions of microbial species remain undiscovered. “Mother Nature” is thus, an inexhaustible source of drugs and lead molecules. The abundant scaffold diversity in natural products is coupled with “purposeful design” — usually to afford an advantage for survival in environments threatening growth and/or survival of producer organism. The quality of leads arising from natural product discovery is better and often more biologically friendly, due to their co-evolution with the target sites in biological systems. Natural products, thus, still serve as an excellent source for modern drug discovery and development. The traditional strengths of natural products in oncology and infectious diseases are still ahead from the compounds under clinical trials against metabolic and other diseases. Through a medicinal chemistry approach, natural products with low bioactivity or known compounds can be modified synthetically to improve their pharmacological profiles. A good number of commercially approved drugs originated from natural products as well as the huge number of natural product-derived compounds in various stages of clinical development indicate that the use of natural product templates is still a viable source of new drug candidates.

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115

Acknowledgements Fruitful and valuable works of numerous researchers worldwide, upon which the present manuscript is based, are being acknowledged herein. The author is grateful to all of them regardless their names are enlisted in the reference section or not.

Abbreviations AChE AD ADHD ADMET AECB AIDS BBB CAM CAP CDAD CDKN1A CDRI CF CGRP CIMAP CKD COPD cSSSIs DNA DTI EMEA ERT FAAH FAH FDA

acetylcholinesterase Alzheimer’s disease attention deficit hyperactivity disorder absorption, distribution, metabolism, excretion, and toxicity acute exacerbations of chronic bronchitis acquired immune deficiency syndrome blood–brain barrier complementary and alternative medicine community-acquired pneumonia Clostridium difficile-associated diarrhea cyclin-dependent kinase inhibitor 1A Central Drug Research Institute cystic fibrosis calcitonin gene-related peptide Central Institute of Medicinal and Aromatic Plants chronic kidney disease chronic obstructive pulmonary disease complicated skin and skin structure infections deoxyribose nucleic acid direct thrombin inhibitor European Medicines Agency enzyme replacement therapy fatty acid amide hydrolase fumaryl acetoacetate hydrolase Food and Drug Administration (USA)

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GLP-1 HAP HCT HCV HDAC HDL-C HIF-1 HIV HMG-CoA HPPD HT-1 IMPDH IND LDL-C MAA MetAP-2 mTOR NCI NDA NET NF-AT NSAID OC OIC PD PGE2 PPAR PTP-1B QSAR RCC RNA S6K1 SEGA SGLT SRT STS

glucagon-like peptide-1 hospital-acquired pneumonia human colon cancer hepatitis C virus histone deacetylase high-density lipoprotein-cholesterol hypoxia-inducible factor human immunodeficiency virus 3-hydroxy-3-methylglutaryl coenzyme A p-hydroxyphenylpyruvate dioxygenase hereditary tyrosinemia type 1 inosine monophosphate dehydrogenase investigational new drug low-density lipoprotein-cholesterol marketing authorization application methionine aminopeptidase-2 mammalian target of rapamycin National Cancer Institute (USA) new drug application (USA) neuroendocrine tumor nuclear factor of activated T cells non-steroidal anti-inflammatory drug ovarian cancer opioid-induced constipation Parkinson’s disease prostaglandin E2 peroxisome proliferator-activated receptor protein tyrosine phosphatase 1B quantitative structure–activity relationship renal cell carcinoma ribose nucleic acid S6 ribosomal protein kinase subependymal giant cell astrocytoma sodium glucose co-transporter substrate reduction therapy soft tissue sarcoma

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TCL tNOX VEGF VR 1 WHO

117

T-cell lymphoma NADH oxidase vascular endothelial growth factor vanilloid receptor subtype 1 World Health Organization

References 1. Brahmachari G. (2009) Mother nature — an inxahaustible source of drugs and lead molecules. In: Brahmachari G. (ed), Natural Products: Chemistry, Biochemistry and Pharmacology, pp. 1–20, Narosa Publishing House, New Delhi, India. 2. Farnsworth NR, Akerele O, Bingel AS, Soejarto DD, Guo Z. (1985) Can variola-like viruses be derived from monkeypox virus? An investigation based on DNA mapping. Bull WHO 63: 695–981. 3. Yong P. (1997) Major microbial diversity initiative recommended. ASM News 63: 417–421. 4. Cragg GM, Newman DJ. (2001) Medicinals for the millennia: The historical record. Ann NY Acad Sci 953: 3–25. 5. Brahmachari G. (2006) Prospects of natural products research in the 21st century: A sketch. In: Brahmachari G. (ed), Chemistry of Natural Products: Recent Trends and Developments, pp. 1–22, Research Signpost, Trivandrum, India. 6. Samuelsson G. (2004) Drugs of Natural Origin: A Textbook of Pharmacognosy, 5th ed, Swedish Pharmaceutical Press, Stockholm. 7. Kinghorn AD. (2001) Pharmacognosy in the 21st century. J Pharm Pharmacol 53: 135–148. 8. Newman DJ, Cragg GM, Snader KM. (2000) The influence of natural products upon drug discovery. Nat Prod Rep 17: 215–234. 9. Butler MS. (2004) The role of natural product chemistry in drug discovery. J Nat Prod 67: 2141–2153. 10. Jachak SM, Saklani A. (2007) Challenges and opportunities in drug discovery from plants. Curr Sci 92: 1251–1257. 11. Cragg GM, Boyd M. (1996) Drug discovery and development at the National Cancer Institute: The role of natural products of plant origin. In: Balick MJ, Elisabetsky E, Laird SA. (eds), Medicinal Plant Resources of the Tropical Forest, pp. 101–136, Columbia University Press, New York.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

118

Page 118

Bioactive Natural Products

Brahmachari

12. Cragg GM, Schepartz SA, Suffness M, Grever MR. (1993) The taxol supply crisis. New NCI policies for handling the largescale production of novel natural product anticancer and anti-HIV agents. J Nat Prod 56: 1657–1668. 13. Firn RD, Jones CG. (2003) Natural products — a simple model to explain chemical diversity. Nat Prod Rep 20: 382–391. 14. Baker JT, Borris RP, Carté B, Cordell GA, Soejarto DD, Cragg GM, Gupta MP, Iwu MM, Madulid DR, Tyler VE. (1995) Natural products drug discovery and development: New perspectives on international collaboration. J Nat Prod 58: 1325–1357. 15. Barron RL, Vanscoy GJ. (1993) Natural products and the athlete: Facts and folklore. Ann Pharmacother 27: 607–615. 16. Chan K. (1995) Progress in traditional Chinese medicine. Trends Pharmacol Sci 16: 182–187. 17. Koh H, Woo S. (2000) Chinese proprietary medicine in Singapore: Regulatory control of toxic heavy metals and undeclared drugs. Drug Safety 23: 351–362. 18. Kaul PN, Joshi BS. (2001) Alternative medicine: Herbal drugs and their critical appraisal — part II. Prog Drug Res 57: 1–75. 19. Kroll DJ. (2001) Concerns and needs for research in herbal supplement pharmacotherapy and safety. J Herbal Pharmacother 1: 3–23. 20. Marriott BM. (2001) The role of dietary supplements in health. An overview in the United States. Adv Exper Med Biol 492: 203–217. 21. Bhattaram VA, Graefe U, Kohlert C, Veit M, Derendorf H. (2002) Pharmacokinetics and bioavailability of herbal medicinal products. Phytomedicine 9: 1–23. 22. Holt GA, Chandra A. (2002) Herbs in the modern healthcare environment — an overview of uses, legalities, and the role of the healthcare professional. Clin Res Regul Aff 19: 83–107. 23. Dev S. (2010) Impact of natural products in modern drug development. Indian J Exp Biol 48: 191–198. 24. Patwardhan B, Vaidya ADB. (2010) Natural product drug discovery: Accelerating the clinical candidate development using reverse pharmacology approaches. Indian J Exp Biol 48: 220–227. 25. Harvey AL. (1999) Medicines from nature: Are natural products still relevant to drug discovery? Trends Pharmacol Sci 20: 196–198. 26. Holland BK. (1994) Prospecting for drugs in ancient texts. Nature 369: 702.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 119

Bioactive Natural Products

Natural Products in Drug Discovery

119

27. Baker DD, Chu M, Oza U, Rajgarhia V. (2007) The value of natural products to future pharmaceutical discovery. Nat Prod Rep 24: 1225–1244. 28. Beghyn T, Deprez-Poulain R, Willand N, Folleas B, Deprez B. (2008) Natural compounds: Leads or ideas? Bioinspired molecules for drug discovery. Chem Biol Drug Des 72: 3–15. 29. Briskin DP. (2000) Medicinal chemicals and phytomedicines. Linking plant biochemistry and physiology to human health. Plant Physiol 124: 507–514. 30. Koehn FE, Carter GT. (2005) The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4: 206–220. 31. Cooper EL. (2004) Commentary on: Traditional and modern biomedical prospecting: Part II — the benefits by Müller WEG, Schröder HC, Wiens M, Perovic´-Ottstadt S, Batel R, Müller IM. Anti-protozoa and antiviral activities of non-cytotoxic truncated and variant analogues of mussel defensin by Roch P, Beschin A, Bernard E. Evid Based Complement Alternat Med 1: 207–209. 32. Patwardhan B, Vaidya ADB, Chorghade M. (2004) Ayurveda and natural products drug discovery. Curr Sci 86: 789–799. 33. Chang HM, But PPH. (1986) Pharmacology and Applications of Chinese Materia Medica. World Scientific Publishing, Singapore. 34. Dev S. (1999) Ancient–Modern concordance in Ayurvedic plants: Some examples. Environ Health Perspect 107: 783–789. 35. Kapoor LD. (1990) CRC Handbook of Ayurvedic Medicinal Plants. CRC Press, Boca Raton, FL. 36. Schultes RE, Raffauf RF. (1990) The Healing Forest. Dioscorides Press, Portland, OR. 37. Farnsworth NR, Akerele AS, Bingel AS, Soejarto DD, Guo Z. (1985) Medicinal Plants in therapy. Bull WHO 63: 965–981. 38. Arvigo R, Balick M. (1993) Rainforest Remedies. Lotus Press, Twin Lakes, WI. 39. De Smet PAGM. (2004) Health risks of herbal remedies: An update. Clin Pharmacol Ther 76: 1–17. 40. Barnes J. (2003) Pharmacovigilance in herbal medicines. A UK perspective. Drug Safety 26: 829–851. 41. Wessjohann LA, Ruijter E, Garcia-Rivera D, Brandt W. (2005) What can a chemist learn from nature’s macrocycles? — a brief, conceptual view. Mol Divers 9: 171–186.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

120

Page 120

Bioactive Natural Products

Brahmachari

42. Newman DJ. (2008) Natural products as leads to potential drugs: An old process or the new hope for drug discovery? J Med Chem 51: 2589–2599. 43. Kong D-X, Li X-J, Zhang H-Y. (2008) Where is the hope for drug discovery? Let history tell the future. Drug Discov Today 14: 115–119. 44. Desai MC, Chackalamannil S. (2008) Rediscovering the role of natural products in drug discovery. Curr Opin Drug Discov Devel 11: 436–437. 45. Cooper EL. (2004) Complementary and alternative medicine, when rigorous, can be science. Evid Based Complement Alternat Med 1: 1–4. 46. Gao XM. (2004) Advanced Traditional Chinese Medicine Series/Chinese Materia Medica (Volume 1). People’s Medical Publishing House, Beijing, China. 47. Lam KS. (2007) New aspects of natural products in drug discovery. Trends in Microbiol 15: 279–289. 48. Butler MS. (2005) Natural products to drug: Natural product-derived compounds in clinical trials. Nat Prod Rep 22: 162–195. 49. Ji HF, Li XJ, Zhang HY. (2009) Natural products and drug discovery: Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO Reports 10: 194–200. 50. Davies J. (1999) In praise of antibiotics. ASM News 65: 304–310. 51. Newman DJ, Cragg GM. (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70: 461–477. 52. Newman DJ, Cragg GM, Snader KM. (2003) Natural products as sources of new drugs over the period 1981–2002. J Nat Prod 66: 1022–1037. 53. Paterson I, Anderson EA. (2005) The renaissance of natural products as drug candidates. Science 310: 451–453. 54. Balunas MJ, Kinghorn AD. (2005) Drug discovery from medicinal plants. Life Sci 78: 431–441. 55. Jones WP, Chin Y-W, Kinghorn AD. (2006) The role of pharmacognosy in modern medicine and pharmacy. Curr Drug Targets 7: 247–264. 56. Hung DT, Jamison TF, Schrieber SL. (1996) Understanding and controlling the cell cycle with natural products. Chem Biol 3: 623–639. 57. Chin Y-W, Balunas MJ, Chai HB, Kinghorn AD. (2006) Drug discovery from natural sources. AAPS J 8: E239–E253. 58. Gansesan A. (2008) The impact of natural products upon modern drug discovery. Curr Opin Chem Biol 12: 306–317.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 121

Bioactive Natural Products

Natural Products in Drug Discovery

121

59. Harvey AL. (2001) Natural Product Pharmaceuticals: A Diverse Approach to Drug Discovery, Scrip Reports. PJB Publications. 60. Rishton GM. (2008) Natural products as a robust source of new drugs and drug leads: Past successes and present day issues. Am J Cardiol 101: 43D–49D. 61. Shu YZ. (1998) Recent natural products based drug development: A pharmaceutical industry perspective. J Nat Prod 61: 1053–1071. 62. Butler MS, Buss AD. (2006) Natural products — the future scaffolds for novel antibiotics. Biochem Pharmacol 71: 919–929. 63. Ma X, Wang Z. (2009) Anticancer drug discovery in the future: An evolutionary perspective. Drug Discov Today 14: 1136–1142. 64. Monneret C. (2010) Current impact of natural products in the discovery of anticancer drugs. Ann Pharm Fr 68: 218–232. 65. Butler MS, Newman DJ. (2008) Mother nature’s gifts to diseases of man: The impact of natural products on anti-infective, anticholestemics and anticancer drug discovery. Prog Drug Res 65: 3–44. 66. Cragg GM, Grothaus PG, Newman DJ. (2009) Impact of natural products on developing new anti-cancer agents. Chem Rev 109: 3012–3014. 67. Bailly C. (2009) Ready for a comeback of natural products in oncology. Biochem Pharmacol 77: 1447–1457. 68. Kingson DGI. (2008) A natural love of natural products. J Org Chem 73: 3975–3984. 69. Pace NR. (1997) A molecular view of microbial diversity and the biosphere. Science 276: 734–738. 70. Molinski TF, Dalisay DS, Lievens SL, Saludes JP. (2009) Drug development from marine natural products. Nat Rev Drug Discov 8: 69–85. 71. Glaser V. (2008) An interview with David Newman. Assay Drug Develop Technol 6: 1–7. 72. Butler MS. (2008) Natural products to drug: Natural product-derived compounds in clinical trials. Nat Prod Rep 25: 475–516. 73. Frenz JL, Kohl AC, Kerr RG. (2004) Marine natural products as therapeutic agents: Part 2. Expert Opin Ther Patents 14: 17–33. 74. Kerr RG, Kerr SS. (1999) Marine natural products as therapeutic agents. Expert Opin Ther Patents 9: 1207–1222. 75. Newman DJ, Cragg GM. (2004) Marine natural products and related compounds in clinical and advanced clinical trials. J Nat Prod 67: 1216–1238.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

122

Page 122

Bioactive Natural Products

Brahmachari

76. Newman DJ, Cragg GM. (2004) Advanced preclinical and clinical trials of natural products and related compounds from marine sources. Curr Med Chem, 11: 1693–1713. 77. Schwartsmann G, Da Rocha AB, Mattei J, Lopes R. (2003) Marine-derived anticancer agents in clinical trials. Expert Opin Invest Drugs 12: 1367–1383. 78. Haefner B. (2003) Drugs from the deep: Marine natural products as drug candidates. Drug Discov Today 8: 536–544. 79. Fenical W. (2006) Marine pharmaceuticals. Past, present, future. Oceanography 219: 109–111. 80. van Kesteren Ch, de Vooght MM, López-Lázaro L, Mathôt RA, Schellens JH, Jimeno JM, Beijnen JH. (2003) Yondelis (trabectedin, ET-743): The development of an anticancer agent of marine origin. Anticancer Drugs 14: 487–502. 81. Nakanishi K. (1999) An historical perspective of natural products chemistry. In: Ushio S. (ed), Comprehensive Natural Products Chemistry, 1: p. 23, Elsevier Science BV, Amsterdam. 82. Cragg GM, Newman DJ. (2001) Natural product drug discovery in the next millennium. Pharm Biol 39: 8–17. 83. Barron RL, Vanscoy GJ. (1993) Natural products and the athlete: Facts and folklore. Ann Pharmacother 27: 607–615. 84. Kaul PN, Joshi BS. (2001) Alternative medicine: Herbal drugs and their critical appraisal. Prog Drug Res 57: 1–75. 85. Patwardhan B, Hooper M. (1992) Ayurveda and future drug development. Int J Altern Complement Med 10: 9–11. 86. Buss AD, Cox B, Waigh RD. (2003) Drug discovery. In: Abraham DJ. (ed), Burger’s Medicinal Chemistry and Drug Discovery, Vol. 1, Chapter 20, pp. 847–900, Wiley, Hoboken, NJ. 87. Grabley S, Thiericke R. (2000) In: Grabley S, Thiericke R. (eds), Drug Discovery from Nature, Chapter 1, pp. 3–37, Springer, Berlin. 87. Sneader W. (1996) Drug Prototypes and their Exploitation, Wiley, Chichester, UK. 88. Mann J. (2000) Murder, Magic and Medicine, 2nd ed, Oxford University Press, Oxford, UK. 89. Henkel T, Brunne RM, Muller H, Reichel F. (1999) Statistical investigation into the structural complementarity of natural products and synthetic compounds. Angew Chem Int Ed 38: 643–647.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 123

Bioactive Natural Products

Natural Products in Drug Discovery

123

90. Feher M, Schmidt JM. (2003) Property distributions: Differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci 43: 218–227. 91. Burke MD, Berger EM, Schreiber SL. (2003) Generating diverse skeletons of small molecules combinatorially. Science 302: 613–618. 92. Lee ML, Schneider GJ. (2001) Scaffold architecture and pharmacophoric properties of natural products and trade drugs: Application in the design of natural product-based combinatorial libraries. Comb Chem 3: 284–289. 93. Harvey A. (2000) Strategies for discovering drugs from previously unexplored natural products. Drug Discov Today 5: 294–300. 94. Piggott AM, Karuso P. (2004) Quality, not quantity: The role of natural products and chemical proteomics in modern drug discovery. Comb Chem High Throughput Screen 7: 607–630. 95. Pommier Y, Cherfils J. (2005) Interfacial inhibition of macromolecular interactions: Nature’s paradigm for drug discovery. Trends Pharmacol Sci 26: 138–145. 96. Ertl P, Roggo S, Schuffenhauer A. (2008) Natural product-likeness score and its application for prioritization of compound libraries. J Chem Inf Model 48: 68–74. 97. Vuorelaa P, Leinonenb M, Saikkuc P, Tammelaa P, Rauhad JP, Wennberge T, Vuorela H. (2004) Natural products in the process of finding new drug candidates. Curr Med Chem 11: 1375–1389. 98. Hinterding K, Alonso-Diaz D, Waldman H. (1998) Organic synthesis and biological signal transduction. Angew Chem Int Ed 37: 688–749. 99. Garret MB, Workmann P. (1999) Discovering novel chemotherapeutic drugs for the third millennium. Eur J Cancer 35: 2010–2030. 100. Barry CE, Slayden RA, Sampson AE, Lee RE. (2000) Use of genomics and combinatorial chemistry in the development of new antimycobacterial drugs. Biochem Pharmacol 59: 221–231. 101. Lenz GR, Hash HM, Jindal S. (2000) Chemical ligands, genomics and drug discovery. Drug Discov Today 5: 145–156. 102. Razvi ES, Leytes LJ. (2000) High-throughput genomics. Mod Drug Discov 3: 40–45. 103. Rosamond J, Allsop A. (2000) Harnessing the power of the genome in the search for new antibiotics. Science 287: 1973–1976.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

124

Page 124

Bioactive Natural Products

Brahmachari

104. Silverman L, Campbell R, Broach JR. (1998) New assay technologies for high-throughput screening. Curr Opin Chem Biol 2: 397–403. 105. Stahura F, Godden JW, Xue L, Bajorath J. (2000) Distinguishing between natural products and synthetic molecules by descriptor Shannon entropy analysis and binary QSAR calculations. J Chem Inf Comput Sci 40: 1245–1252. 106. Wessjohann LA. (2000) Synthesis of natural-product-based compound libraries. Curr Opin Chem Biol 4: 303–309. 107. Abreu PM, Branco PS. (2003) Natural product-like combinatorial libraries. J Braz Chem Soc 14: 675–712. 108. Rouhi AM. (2003) Moving beyond natural products. Chem Eng News 13: 104–107. 109. Breinbauer RP, Vetter IR, Waldmann H. (2002) From protein domains to drug candidates — natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed 41: 2878–2890. 110. Kingston DGI, Newman DJ. (2002) Mother’s nature combinatorial libraries: Their influence on the synthesis of drugs. Curr Opin Drug Discovery Dev 5: 304–316. 111. Hall DG, Manku S, Wang F. (2001) Solution- and solid-phase strategies for the design, synthesis, and screening of libraries based on natural product templates: A comprehensive survey. J Comb Chem 3: 125–150. 112. Horton DA, Bourne GT, Smythe ML. (2003) The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem Rev 103: 893–890. 113. Ortholand J-Y, Ganesan A. (2004) Natural products and combinatorial chemistry: Back to the future. Curr Opin Chem Biol 8: 271–280. 114. Schultes RE, Raffauf RF. (1990) The Healing Forest. Dioscorides Press, Portland, OR. 115. Ayensu ES. (1981) Medicinal Plants of the West Indies. Reference Publications, Algonac, MI. 116. Jain SK. (1991) Medicinal Plants of India. Reference Publications, Algonac, MI. 117. Iwu MM. (1993) Handbook of African Medicinal Plants. CRC Press, Boca Raton, FL. 118. Gupta MP. (1995) 270 Plantas Medicinales Iberoamericans. CYTED, Bogota, Colombia.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 125

Bioactive Natural Products

Natural Products in Drug Discovery

125

119. Kim J, Park EJ. (2002) Cytotoxic anticancer candidates from natural resources. Curr Med Chem Anti-Canc Agents 2: 485–537. 120. Patwardhan B. (2000) Ayurdeva: The ‘Designer’ medicine: A review of ethnopharmacology and bioprospecting research. Indian Drugs 37: 213–227. 121. Seamon KB, Padgett W, Daly JW. (1981) Forskolin: Unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci USA 78: 3363–3367. 122. Das B, Tandon V, Lyndem LM, Gray AI, Ferro VA. (2009) Phytochemicals from Flemingia Vestia (Fabaceae) and Stephania Glabra (Menispermeaceae) alter cGMP concentration in the cestode Raillietina Echinobothrida. Comp Biochem Physiol C Toxicol Pharmacol 149: 397–403. 123. Birari RB, Bhutani KK. (2007) Pancreatic lipase inhibitors from natural sources: Unexplored potential. Drug Dicov Today 12: 879–889. 124. Gautam R, Jachak SM. (2009) Recent developments in anti-inflammatory natural products. Med Res Rev 29: 767–820. 125. Berdy J. (2005) Bioactive microbial metabolites. A personal view. J Antibiot 58: 1–26. 126. Demain AL, Sanchez S. (2009) Microbial drug discovery: 80 years of progress. J Antibiot 62: 5–16. 127. Brown AG, Smale TC, King TJ, Hasenkamp R, Thompson RH. (1976) Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium Brevicompactum. J Chem Soc, Perkin Trans 1: 1165–1170. 128. Endo A. (1985) Compactin (ML-236B) and related compounds as potential cholesterol-lowering agents that inhibit HMG-CoA reductase. J Med Chem 28: 401–405. 129. Endo A, Kuroda M, Tanzawa K. (1976) Competitive inhibition of 3-hydroxy3methylglutaryl coenzyme A reductase by ML236A and ML236B, fungal metabolites having hypocholesterolemic activity. FEBS Lett 72: 323–326. 130. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J. (1980) Mevinolin: A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77: 3957–3961.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

126

Page 126

Bioactive Natural Products

Brahmachari

131. Alekshun MN. (2005) New advances in antibiotic development and discovery. Expert Opin Investig Drugs 14: 117–134. 132. Appelbaum PC, Jacobs MR. (2005) Recently approved and investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria. Curr Opin Microbiol 8: 510–517. 133. Rogers BL. (2004) Bacterial targets to antimicrobial leads and development candidates. Curr Opin Drug Discov Dev 7: 211–222. 134. Bush K, Macielag M, Weidner-Wella M. (2004) Taking inventory: Antibacterial agents currently at or beyond phase 1. Curr Opin Microbiol 7: 466–476. 135. Hay ME. (1996) Marine chemical ecology: What’s known and what’s next? J Exp Mar Biol Ecol 200: 103–134. 136. Chang C. (1999) Looking back on the discovery of alpha-bungarotoxin. J Biomed Sci 6: 368–375. 137. Chu N. (2005) Contribution of a snake venom toxin to myasthenia gravis: The discovery of alpha-bungarotoxin in Taiwan. J Hist Neurosci 14: 138–148. 138. Noguchi T, Hwang DF, Arakawa O, Sugita H, Deguchi Y, Shida Y, Hashimoto K. (1987) Alginolyticus, a tetrodotoxin-producing bacterium, in the intestines of the fish Fugu Vermicularis. Marine Biology 94: 625–630. 139. Hwang DF, Noguchi T. (2007) Tetrodotoxin poisoning. Adv Food Nutr Res 52: 141–236. 140. Hwang DF, Tai KP, Chueh CH, Lin LC, Jeng SS. (1991) Tetrodotoxin and derivatives in several species of the gastropod Naticidae. Toxicon 29: 1019–1024. 141. Hwang DF, Arakawa O, Saito T, Noguchi T, Simidu U, Tsukamoto K, Shida Y, Hashimoto K. (1988) Tetrodotoxin-producing bacteria from the blue-ringed octopus Octopus Maculosus. Marine Biology 100: 327–332. 142. Thuesen EV, Kogure K. (1989) Bacterial production of tetrodotoxin in four species of Chaetognatha. Biol Bull 176: 191–194. 143. Carroll S, McEvoy EG, Gibson R. (2003) The production of tetrodotoxinlike substances by nemertean worms in conjunction with bacteria. J Exp Mar Biol Ecol 288: 51–63. 144. Niarchos AP, Pickering TG, Wallace JM, Case DB, Laragh JH. (1980) Hemodynamic effects of the converting enzyme inhibitor teprotide in normal- and high-renin hypertension. Clin Pharmacol Ther 28: 592–601.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 127

Bioactive Natural Products

Natural Products in Drug Discovery

127

145. Doyle MP. (2007) Food Microbiology: Fundamentals and Frontiers. ASM Press. 146. Harvey AL. (2008) Natural products in drug discovery. Drug Discov Today 13: 894–901. 147. Grifo F, Newman D, Fairfield A, Bhattacharya B, Grupenhoff J. (1997) The origins of prescription drugs. In: Grifo F, Rosenthal J. (eds), Biodiversity and Human Health, pp. 131–163, Island Press, Washington, DC. 148. Thayer A. (2003) Bristol-Myers to settle suits. Chem Eng News 81: 6. 149. Oberlies NH, Kroll DJ. (2004) Camptothecin and taxol: Historic achievements in natural products research. J Nat Prod 67:129–135. 150. Singh SB, Barrett JF. (2006) Empirical antibacterial drug discovery — foundation in natural products. Biochem Pharmacol 71: 1006–1015. 151. Dickson M, Gagnon JP. (2004) Key factors in the rising cost of new drug discovery and development. Nat Rev Drug Discov 3: 417–429. 152. Salvatella X, Giralt E. (2003) NMR-based methods and strategies for drug discovery. Chem Soc Rev 32: 365–372. 153. Homans SW. (2004) NMR spectroscopy tools for structure-aided drug design. Angew Chem Int Ed 43: 290–300. 154. Anderson AC. (2003) The process of structure-based drug design. Chem Biol 10: 787–797. 155. Jain AN. (2004) Virtual screening in lead discovery and optimization. Curr Opin Drug Discov Dev 7: 396–403. 156. Balkenhohl F, von dem Bussche-Hünnefeld C, Lansky A, Zechel C. (1996) Combinatorial synthesis of small molecules. Angew Chem, Int Ed Engl 35: 2288–2337. 157. Lee A, Breitenbucher JG. (2003) The impact of combinatorial chemistry on drug discovery. Curr Opin Drug Discov Dev 6: 494–508. 158. Young SS, Ge N. (2004) Design of diversity and focused combinatorial libraries in drug discovery. Curr Opin Drug Discov Dev 7: 318–324. 159. Sanchez-Martin RM, Mittoo S, Bradley M. (2004) The Impact of Combinatorial Methodologies on Medicinal Chemistry. Curr Top Med Chem (Hilversum, Neth) 4: 653–669. 160. Rouchi AM. (2003) Rediscovering natural products. Chem Eng News 81: 77–91. 161. Rouchi AM. (2003) Betting on natural products for cures. Chem Eng News 81: 93–103.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

128

Page 128

Bioactive Natural Products

Brahmachari

162. Cordell GA. (2002) Natural Products in Drug Discovery — creating a new vision. Phytochem Rev 1: 261–273. 163. Okuda T. (2002) Trends in Natural Product-Based Drug Discovery, and Roles of Biotech Ventures and Biological Resource Centers. Vol. 35, WFCC Newsletter. (http://www.wfcc.info/NEWSLETTER/newsletter35/a4.pdf). 164. Strohl WR. (2000) The role of natural products in modern drug discovery. Drug Discov Today 5: 39–41. 165. Marris E. (2006) Marine natural products — drugs from the deep. Nature 443: 904–905. 166. Bibb MJ. (2005) Regulation of secondary metabolism in streptomycetes. Curr Opin Microbiol 8: 208–215. 167. Cundliffe E. (2006) Antibiotic production by actinomycetes: The Janus faces of regulation. J Ind Microbiol Biotechnol 33: 500–506. 168. Kiefer W, Dannhardt G. (2004) Novel insights and therapeutical applications in the field of inhibitors of COX-2. Curr Med Chem 11: 3147–3161. 169. Gullo VP, McAlpine J, Lam KS, Baker D, Petersen F. (2006) Drug discovery from natural products. J Ind Microbiol Biotechnol 33: 523–531. 170. Lee K-H. (2010) Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J Nat Prod 73: 500–516. 171. Ziffer H, Highet RJ, Klayman DL. (1997) An endoperoxidic antimalarial from Artemisia Annua L. In: Herz W, Kirby GW, Moore RE, Steglich W. (eds), Progress in the Chemistry of Organic Natural Products, pp. 121–202, Spinger-Verlag, Wien. 172. van Agtmael MA, Eggelte TA, van Boxtel CJ. (1999) Artemisinin drugs in the treatment of malaria: From medicinal herb to registered medication. Trends Pharmacol Sci 20: 199–205. 173. Graul AI. (2001) The year’s new drugs. Drug News Perspect 14: 12–31. 174. Hsu E. (2006) The history of Qinghao in the Chinese materia medica. Trans R Soc Trop Med Hygiene 100: 505–508. 175. Gaudilliere B, Bernardelli P, Berna P. (2001) To Market, to Market-2000. In: Doherty AM. (ed), Annual Reports in Medicinal Chemistry, Chapter 28, Vol. 36, pp. 293–318, Academic Press, Amsterdam. 176. Yeates RA. (2002) Artemotil (Artecef). Curr Opin Investig Drugs 3: 545–549. 177. Barradell LB, Fitton A. (1995) Artesuanate — a review of its pharmacology and therapeutic efficacy in the treatment of malaria. Drugs 50: 714–741.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 129

Bioactive Natural Products

Natural Products in Drug Discovery

129

178. White NJ, Pongtavornpinyo W. (2003) The de-novo selection of drug resistance in malaria parasites. Philos Trans R Soc Lond B Biol Sci 270: 545–554. 179. http://www.cdriindia.org/Arteether.htm (accessed on 14.12.2010). 180. Graul AI. (2002) The Year’s New Drugs. Drug News & Perspect 15: 29–43. 181. Bernardelli P, Gaudilliere B, Vergne F. (2002) To Market, to Market-2001. In: Doherty AM. (ed), Annual Reports in Medicinal Chemistry, Chapter 26, Vol. 37, pp. 257–277, Academic Press, Amsterdam. 182. Keating G, Figgitt D. (2003) Caspofungin: A review of its use in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis. Drugs 63: 2235–2263. 183. Letscher-Bru V, Herbrecht R. (2003) Caspofungin: The first representative of a new antifungal class. J Antimicrob Chemother 51: 513–521. 184. McCormack PL, Perry CM. (2005) Caspofungin A: Review of its use in the treatment of fungal infections. Drugs 65: 2049–2068. 185. Kartsonis NA, Nielsen J, Douglas CM. (2003) Caspofungin: The first in a new class of antifungal agents. DrugResist Update 6: 197–218. 186. Jarvis B, Friggitt DP, Scott LJ. (2004) Micafungin. Drugs 64: 969–982. 187. Shah PM, Issaca RD. (2003) Ertapenem, the first of a new group of carbapenem. J Antimicrob Chemother 52: 538–542. 188. Livermore DM, Sefton AM, Scott GM. (2003) Properties and potential of 274 ertapenem. J Antimicrob Chemother 52: 331–344. 189. Hammond ML. (2004) Ertapenem: A Group 1 carbapenem with distinct antibacterial and pharmacological properties. J Antimicrob. Chemother 53: ii7–9. 190. Sader HS, Gales AC. (2001) Emerging strategies in infectious diseases: New carbapenem and trinem antibacterial agents. Drugs 61: 553–564. 191. Kahan JS, Kahan FM, Goegelman R, Currie SA, Jackson M, Stapley EO, Miller TW, Miller AK, Hendlin D, Mochales S, Hernandez S, Woodruff HB, Birnbaum J. (1979) Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties. J Antibiot 32: 1–12. 192. Livermore DM, Mushtaq S, Warner M. (2005) Selectivity of ertapenem for Pseudomonas Aeruginosa mutants cross-resistant to other carbapenems. J Antimicrob Chemother 55: 306–311. 193. Gesser RM, Carrol KA, Teppler H. (2003) Efficacy of ertapenem in the treatment of serious infections caused by Enterobacteriaceae: Analysis of pooled clinical trial data. J Antimicrob Chemother 51: 1253–1260.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

130

Page 130

Bioactive Natural Products

Brahmachari

194. Bassetti M, Righi E, Fasce R, Molinari MP, Rosso R, Di Biagio A, Mussap M, Pallavicini FB, Viscoli C. (2007) Efficacy of Ertapenem in the treatment of early ventilator-associated pneumonia caused by extended-spectrum betalactamase-producing organisms in an intensive care unit. J Antimicrob Chemother 60: 433–435. 195. Parakh A, Krishnamurthy S, Bhattacharya M. (2009) Ertapenem. Kathmandu Univ Med J 7: 454–460. 196. Nix DE, Majumdar AK, DiNubile MJ. (2004) Pharmacokinetics and pharmacodynamics of ertapenem: An overview for clinicians. J Antimicrob Chemother 53: 23–28. 197. Teppler H, Gesser RM, Friedland IR, Woods GL, Meibohm A, Herman G, Mistry G, Isaacs R. (2004) Safety and tolerability of ertapenem. J Antimicrob Chemother 53: 75–81. 198. Wellington K, Curran MP. (2005) Spotlight on cefditoren pivoxil in bacterial infections. Treat Respir Med 4: 149–152. 199. Darkes MJM, Plosker GL. (2002) Cefditoren pivoxil. Drugs 62: 319–336. 200. Fuchs T. (2007) Case Study: Cefditoren pivoxil: An oral prodrug of cefditoren. In: Stella VJ, Borchardt RT, Hageman MJ, Oliyai R, Maag H, Tilley JW. (eds), Prodrugs: Challenges and Rewards, Part 1 & 2, pp. 486–495, Springer, USA. 201. Catchpole CR, Wise R, Thornber D, Andrews JM. (1992) In vitro activity of L-627, a new carbapenem. Antimicrob Agents Chemother 36: 1928–1934. 202. Malanoski GJ, Collins L, Wennersten C, Moellering R, Jr, Eliopoulos GM. (1993) In vitro activity of biapenem against clinical isolates of grampositive and gram-negative bacteria. Antimicrob Agents Chemother 37: 2009–2016. 203. Chen HY, Livermore DM. (1994) In vitro activity of biapenem, compared with imipenem and meropenem, against Pseudomonas Aeruginosa strains and mutants with known resistance mechanisms. J Antimicrob Chemother 33: 949–958. 204. Aldridge KE, Morice N, Schiro DD. (1994) In vitro activity of biapenem (L-627), a new carbapenem, against anaerobes. Antimicrob Agents Chemother 38: 889–893. 205. Felici A, Perilli M, Segatore B, Franceschini N, Setacci D, Oratore A, Stefani S, Galleni M, Amicosante G. (1995) Interactions of biapenem with active-site serine and metallo-β-lactamases. Antimicrob Agents Chemother 39: 1300–1305.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 131

Bioactive Natural Products

Natural Products in Drug Discovery

131

206. Nagashima S, Kozawa O, Otsuka T, Kohno K, Minamoto M, Yokokawa M, Kanamaru M, Uematsua T. (2000) Pharmacokinetics of a parenteral carbapenem, biapenem, in patients with end-stage renal disease and influence of haemodialysis. J Antimicrob Chemother 46: 839–842. 207. Perry CM, Ibbotson T. (2002) Biapenem. Drugs 62: 2221–2234. 208. Graul AI. (2003) The year’s new drugs. Drug News & Perspect 16: 22–40. 209. Boyer-Joubert C, Lorthiois E, Moreau F. (2003) To Market, to Market2002. In: Doherty AM. (ed), Annual Reports in Medicinal Chemistry, Vol. 38, pp. 347–374, Academic Press, Amsterdam. 210. Frantz S, Smith A. (2003) New drug approvals for 2002. Nat Rev Drug Discov 2: 95–96. 211. Woodworth JR, Nyhart EH, Brier GL, Wolny JD, Black HR. (1992) Singledose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers. Antimicrob Agents Chemother 36: 318–325. 212. Debono M, Abbott BJ, Malloy RM, Fukuda DS, Hunt AH, Daupert VM, Counter FT, Ott JL, Carrell CB, Howard LC, Boeck LD, Hamill RL. (1988) Enzymatic and chemical modifications of lipopeptide antibiotic A21978C: The synthesis and evaluation of daptomycin (LY146032). J Antibiot 41: 1093–1105. 213. Tally FP, DeBruin MF. (2000) Development of daptomycin for grampositive infections. J Antimicrob Chemother 46: 523–526. 214. Raja A, LaBonte J, Lebbos J, Kirkpatrick P. (2003) Daptomycin. Nat Rev Drug Discov 2: 943–944. 215. Graul AI. (2004) The year’s new drugs. Drug News & Perspect 17: 43–57. 216. Frantz S. (2004) 2003 approvals: A year of innovation and upward trends. Nat Rev Drug Discov 3: 103–105. 217. Hegde S, Carter J. (2004) To Market, to Market-2003. In: Doherty AM. (ed), Annual Reports in Medicinal Chemistry, Vol. 39, pp. 335–368, Academic Press, Amsterdam. 218. Fenton C, Keating GM, Curran MP. (2004) Daptomycin. Drugs 64: 445–455. 219. Jung D, Rozek A, Okon M, Hancock RE. (2004) Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin. Chem Biol 11: 949–957. 220. Steenbergen JN, Alder J, Thorne GM, Tally FP. (2005) Daptomycin: A lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother 55: 283–288.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

132

Page 132

Bioactive Natural Products

Brahmachari

221. Mathiesen L, Midtvedt T, Solberg CO. (2006) Daptomycin — a new antibiotic for the treatment of skin and soft tissue infections. Tidsskr Nor Laegeforen 126: 2383–2384. 222. Hair PI, Keam SJ. (2007) Daptomycin: A review of its use in the management of complicated skin and soft-tissue infections and Staphylococcus aureus bacteraemia. Drugs 67: 1483–512. 223. Fowler VG, Boucher HW, Corey GR. (2006) Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus Aureus. N Engl J Med 355: 653–665. 224. Straus SK, Hancock RE. (2006) Mode of action of the new antibiotic for Gram-positive pathogens daptomycin: Comparison with cationic antimicrobial peptides and lipopeptides. Biochim Biophys Acta 1758: 1215–1223. 225. Dhawan B, Gadepalli R, Kapil A. (2009) In vitro activity of daptomycin against Staphylococcus Aureus and vancomycin-resistant Enterococcus Faecium isolates associated with skin and soft tissue infections: First results from India. Diagn Microbiol Infect Dis 65: 196–198. 226. Zhanel GG, Walters M, Noreddin A, Vercaigne LM, Wierzbowski A, Embil JM, Gin AS, Douthwaite S, Hoban DJ. (2002) The ketolides: A critical review. Drugs 62: 1771–1804. 227. Ackermann G, Rodloff AC. (2003) Drugs of the 21st century: Telithromycin (HMR 3647) — the first ketolide. J Antimicrob Chemother 51: 497–511. 228. Wellington K, Noble S. (2004) Telithromycin. Drugs 64: 1683–1694. 229. Raja A, Lebbos J, Kirkpatrick P. (2004) Telithromycin. Nat Rev Drug Discov 3: 733–734. 230. Sanofi Aventis: Further information available at http://www.ketek.com/ (accessed on 14.12.2010). 231. Sum PE, Lee VJ, Testa RT, Hlavka JJ, Ellestad GA, Bloom JD, Gluzman Y, Tally FP. (1994) Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J Med Chem 37: 184–188. 232. Lounis N, Roscigno G. (2004) In vitro and in vivo activities of rifamycin derivatives against mycobacterial infections. Curr Pharm Des 10: 3229–3238. 233. Zhanel GG, Homenuik K, Nichol K, Noreddin A, Vercaigne L, Embil J, Gin A, Karlowsky JA, Hoban DJ. (2004) The glycylcyclines: A comparative review with the tetracyclines. Drugs 64: 63–88.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 133

Bioactive Natural Products

Natural Products in Drug Discovery

133

234. Rose W, Rybak M. (2006) Tigecycline: First of a new class of antimicrobial agents. Pharmacotherapy 26: 1099–1110. 235. Breedt J, Teras J, Gardovskis J, Maritz FJ, Vaasna T, Ross DP, GioudPaquet M, Dartois N, Ellis-Grosse EJ, Loh E. (2005) Safety and efficacy of tigecycline in treatment of skin and skin structure infections: Results of a double-blind phase 3 comparison study with vancomycin-aztreonam. Antimicrob Agents Chemother 49: 4658–4666. 236. Stein GE, Craig WA. (2006) Tigecycline: A critical analysis. Clin Infect Dis 43: 518–524. 237. Kasbekar N. (2006) Tigecycline: A new glycylcycline antimicrobial agent. Am J Health Syst Pharm 63: 1235–1243. 238. Slover CM, Rodvold KA, Danziger LH. (2007) Tigecycline: A novel broadspectrum antimicrobial. Ann Pharmacother 41: 965–972. 239. Iso Y, Irie T, Nishino Y, Motokawa K, Nishitani Y. (1996) A novel 1βmethylcarbapenem antibiotic, S-4661. Synthesis and structure-activity relationships of 2-(5-substituted pyrroldin-3-ylthio)-1β-methylcarbapenems. J Antibiot 49: 199–209. 240. U.S. Food and Drug Administration (FDA): Press release October 17, 2007. FDA approves new drug to treat complicated urinary tract and intra-abdominal infections. Available at http://www.fda.gov/ (accessed on 14.12.2010). 241. Mandell L. (2009) Doripenem: A new carbapenem in the treatment of nosocomial infection. Clin Infect Dis 49(Suppl 1): S1–S3. 242. Inoue M, Mitsuhashi S. (1996) Antibacterial activity of new carbapenem S-4661 and stability to beta-lactamase. In Program and Abstracts of the Thirty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, p. F112. American Society for Microbiology, Washington, DC, USA. 243. Jones RN, Huynh HK, Biedenbach DJ, Fritsche TR, Sader HS. (2004) Doripenem (S-4661), a novel carbapenem: Comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations. J Antimicrob Chemother 54: 144–154. 244. Zhanel GG, Wiebe R, Dilay L, Thomson K, Rubinstein E, Hoban DJ, Noreddin AM, Karlowsky JA. (2007) Comparative review of the carbapenems. Drugs 67: 1027–1052. 245. Lister PD. (2007) Carbapenems in the USA: Focus on doripenem. Expert Rev Anti Infect Ther 5: 793–809.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

134

Page 134

Bioactive Natural Products

Brahmachari

246. Kaniga K, Flamm R, Tong SY, Lee M, Friedland I, Redman R. (2010) Worldwide experience with the use of doripenem against extended-spectrumβ-lactamase-producing and ciprofloxacin-resistant enterobacteriaceae: Analysis of sixphase 3 clinical studies. Antimicrob Agents Chemother 54: 2119–2124. 247. Ikawa K, Morikawa N, Ikeda K, Ohge H, Sueda T. (2008) Pharmacodynamic assessment of doripenem in peritoneal fluid against Gram-negative organisms: Use of population pharmacokinetic modeling and Monte Carlo simulation. Diagn Microbiol Infect Dis 62: 292–297. 248. Debono M, Turner WW, LaGrandeur L, Burkhardt FJ, Nissen JS, Nichols KK, Rodriguez MJ, Zweifel MJ, Zeckner DJ, Gordee RS, Tang J, Parr TR Jr. (1995) Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): Structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem 38: 3271–3281. 249. Barrett D. (2002) From natural products to clinically useful antifungals. Biochim Biophys Acta 1587: 224–233. 250. Frattarelli DAC, Reed MD, Giacoia GP, Aranda JV. (2004) Antifungals in systemic neonatal candidiasis. Drugs 64: 949–968. 251. Kakeya H, Miyazaki Y, Senda H, Kobayashi T, Seki M, Izumikawa K, Yanagihara K, Yamamoto Y, Tashiro T, Kohno S. (2008) Efficacy of SPK843, a novel polyene antifungal, in comparison with amphotericin B, liposomal amphotericin B, and micafungin against murine pulmonary aspergillosis. Antimicrob Agents Chemother 52: 1868–1870. 252. Cross SA, Scott LJ. (2008) Micafungin: A review of its use in adults for the treatment of invasive and oesophageal candidiasis, and as prophylaxis against Candida infections. Drugs 68: 2225–2255. 253. Carter NJ, Keating GM. (2009) Micafungin: A review of its use in the prophylaxis and treatment of invasive Candida infections in pediatric patients. Paediatr Drugs 11: 271–291. 254. Jarque I, Angel Sanz M. (2009) Micafungin in invasive candidiasis among oncohematological patients. Rev Iberoam Micol 26: 75–77. 255. Joseph JM, Jain R, Danziger LH. (2007) Micafungin: A new echinocandin antifungal. Pharmacotherapy 27: 53–67. 256. Pappas PG, Rotstein CMF, Betts RF, Nucci M, Talwar D, De Waele JJ, Vazquez JA, Dupont BF, Horn DL, Ostrosky-Zeichner L, Reboli AC,

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 135

Bioactive Natural Products

Natural Products in Drug Discovery

257.

258. 259.

260. 261. 262. 263. 264. 265.

266.

267. 268.

269.

135

Suh B, Digumarti R, Wu C, Kovanda LL, Arnold LJ, Buell DN. (2007) Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 45: 883–893. Pettengell K, Mynhardt J, Kluyts T, Lau W, Facklam D, Buell D. (2004) Successful treatment of oesophageal candidiasis by micafungin: A novel systemic antifungal agent. Aliment Pharmacol Ther 20: 475–481. Carver PL. (2004) Micafungin. Ann Pharmacother 38: 1707–1721. Kohno S, Masaoka T, Yamaguchi H, Mori T, Urabe A, Ito A, Niki Y, Ikemoto H. (2004) A multicenter, open-label clinical study of micafungin (fk463) in the treatment of deep-seated mycosis in japan. Scand J Infect Dis 36: 372–379. Fujie A. (2007) Discovery of micafungin (FK463): A novel antifungal derived from a novel product lead. Pure Appl Chem 79: 603–614. Hanson FR, Elbe TE. (1949) An antiphage agent isolated from Aspergillus sp. J Bacteriol 58: 527–529. McCowen MC, Callender ME, Lawlis JF Jr. (1951) Fumagillin (H-3), a new antibiotic with amebicidal properties. Science 113: 202–203. Killough JH, Magill GB, Smith RC. (1952) The treatment of amebiasis with fumagillin. Science 115: 71–72. El-Din GN. (1956) The use of fumagillin in the treatment of amebiasis. Am J Trop Med Hyg 5: 67–71. Kotler DP, Orenstein JM. (1999) Clinical syndromes associated with microsporidiosis. In: Wittner M, Weiss LM. (eds), The Microsporidia and Microsporidiosis, pp. 258–292, ASM Press, Washington, D.C. Molina J-M, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert J-G, Balkan S, Derouin F. (2002) Fumagillin treatment of intestinal microsporidiosis. N Engl J Med 346: 1963–1969; Comment: Carr A, Cooper DA. (2002) N Engl J Med 347: 1381. Reply: Molina JM, Tourneur M. (2002) N Engl J Med 347: 1381. Didier ES, Weiss LM. (2006) Microsporidiosis: Current status. Curr Opin Infect Dis 19: 485–492. Lefkove B, Govindarajan B, Arbiser JL. (2007) Fumagillin: An antiinfective as a parent molecule for novel angiogenesis inhibitors. Expert Rev Anti Infect Ther 5: 573–579. Lanternier F, Boutboul D, Menotti J, Chandesris MO, Sarfati C, Bruneel MFM, Calmus Y, Mechai F, Viard JP, Lecuit M, Bougnoux ME, Lortholary O.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

136

270.

271.

272.

273.

274.

275.

276.

277.

278. 279.

Page 136

Bioactive Natural Products

Brahmachari

(2009) Microsporidiosis in solid organ transplant recipients: Two Enterocytozoon Bieneusi cases and review. Transpl Infect Dis 11: 83–88. Liu S, Widom J, Kemp CW, Crews CM, Clardy J. (1998) Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science 282: 1324–1327. Didier PJ, Phillips JN, Kuebler DJ, Nasr M, Brindley PJ, Stovall ME, Bowers LC, Didier ES. (2006) Antimicrosporidial activities of fumagillin, TNP-470, ovalicin, and ovalicin derivatives in vitro and in vivo. Antimicrob Agents Chemother 50: 2146–2155. Molina JM, Goguel J, Sarfati C, Chastang C, Desportes-Livage I, Michiels JF, Maslo C, Katlama C, Cotte L, Leport C, Raffi F, Derouin F, Modaï J. (1997) Potential efficacy of fumagillin in intestinal microsporidiosis due to Enterocytozoon Bieneusi in patients with HIV-infection: Results of a drug screening study. AIDS 11: 1603–1610. Molina JM, Goguel J, Sarfati C, Michiels J-F, Desportes-Livage I, Balkan S, Chastang C, Cotte L, Maslo C, Struxiano A, Derouin F, Decazes J-M. (2000) Trial of oral fumagillin for thetreatment of intestinal microsporidiosis in patients with HIV infection. AIDS 14: 1341–1348. Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J. (1990) Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growt. Nature 348: 555–557. Zhang Y, Yeh JR, Mara A, Ju R, Hines JF, Cirone P, Griesbach HL, Schneider I, Slusarski DC, Holley SA, Crews CM. (2006) A chemical and genetic approach to the mode of action of fumagillin. Chem Biol 13: 1001–1009. DiPaolo JA, Tarbell DS, Moore GE. (1958–1959) Studies on the carcinolytic activity of fumagillin and some of its derivatives. Antibiotics Annu 541–546. Sin N, Meng L, Wang MQW, Wen JJ, Bornmann WG, Crews CM. (1997) The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci USA 94: 6099–6103. Gervaz P, Fontolliet C. (1998) Therapeutic potential of the anti-angiogenesis drug TNP-470. Int J Exp Pathol 79: 359–362. de la Torre P, Reboli AC. (2007) Anidulafungin: A new echinocandin for candidal infections. Expert Rev Anti-Infect Ther 5: 45–52.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 137

Bioactive Natural Products

Natural Products in Drug Discovery

137

280. Vazquez JA, Sobel JD. (2006) Anidulafungin: A novel echinocandin. Clin Infect Dis 43: 215–222. 281. Pfaller MA, Diekema DJ, Boyken L, Messer SA, Tendolkar S, Hollis RJ, Goldstein BP (2005). Effectiveness of anidulafungin in eradicating Candida species in invasive candidiasis. Antimicrob Agents Chemother 49: 4795–4797. 282. Debono M, Turner WW, LaGrandeur L, Burkhardt FJ, Nissen JS, Nichols KK, Rodriguez MJ, Zweifel MJ, Zeckner DJ, Gordee RS, Tang J, Parr TR. (1995) Semi-synthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): Structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem 38: 3271–3281. 283. FDA: Press release 21 February 2006. Available at http://www.fda.gov/. 284. Vazquez JA. (2005) Anidulafungin: A new echinocandin with a novel profile. Clin Ther 27: 657–673. 285. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik J-A, Wingard JR, Patterson TF. (2008) Treatment of aspergillosis: Clinical practice guidelines of the infectious diseases society of America. Clin Infect Dis 46: 327–360. 286. Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, Henkel T. (2004) Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother 48: 2021–2024. 287. Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ. (2005) In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol 43: 5425–5427. 288. Dowell JA, Stogniew M, Krause D, Henkel T. (2003) Anidulafungin (ANID) pharmacokinetic (PK)/Pharmacodynamic (PD) correlation: Treatment of esophageal candidiasis. 43rd Interscience Conference of Antimicrobial Agents and Chemotherapy Abstract A-1578. 289. Groll AH, Mickiene D, Petraitiene R, Petraitis V, Lyman CA, Bacher JS. (2001) Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): Reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling. Antimicrob Agents Chemother 45: 2845–2855.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

138

Page 138

Bioactive Natural Products

Brahmachari

290. Gumbo T, Drusano GL, Liu W, Ma L, Deziel MR, Drusano MF, Louie A. (2006) Anidulafungin pharmacokinetics and microbial response in neutropenic mice with disseminated candidiasis. Antimicrob Agents Chemother 50: 3695–3700. 291. Trissel LA, Ogundele AB. (2005) Compatibility of anidulafungin with other drugs during simulated Y-site administration. Am J Health Syst Pharm 62: 834–837. 292. Denning DW. (1997) Echinocandins and pneumocandins — a new antifungal class with a novel mode of action. J Antimicrob Chemother 40: 611–614. 293. Sabol K, Gumbo T. (2008) Anidulafungin in the treatment of invasive fungal infections. Ther Clin Risk Manag 4: 71–78. 294. Rittenhouse S, Biswas S, Broskey J, McCloskey L, Moore T, Vasey S, West J, Zalacain M, Zonis R, Payne D. (2006) Selection of retapamulin, a novel pleuromutilin for topical use. Antimicrob Agents Chemother 50: 3882–3885. 295. Daum RS, Kar S, Kirkpatrick P. (2007) Retapamulin. Nat Rev Drug Discov 6: 865–866. 296. Jacobs MR. (2007) Retapamulin: A semisynthetic pleuromutilin compound for topical treatment of skin infections in adults and children. Future Microbiol 2: 591–600. 297. GSK: Press release 12 April 2007. Available at http://www.gsk.com/ (accessed on 14.12.2010). 298. Kavanagh F, Hervey A, Robbins WJ. (1950) Antibiotic substances from Basidiomycetes: VI. Agrocybe Dura. Proc Natl Acad Sci USA 36: 102–106. 299. Yan K, Madden L, Choudhry AE, Voigt CS, Copeland RA, Gontarek RR. (2006) Selection of retapamulin, a novel pleuromutilin for topical use. Antimicrob Agents Chemother 50: 3875–3881. 300. Lolk L, Pohlsgaard J, Jepsen AS, Hansen LH, Nielsen H, Steffansen SI, Sparving L, Nielsen AB, Vester B, Nielsen P. (2008) A click chemistry approach to pleuromutilin conjugates with nucleosides or acyclic nucleoside derivatives and their binding to the bacterial ribosome. J Med Chem 51: 4957–4967. 301. Jones R, Fritsche T, Sader H, Ross JE. (2006) Activity of retapamulin (SB-275833), a novel pleuromutilin, against selected resistant gram-positive Cocci. Antimicrob Agents Chemother 50: 2583–2586.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 139

Bioactive Natural Products

Natural Products in Drug Discovery

139

302. Hogenauer G. (1975) The mode of action of pleuromutilin derivatives. Eur J Biochem 52: 93–98. 303. Long KS, Hansen LH, Jakobsen L, Vester B. (2006) Interaction of pleuromutilin derivatives with the ribosomal peptidyl transferase center. Antimicrob Agents Chemother 50: 1458–1462. 304. Judice JK, Pace JL. (2003) Semi-synthetic glycopeptide antibacterials. Bioorg Med Chem Lett 13: 4165–4168. 305. Leadbetter MR, Adams SM, Bazzini B, Fatheree PR, Karr DE, Krause KM, Lam BM, Linsell MS, Nodwell MB, Pace JL, Quast K, Shaw JP, Soriano E, Trapp SG, Villena JD, Wu TX, Christensen BG, Judice JK. (2004) Hydrophobic vancomycin derivatives with improved ADME properties: Discovery of telavancin (TD-6424). J Antibiot 57: 326–336. 306. Kanafani ZA. (2006) Telavancin: A new lipoglycopeptide with multiple mechanisms of action. Expert Rev Anti-Infect Ther 4: 743–749. 307. Laohavaleeson S, Kuti JL, Nicolau DP. (2007) Telavancin: A novel lipoglycopeptide for serious Gram-positive infections. Expert Opin Invest Drugs 16: 347–357. 308. Higgins DL, Chang R, Debabov DV, Leung J, Wu T, Krause KM, Sandvik E, Hubbard JM, Kaniga K, Schmidt DE, Gao Q, Cass RT, Karr DE, Benton BM, Humphrey PP. (2005) Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus Aureus. Antimicrob Agents Chemother 49: 1127–1134. 309. Theravance: Press release 11 September 2009. Available at http://investor. theravance.com/. 310. Theravance: Press release 22nd October 2007. Available at http://www. theravance.com/. 311. Theravance: Press release 27 November 2009. Available at http://investor. theravance.com/. 312. Adkinson NF, Swabb EA, Sugerman AA. (1984) Immunology of the monobactam aztreonam. Antimicrob Agents Chemother 25: 93–97. 313. McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. (2008) Inhaled aztreonam lysine for chronic airway Pseudomonas Aeruginosa in cystic fibrosis. Am J Respir Crit Care Med 178: 921–928.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

140

Page 140

Bioactive Natural Products

Brahmachari

314. Retsch-Bogart GZ, Burns JL, Otto KL, Liou TG, McCoy K, Oermann C, Gibson RL. (2008) A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas Aeruginosa infection. Pediatr Pulmonol 43: 47–58. 315. Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM, McCoy KS, Montgomery AB, Cooper PJ. (2009) Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest 135: 1223–1232. 316. Neu HC. (1990) Aztreonam’s role in the treatment of gram-negative infections. Am J Med 88: S2–S6. 317. Orlicek MD, Shari L. (1999) Aztreonam. Seminars in pediatric infectious diseases. Antimicrobial Therapy, Part-2 10: 45–50. 318. Gilead Sciences: Press release 22 February 2010. Available at http://www. gilead.com. 319. Giles F, Estey E, O’Brien S. (2003) Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Cancer 98: 2095–2104. 320. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R. (2001) Approval summary: Gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7: 1490–1496. 321. Giles FJ, Kantarjian HM, Kornblau SM, Thomas DA, Garcia-Manero G, Waddelow TA, David CL, Phan AT, Colburn DE, Rashid A, Estey EH. (2001) Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer 92: 406–413. 322. Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, Alyea EP, Antin JH, Stone RM, Soiffer RJ, DeAngelo DJ. (2003) Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 102: 1578–1582. 323. Wyeth Pharmaceuticals: Press Releases 31 March 2003 and 23 August 2004. Available at http://www.wyeth.com/. 324. Pagano L, Fianchi L, Caira M, Rutella S, Leone G. (2007) The role of gemtuzumab ozogamicin in the treatment of acute myeloid leukemia patients. Oncogene 26: 3679–3690. 325. Rooseboom M, Commandeur JNM, Vermeulen NPE. (2004) Enzymecatalyzed activation of anti-cancer prodrugs. Pharmacol Rev 56: 53–102.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 141

Bioactive Natural Products

Natural Products in Drug Discovery

141

326. Abou-Gharbia M. (2002) Optimization of natural procedures lead: Discovery of mylotarg™, CCI-779 and GAR-936. In: Sener B. (ed), Biodiversity: Biomolecular Aspects of Biodiversity and Innovation Utilization, pp. 63–70, Kluwer Academic, New York. 327. Lee MD, Dunne TS, Siegel MM, Chang CC, Morton GO, Borders DB. (1987) Calichemicins, a novel family of antitumor antibiotics. 1. Chemistry and partial structure of calichemicin γ11. J Am Chem Soc 109: 3464–3466. 328. DiJoseph JF, Armellino DC, Boghaert ER, Khandke K, Dougher MM, Sridharan L, Kunz A, Hamann PR, Gorovits B, Udata C, Moran JK, Popplewell AG, Stephens S, Frost P, Damle NK. (2004) Antibody-targeted chemotherapy with CMC-544: A CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 103: 1807–1814. 329. Boghaert ER, Sridharan L, Armellino DC, Khandke KM, DiJoseph JF, Kunz A, Dougher MM, Jiang F, Kalyandrug LB, Hamann PR, Frost P, Damle NK. (2004) Antibody-targeted chemotherapy with the calicheamicin conjugate hu3s193-n-acetyl γ calicheamicin dimethyl hydrazide targets lewisy and eliminates lewisy-positive human carcinoma cells and xenografts. Clin Cancer Res 10: 4538–4549. 330. Singh S, Hager MH, Zhang C, Griffith BR, Lee MS, Hallenga K, Markley JL, Thorson JS. (2006) Structural insight into the self-sacrifice mechanism of enediyne resistance. ACS Chem Biol 1: 451–460. 331. Nicolaou KC, Smith AL, Yue EW. (1993) Chemistry and biology of natural and designed enediynes. Proc Natl Acad Sci USA 90: 5881–5888. 332. Sugiura T, Ariyoshi Y, Negoro S, Nakamura S, Ikegami H, Takada M, Yana T, Fukuoka M. (2005) Phase I/II study of amrubicin, a novel 9-aminoanthracycline, in patients with advanced non-small-cell lung cancer. Invest New Drugs 23: 331–337. 333. Ogawa M. (1999) Novel anticancer drugs in Japan. J Cancer Res Clin Oncol 125: 134–140. 334. Yamaoka T, Hanada M, Ichii S, Morisada S, Noguchi T, Yanagi Y. (1999) Uptake and intracellular distribution of amrubicin, a novel 9-aminoanthracycline, and its active metabolite amrubicinol in P388 murine leukemia cells. Jpn J Cancer Res 90: 685–690. 335. Ueoka H, Ohnoshi T, Kimura I. (1992) New anthracycline analogues in the treatment of lung cancer (in Japanese). Gan To Kagaku Ryoho 19: 2146–2149.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

142

Page 142

Bioactive Natural Products

Brahmachari

336. Ogawara D, Fukuda M, Nakamura Y, Kohno S. (2010) Efficacy and safety of amrubicin hydrochloride for treatment of relapsed small cell lung cancer. Cancer Management Res 2: 191–195. 337. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ. (2007) Temsirolimus, interferon alfa, or both for advancedrenal-cell carcinoma. New Engl J med 356: 2271–2281. 338. FDA: Press release 30 May 2007. Available at http://www.fda.gov/. 339. Gu J, Ruppen ME, Cai P. (2005) Lipase-catalyzed regioselective esterification of rapamycin: Synthesis of temsirolimus (CCI-779). Org Lett 7: 3945–3948. 340. Gore ME. (2007) Temsirolimus in the treatment of advanced renal cell carcinoma. Ann Oncol 18(Suppl 9): ix87–ix88. 341. Vézina C, Kudelski A, Sehgal SN. (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. J Antibiot 28: 721–726. 342. Wan X, Helman LJ. (2007) The biology behind mTOR inhibition in sarcoma. Oncologist 12: 1007–1018. 343. Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A. (2008) Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 19: 1387–1392. 344. Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL. (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12: 122–127. 345. Dancey JE. (2006) Therapeutic targets: mTOR and related pathways. Cancer Biol Ther 5: 1065–1073. 346. Lin F, Zhang PL, Yang XJ, Prichard JW, Lun M, Brown RE. (2006) Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal cell carcinomas. Ann Clin Lab Sci 36: 283–293. 347. Boni JP, Leister C, Bender G, Fitzpatrick V, Twine N, Stover J, Dorner A, Immermann F, Burczynski ME. (2005) Population pharmacokinetics of CCI-779: Correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther 77: 76–89. 348. Wan X, Shen N, Mendoza A, Khanna C, Helman LJ. (2006) CCI-779 Inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 143

Bioactive Natural Products

Natural Products in Drug Discovery

349. 350.

351.

352.

353.

354.

355. 356.

357. 358.

143

linked to the targeting of mTOR/HIF-1alpha/VEGF signaling. Neoplasia 8: 394–401. Rubio-Viqueira B, Hidalgo M. (2006) Targeting mTOR for cancer treatment. Curr Opin Investig Drugs 7: 501–512. Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M. (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66: 5549–5554. Pommier Y, Kohlagen G, Bailly C, Waring M, Mazumder A, Kohn K. (1996) DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the caribbean tunicate Ecteinascidia turbinata. Biochemistry 35: 13303–13309. Schmitt T, Keller E, Dietrich S, Wuchter P, Ho AD, Egerer G. (2010) Trabectedin for metastatic soft tissue sarcoma: A retrospective single center analysis. Mar Drugs 8: 2647–2658. Sakai R, Rinehart KL, Guan Y, Wang AH. (1992) Additional antitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo. Proc Natl Acad Sci USA 89: 11456–11460. Sakai R, Jares-Erijman EA, Manzanares I, Elipe MVS, Rinehart KL. (1996) Ecteinascidins: Putative biosynthetic precursors and absolute stereochemistry. J Am Chem Soc 118: 9017–9023. Rinehart KL. (2000) Antitumor compounds from tunicates. Med Res Rev 20: 1–27. Soares DG, Escargueil AE, Poindessous V, Sarasin A, de Gramont A, Bonatto D, Henriques JA, Larsen AK. (2007) Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743. Proc Natl Acad Sci USA 104: 13062–13067. Carter NJ, Keam SJ. (2007) Trabectedin: A review of its use in the management of soft tissue sarcoma and ovarian cancer. Drugs 67: 2257–2276. Grosso F, Jones RL, Demetri GD, Judson IR, Blay JY, Le Cesne A, Sanfilippo R, Casieri P, Collini P, Dileo P, Spreafico C, Stacchiotti S, Tamborini E, Tercero JC, Jimeno J, DIncalci M, Gronchi A, Fletcher JA, Pilotti S, Casali PG. (2007) Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: A retrospective study. Lancet Oncol 8: 595–602.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

144

Page 144

Bioactive Natural Products

Brahmachari

359. European Medicines Agency (EMA): Press release 16 February 2010. Available at http://www.ema.europa.eu/. 360. For further information: http://www.pharmamar.com/ (accessed on 24.12. 2010). 361. Corey EJ, Gin DY, Kania RS. (1996) Enantioselective total synthesis of ecteinascidin 743. J Am Chem Soc 118: 9202–9203. 362. Cuevas C, Pérez M, Martín MJ, Chicharro JL, Fernández-Rivas C, Flores M, Francesch A, Gallego P, Zarzuelo M, de La Calle F, García J, Polanco C, Rodríguez I, Manzanares I. (2000) Synthesis of ecteinascidin ET-743 and phthalascidin PT-650 from cyanosafracin. B Org Lett 2: 2545–2548. 363. Hofle G, Bedorf N, Steinmertz H, Schomburg D, Gerth K, Reichenach H. (1996) Epothilone A and B — novel 16-membered macrolides with cytotoxic activity: Isolation, crystal structure, and conformation in solution. Angew Chem 35: 1567–1569. 364. Borzilleri RM, Zheng X, Schmidt RJ, Johnson JA, Kim S-H, DiMarco JD, Fairchild CR, Gougoutas JZ, Lee FYF, Long BH, Vite GD. (2000) A novel application of a pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products. J Am Chem Soc 122: 8890–8897. 365. Conlin A, Fornier M, Hudis C, Kar S, Kirkpatrick P. (2007) Ixabepilone. Nat Rev Drug Discov 6: 953–954. 366. Cardoso F, de Azambuja E, Lago LD. (2008) Current perspectives of epothilones in breast cancer. Eur J Cancer 44: 341–352. 367. Bristol-Meyers Squibb (BMS): Press release 16 October 2007. Available at http://www.bms.com/. 368. Pronzato P. (2008) New therapeutic options for chemotherapy resistant metastatic breast cancer: The epothilones. Drugs 68: 139–146. 369. Lee FYF, Borzilleri R, Fairchild CR, Kamath A, Smykla R, Kramer R, Vite G. (2008) Preclinical discovery of ixabepilone, a highly active antineoplastic agent. Cancer Chemother Pharmacol 63: 157–166. 370. Goodin S. (2008) Novel cytotoxic agents: Epothilones. Am J Health Syst Pharm 65: S10–S15. 371. Goodin S. (2008) Ixabepilone: A novel microtubule-stabilizing agent for the treatment of metastatic breast cancer. Am J Health Syst Pharm 65: 2017–2026. 372. Denduluri N, Swain SM. (2008) Ixabepilone for the treatment of solid tumors: A review of clinical data. Expert Opin Investig Drugs 17: 423–435.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 145

Bioactive Natural Products

Natural Products in Drug Discovery

145

373. Thomas ES, Gomez HL, Li RK, Chung H-C, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. (2007). Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25: 5210–5217. 374. Aghajanian C, Burris III HA, Jones S, Spriggs DR, Cohen MB, Peck R, Sabbatini P, Hensley ML, Greco FA, Dupont J, O’Connor OA. (2007) Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol 25: 1082–1088. 375. Wan X, Helman LJ. (2007) The biology behind mTOR inhibition in sarcoma. Oncologist 12: 1007–1018. 376. Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, Tobler S, Heusser C, O’Reilly T, Stolz B, Marti A, Thomas G, Lane HA. (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative rad001 correlates with prolonged inactivation of ribosomal protein s6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64: 252–261. 377. Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G, Marciano R, Ciardiello F, Tortora G. (2008) Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 98: 923–930. 378. Formica Jr RN, Lorberb KM, Friedmanb AL, Biaa MJ, Lakkisa F, Smitha JD, Lorber MI. (2004) The evolving experience using everolimus in clinical transplantation. Transplant Proc 36(Suppl 2): 495S-499S. 379. Novartis. (2009) Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib. Press release: http://www.novartis.com. 380. Novartis. (2010). Novartis receives US FDA approval for zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients. Press release: http://www.novartis.com. 381. http://www.tradingmarkets.com/news/stock-alert/nvs_novartis-reportspositive-results-from-phase-ii-tuberous-sclerosis-study-969038.html (accessed on 14.12.2010) 382. http://www.genengnews.com/gen-news-highlights/novartis-afinitor-clearedby-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159 (accessed on 14.12. 2010).

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

146

Page 146

Bioactive Natural Products

Brahmachari

383. Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, Okuhara M. (1994) FR901228, a novel antitumor bicyclic depsipeptide produced by chromobacterium. J Antibiot 47: 301–310. 384. Shigematsu N, Ueda H, Takase S, Tanaka H, Yamamoto K, Tada T. (1994) FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium. J Antibiot 47: 311–314. 385. Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S. (1998) FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 241: 126–133. 386. Li KW, Wu J, Xing W, Simon JA. (1996) Total synthesis of the antitumor depsipeptide FR-901228. J Am Chem Soc 118: 7237–7238. 387. Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, Zain J, Prince HM, Leonard JP, Geskin LJ, Reeder C, Joske D, Figg WD, Gardner ER, Steinberg SM, Jaffe ES, Stetler-Stevenson M, Lade S, Fojo AT, Bates SE. (2009) Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27: 5410–5417. 388. Woo S, Gardner ER, Chen X, Ockers SB, Baum CE, Sissung TM, Price DK, Frye R, Piekarz RL, Bates SE, Figg WD. (2009) Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res 15: 1496–1503. 389. FDA: Press release 9 November 2009. Available at http://www.fda.gov/. 390. Jones P, Steinkuhler C. (2008) From natural products to small molecule ketone histone deacetylase inhibitors: Development of new class specific agents. Curr Pharm Des 14: 545–561. 391. Konstantinopoulos PA, Vandoros GP, Papavassiliou AG. (2006) FK228 (depsipeptide): A HDAC inhibitor with pleiotropic antitumor activities. Cancer Chemother Pharmacol 58: 711–715. 392. Romidepsin: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 022393lbl.pdf. 393. Heinrich M, Teoh HL. (2004) Galanthamine from snowdrop — the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J Ethnopharmacol 92: 147–162. 394. Raskind MA. (2003) Update on Alzheimer drugs (galantamine). Neurologist 9: 235–240.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 147

Bioactive Natural Products

Natural Products in Drug Discovery

147

395. Mashkovsky MD, Kruglikova-Lvova RP. (1951) On the pharmacology of the new alkaloid galantamine. Farmakologia Toxicologia (Moscow) 14: 27–30. 396. Scott LJ, Goa KL. (2000) Galantamine: A review of its use in Alzheimer’s disease. Drugs 60: 1095–1122. 397. Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL. (1999) Structure of acetylcholinesterase complexed with (–)-galanthamine at 2.3 Å resolution. FEBS Lett 463: 321–326. 398. Howes M-JR, Perry NSL, Houghton PJ. (2003) Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res 17: 1–18. 399. Heinrich M, Teoh HL. (2004) Galanthamine from snowdrop — the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J Ethnopharmacol 92: 147–162. 400. Woodruff-Pak DS, Vogel RW 3rd, Wenk GL. (2001) Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci USA 98: 2089–2094. 401. Birks J. (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 25: CD005593. 402. Yuschak T. (2006) Advanced Lucid Dreaming. 1st ed, Lulu Enterprises. ISBN 978-1-4303-0542-2. 403. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, NewmanTancredi A. (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 303: 791–804. 404. http://www.ema.europe.eu/docs/en_GB/document_library/Orphan-designation/2011/05/WC500106734.pdf 405. Schwab R, Amador L, Lettvin J. (1951) Apomorphine in Parkinson’s disease. Trans Am Neurol Assoc 56: 251–253. 406. Cotzias G, Papavasiliou P, Fehling C, Kaufman B, Mena I. (1970) Similarities between neurologic effects of L-dopa and of apomorphine. N Engl J Med 282: 31–33. 407. Corsini G, Del Zompo M, Gessa G, Mangoni A. (1979) Therapeutic efficacy of apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson’s disease. Lancet 1: 954–956.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

148

Page 148

Bioactive Natural Products

Brahmachari

408. Hughes AJ. (1997) Drug treatment of Parkinson’s disease in the 1990s: Achievements and future possibilities. Drugs 53: 195–205. 409. Deleu D, Hanssens Y, Northway MG. (2004) Subcutaneous apomorphine: An evidence-based review of its use in Parkinson’s disease. Drugs Aging 21: 687–709. 410. Matsumoto K, Yoshida M, Andersson K, Hedlund P. (2005) Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum. Br J Pharmacol 146: 259–267. 411. Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, Millan MJ. (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor. J Pharmacol Exp Ther 303: 805–814. 412. Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, Millan MJ. (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes. J Pharmacol Exp Ther 303: 815–822. 413. Hsieh GC, Hollingsworth PR, Martino B, Chang R, Terranova MA, O’Neill AB, Lynch JJ, Moreland RB, Donnelly-Roberts DL, Kolasa T, Mikusa JP, McVey JM, Marsh KC, Sullivan JP, Brioni JD. (2004) Central mechanisms regulating penile erection in conscious rats: The dopaminergic systems related to the proerectile effect of apomorphine. J Pharmacol Exp Ther 308: 330–338. 414. Chaudhuri K, Clough C. (1998) Subcutaneous apomorphine in Parkinson’s disease. Br Med J 316: 641. 415. Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJE. (2002) New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer’s disease. J Biol Chem 277: 42881–42890. 416. For further information: http://www.faqs.org/patents/app/20090270439 (accessed on 14.12.2010). 417. McIntosh M, Cruz LJ, Hunkapiller MW, Gray WR, Olivera BM. (1982) Isolation and structure of a peptide toxin from the marine snail Conus magus. Arch Biochem Biophys 218: 329–334. 418. Olivera BM, Cruz LJ, De Santos V, LeCheminant G, Griffin D, Zeikus R, McIntosh JM, Galyean R, Varga J. (1987) Neuronal calcium channel

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 149

Bioactive Natural Products

Natural Products in Drug Discovery

419.

420.

421.

422. 423. 424. 425.

426. 427.

428. 429.

430.

431.

149

antagonists. Discrimination between calcium channel subtypes using ω-conotoxin from Conus magus venom. Biochemistry 26: 2086–2090. Olivera BM. (2000) ω-Conotoxin MVIIA: From marine snail venom to analgesic drug. In: Fusetani N. (ed), Drugs from the Sea, pp. 74–85. Karger, Basel. Skov MJ, Beck JC, Kater AW, Shopp GM. (2007) Nonclinical safety of ziconotide: An intrathecal analgesic of a new pharmaceutical class. Int J Toxicol 26: 411–421. Schroeder CI, Smythe ML, Lewis RJ. (2004) Development of small molecules that mimic the binding of ω-conotoxins at the N-type voltage-gated calcium channel. Mol Divers 8: 127–134. Wallace MS. (2006) Ziconotide: A new nonopioid intrathecal analgesic for the treatment of chronic pain. Expert Rev Neurother 6: 1423–1428. Prommer E. (2006) Ziconotide: A new option for refractory pain. Drugs Today 42: 369–378. Miljanich GP. (2004) Ziconotide: Neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem 11: 3029–3040. Klotz U. (2006) Ziconotide — a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain — a short review. Int J Clin Pharmacol Ther 44: 478–483. McGivern JG. (2007) Ziconotide: A review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat 3: 69–85. Skov MJ, Beck JC, de Kater AW, Shopp GM. (2007) Nonclinical safety of ziconotide: An intrathecal analgesic of a new pharmaceutical class. Int J Toxicol 26: 411–421. EMA: Press release 9 July 2007. Available at http://www.ema.europa.eu/. Wade D, Robson P, House H, Makela P, Aram J. (2003) A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 17: 21–29. Russo EB, Guy GW, Robson PJ. (2007) Cannabis, pain, and sleep: Lessons from therapeutic clinical trials of Sativex®, a cannabis-based medicine. Chem Biol 4: 1729–1743. Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. (2007) Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebocontrolled clinical trial. Pain 133: 210–220.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

150

Page 150

Bioactive Natural Products

Brahmachari

432. Smith PF. (2007) Symptomatic treatment of multiple sclerosis using cannabinoids: Recent advances. Expert Rev Neurother 7: 1157–1163. 433. Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. (2007) Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial. Pain 133: 210–220. 434. Johnson JR , Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. (2010) Multicenter, double-blind, randomized, placebocontrolled, parallel-group study of the efficacy, safety, and tolerability of THC: CBD extract and THC extract in patients with intractable can correlated pain. J Pain Symptom Manage 39: 167–179. 435. GW Pharmaceuticals: Press release 18 March 2010. Available at http:// www.gwpharm.com/. 436. GW Pharmaceuticals. Cannabinoid Science: Mechanism of action. Available at http://www.gwpharm.com/mechanism-of-action.aspx. 437. GW Pharmaceuticals. Cannabinoid science: Cannabinoid compounds. Available at http://www.gwpharm.com/typescompounds.aspx. 438. http://www.doctordeluca.com/Library/AddictionMeds/SativexProduct Monograph05.pdf (accessed on 14.12.2010). 439. Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL. (2007) Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: A Phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther 29: 450–463. 440. Elia J, Easley C, Kirkpatrick P. (2007) Lisdexamfetamine dimesylate. Nat Rev Drug Discov 6: 343–344. 441. Zwi M, Ramchandani P, Joughin C. (2000) Evidence and belief in ADHD. Br Med J 321: 975–976. 442. Blick SK, Keating GM. (2007) Lisdexamfetamine. Paediatr Drugs 9: 129–135. 443. Popovic B, Bhattacharya P, Sivaswamy L. (2009) Lisdexamfetamine: A prodrug for the treatment of attention-deficit/hyperactivity disorder. Am J Health-Sys Pharm 66: 2005–2012. 444. Jasinski DR, Krishnan S. (2009) Human pharmacology of intravenous lisdexamfetamine dimesylate: Abuse liability in adult stimulant abusers. J Psychopharmacol 23: 410–418. 445. Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. (2006) Efficacy and safety of mixed amphetamine salts extended release (Adderall

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 151

Bioactive Natural Products

Natural Products in Drug Discovery

446.

447.

448.

449.

450.

451.

452.

453.

454. 455. 456.

151

XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: A 4-week, randomized, double-blind, placebocontrolled, parallel-group study. Clin Ther 28: 266–279. Ambrosini PJ, Sallee FR, Lopez FA, Shi L, Michaels MA. (2006) LADD.CAT study group A community assessment, open-label study of the safety, tolerability, and effectiveness of mixed amphetamine salts extended release in school-age children with ADHD. Curr Med Res Opin 22: 427–240. Kramer WG, Read SC, Tran BV, Zhang Y, Tulloch SJ. (2005) Pharmacokinetics of mixed amphetamine salts extended release in adolescents with ADHD. CNS Spectrums 10: 6–13. Gillberg C, Melander H, von Knorring AL, Janols LO, Thernlund G, Hagglof B, Eidevall-Wallin L, Gustafsson P, Kopp S. (1997) Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms. A randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 54: 857–864. Guay DRP. (2009) Methylnaltrexone methobromide: The first peripherally active, centrally inactive opioid receptor-antagonist. Consult Pharm 24: 210–226. Slatkin N, Thomas J, Lipman AG, Wilson G, Boatwright ML, Wellman C, Zhukovsky DS, Stephenson R, Portenoy R, Stambler N, Israel R. (2009) Methylnaltrexone for treatment of opioidinduced constipation in advanced illness patients. J Support Oncol 7: 39–46. Reichle FM, Conzen PF. (2008) Methylnaltrexone, a new peripheral µreceptor antagonist for the prevention and treatment of opioid-induced extracerebral side effects. Curr Opin Invest Drugs 9: 90–100. Yuan CS. (2007) Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother 41: 984–993. Yuan CS, Foss JF, Moss J. (1995) Effects of methylnaltrexone on morphineinduced inhibition of contraction in isolated guinea-pig ileum and human intestine. Eur J Pharmacol 276: 107–111. Yuan CS, Foss JF. (2000) Oral methylnaltrexone for opioid-induced constipation. J Am Med Assoc (JAMA) 284: 1383–1384. Kraft MD. (2007) Emerging pharmacologic options for treating postoperative ileus. Am J Health Syst Pharm 64: S13–S20. Holzer P. (2007) Treatment of opioid-induced gut dysfunction. Expert Opin Investig Drugs 16: 181–194.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

152

Page 152

Bioactive Natural Products

Brahmachari

457. Russell J, Bass P, Goldberg LI, Schuster CR, Merz H. (1982) Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists. Eur J Pharmacol 78: 255–261. 458. Foss JF, Orelind E, Goldberg LI. (1996) Effects of methylnaltrexone on morphine-induced cough suppression in guinea pigs. Life Sciences 59: PL235–PL238. 459. Foss JF, Bass AS, Goldberg LI. (1993) Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs. J Clin Pharmacol 33: 747–751. 460. Thresh JC. (1876) Capsaicin, the active principle in Capsicum fruits. The Analyst 1: 148–149. 461. Remadevi R, Szallasi A. (2008) Adlea (ALGRX-4975), an injectable capsaicin (TRPV1 receptor agonist) formulation for longlasting pain relief. IDrugs 11: 120–132. 462. Simpson DM, Estanislao L, Brown SJ, Sampson J. (2008) An open-label pilot study of high-concentration capsaicin patch in painful hiv neuropathy. J Pain Symptom Manage 35: 299–306. 463. Knotkova H, Pappagallo M, Szallasi A. (2008) Capsaicin (TRPV1 agonist) therapy for pain relief: Farewell or revival. Clin J Pain 24: 142–154. 464. Szallasi A, Cortright DN, Blum CA, Eid SR. (2007) The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6: 357–372. 465. Gunthorpe MJ, Szallasi A. (2008) Peripheral TRPV1 receptors as targets for drug development: New molecules and mechanisms. Curr Pharm Des 14: 32–41. 466. NeurogesX: Press release 5 April 2010. Available at http://www.neurogesx. com/. 467. Vezina C, Kudelski A, Sehgal SN. (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot 28: 721–726. 468. Pritchard DI. (2005) Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today 10: 688–691. 469. Chen Y, Brill GM, Benz NJ, Leanna MR, Dhaon MK, Rasmussen M, Zhou CC, Bruzek JA, Bellettini JR. (2007) Normal phase and reverse phase HPLC-UV-MS analysis of process impurities for rapamycin analog

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 153

Bioactive Natural Products

Natural Products in Drug Discovery

470.

471.

472. 473. 474. 475.

476.

477.

478.

479. 480.

153

ABT-578: Application to active pharmaceutical ingredient process development. J Chromatogr B 858: 106–117. Chen YW, Smith ML, Sheets M, Ballaron S, Trevillyan JM, Burke SE, Rosenberg T, Henry C, Wagner R, Bauch J, Marsh K, Fey TA, Hsieh G, Gauvin D, Mollison KW, Carter GW, Djuric SW. (2007) Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression. J Cardiovasc Pharmacol 49: 228–235. Gershlick A, Kandzari DE, Leon MB, Wijns W, Meredith IT, Fajadet J, Popma JJ, Fitzgerald PJ, Kuntz RE. (2007) Zotarolimus-eluting stents in patients with native coronary artery disease: Clinical and angiographic outcomes in 1,317 patients. Am J Cardiol 100: 45M–55M. Burke SE, Kuntz RE, Schwartz LZ. (2006) Zotarolimus (ABT-578) eluting stents. Adv Drug Delivery Rev 58: 437–446. Medtronic: Press release 1 February 2008. Available at http://wwwp. medtronic.com/. Cordis: Press release 21 September 2009. Available at http://www.cordis.com/. Koumis T, Samuel S. (2005) Tiotropium bromide: A new long-acting bronchodilator for the treatment of chronic obstructive pulmonary disease. Clin Ther 27: 377–392. Kato M, Komamura K, Kitakaze M. (2006) Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure. Circ J 70: 1658–1660. Singh S, Loke YK, Furberg CD. (2008) Inhaled anticholinergics and the risk of major adverse cardiovascular events. J Am Med Assoc (JAMA) 300: 1439–1450. Prakash O, Kumar R, Rahman M, Gaur SN. (2006) The clinico-physiological effect of inhaled tiotropium bromide and inhaled ipratropium bromide in severe chronic obstructive pulmonary disease. Ind J Allergy Asthma Immunol 20: 105–111; For further information: http://www.rxlist.com/spirivadrug.htm (accessed on 24.12.2010). Gladwell TD. (2002) Bivalirudin: A direct thrombin inhibitor. Clin Ther 24: 38–58. Warkentin TE, Greinacher A, Koster A. (2008) Bivalirudin. Thromb Haemost 99: 830–839.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

154

Page 154

Bioactive Natural Products

Brahmachari

481. Ledizet M, Harrison LM, Koskia RA, Cappello M. (2005) Discovery and pre-clinical development of antithrombotics from hematophagous invertebrates. Curr Med Chem Cardiovasc Hematol Agents 3: 1–10. 482. Anand SX, Kim MC, Kamran M, Sharma SK, Kini AS, Fareed J, Hoppensteadt DA, Carbon F, Cavusoglu E, Varon D, Viles-Gonzalez JF, Badimon JJ, Marmur JD. (2007) Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin. Am J Cardiol 100: 417–424. 483. Weitz JI, Hudoba M, Messel D, Maraganore J, Hirsh J. (1990) Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 86: 385–391. 484. Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht H-J, Hoekstra J, Mehran R, Ohman EM. (2006) Bivalirudin for patients with acute coronary syndromes. N Engl J Med 355: 2203–2216. 485. Xiao Z, Theroux P. (1998) Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular weight heparin and with a direct thrombin inhibitor. Circulation 97: 251–256. 486. Weitz JI, Bates SM. (2002) Acute coronary syndromes: A focus on thrombin. J Invasive Cardiol 14: 2B–7B. 487. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. (2001) Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the bivalirudin angioplasty study. Am Heart J 142: 952–959. 488. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ. (2003) Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. J Am Med Assoc (JAMA) 289: 853–863. 489. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G,

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 155

Bioactive Natural Products

Natural Products in Drug Discovery

490. 491. 492. 493. 494. 495. 496.

497.

498. 499.

500. 501.

502. 503. 504.

155

Wong SC, Kirtane AJ, Parise H, Mehran R. (2008) Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 358: 2218–2230. For further information: http://en.wikipedia.org/wiki/Bivalirudin (accessed on 14.12.2010). For further information: http://wiki.medpedia.com/Bivalirudin (accessed on 14.12.2010). Carswell CI, Plosker GL, Jarvis B. (2002) Rosuvastatin. Drugs 62: 2075–2085. Quirk J, Thornton M, Kirkpatrick P. (2003) Rosuvastatin calcium. Nat Rev Drug Discov 2: 769–770. Scott LJ, Curran MP, Figgitt DP. (2004) Rosuvastatin: A review of its use in the management of dyslipidemia. Am J Cardiovasc Drugs 4: 117–138. Mukhtar RYA, Reid J, Reckless JPD. (2005) Pitavastatin. Int J Clin Pract 59: 239–252. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. (1992) Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 267: 7402–7405. Malhotra R, Singh L, Eng J, Raufman J-P. (1992) Exendin-4, a new peptide from Heloderma suspectum venom, potentiates cholecystokinin-induced amylase release from rat pancreatic acini. Regul Pept 41: 149–156. Wolfson W. (2007) Leapin’ lizards: Amylin targets diabetes and obesity via incretins. Chem Biol 14: 235–236. Holz GG, Chepurny OG. (2003) Glucagon-like peptide-1 synthetic analogs: New therapeutic agents for use in the treatment of diabetes mellitus. Curr Med Chem 10: 2471–2483. Keating GM. (2005) Exenatide. Drugs 65: 1681–1692. Nielsen LL, Young AA, Parkes DG. (2004) Pharmacology of exenatide (synthetic exendin-4): A potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept 117: 77–88. Amylin Pharmaceuticals: Press Release 1 September 2004. Available at http://www.amylin.com. Barnett A. (2007) Exenatide. Expert Opin Pharmacother 8: 2593–2608. Cvetkovic RS, Plosker GL. (2007) Exenatide: A review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea). Drugs 67: 935–954.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

156

Page 156

Bioactive Natural Products

Brahmachari

505. Nghiem P, Pearson G, Langley RG. (2002) Tacrolimus and pimecrolimus: From clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 46: 228–241. 506. Gupta AK, Chow M. (2003) Pimecrolimus: A review. J Eur Acad Dermatol Venereol 17: 493–503. 507. Allen BR, Lakhanpaul M, Morris A, Lateo S, Davies T, Scott G, Cardno M, Ebelin ME, Burtin P, Stephenson TJ. (2003) Systemic exposure, tolerability, and efficacy of pimecrolimus cream 1% in atopic dermatitis patients. Arch Dis Child 88: 969–973. 508. Meingassner JG, Kowalsky E, Schwendinger H, Elbe-Bürger A, Stütz A. (2003) Pimecrolimus does not affect Langerhans cells in murine epidermis. Br J Dermatol 149: 853–857. 509. Grunwald MH, Ben Amitai D, Amichai B. (2004) Macrolactam immunomodulators (tacrolimus and pimecrolimus): New horizons in the topical treatment of inflammatory skin diseases. J Dermatol 31: 592–602. 510. Billich A, Aschauer H, Aszódi A, Stuetz A. (2004) Percutaneous absorption of drugs used in atopic eczema: Pimecrolimus permeates less through skin than corticosteroids and tacrolimus. Int J Pharm 269: 29–35. 511. Kreuter A, Gambichler T, Breuckmann F, Pawlak FM, Stücker M, Bader A, Altmeyer P, Freitag M. (2004) Pimecrolimus 1% cream for cutaneous lupus erythematosus. J Am Acad Dermatol 51: 407–410. 512. Scheinfeld NS. (2004) Use of topical tacrolimus and pimecrolimus to treat psoriasis. Dermatol Online J 10: 3. 513. Firooz A, Solhpour A, Gorouhi F, Daneshpazhooh M, Balighi K, Farsinejad K, Rashighi-Firoozabadi M, Dowlati Y. (2006) Pimecrolimus cream, 1%, vs hydrocortisone acetate cream, 1%, in the treatment of facial seborrheic dermatitis: A randomized, investigator-blind, clinical trial. Arch Dermatol 142: 1066–1067. 514. Kreuter A, Sommer A, Hyun J, Bräutigam M, Brockmeyer NH, Altmeyer P, Gambichler T. (2006) 1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone in the treatment of intertriginous psoriasis: A double-blind, randomized controlled study. Arch Dermatol 142: 1138–1143. 515. Gorouhi F, Solhpour A, Beitollahi JM, Afshar S, Davari P, Hashemi P, Nassiri Kashani M, Firooz A. (2007) Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus. J Am Acad Dermatol 57: 806–813.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 157

Bioactive Natural Products

Natural Products in Drug Discovery

157

516. Boone B, Ongenae K, Van Geel N, Vernijns S, De Keyser S, Naeyaert JM. (2007) Topical pimecrolimus in the treatment of vitiligo. Eur J Dermatol 17: 55–61. 517. Jacobi A, Braeutigam M, Mahler V, Schultz E, Hertl M. (2008) Pimecrolimus 1% cream in the treatment of facial psoriasis: A 16-week open-label study. Dermatology 216: 133–136. 518. Jeong E-Y, Jeon J-H, Kim H-W, Kim M-G, Lee H-S. (2009) Antimicrobial activity of leptospermone and its derivatives against human intestinal bacteria. Food Chemistry 115: 1401–1404. 519. Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, Smith LL, Prisbylla MP, Mutter LC, Lee DL. (1998) From toxicological problem to therapeutic use: The discovery of the mode of action of 2-(2-nitro-4trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug. J Inherit Met Dis 42: 498–506. 520. Yang DY. (2003) 4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target. Drug News & Perspect 16: 493–496. 521. Hall MG, Wilks MF, Provan WM, Eksborg S, Lumholtz B. (2001) Pharmaco-kinetics and pharmacodynamics of NTBC [2-(2-nitro-4-fluoromethyl-benzoyl)-1,3-cyclohexanedione] and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers. Br J Clin Pharmacol 52: 169–177. 522. Mitchell G, Bartlett DW, Fraser TEM, Hawkes TR, Holt DC, Townson JK, Wichert RA. (2001) Mesotrione: A new selective herbicide for use in maize. Pest Manag Sci 57: 120–128. 523. Kavana M, Moran GR. (2003) Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl) benzoyl]-1,3-cyclohexanedione. Biochemistry 42: 10238–10245. 524. McKiernan PJ. (2006) Nitisinone in the treatment of hereditary tyrosinaemia type 1. Drugs 66: 743–750. 525. Pastores GM, Barnett NL, Kolodny EH. (2005) An open-label, noncomparative study of miglustat in type I Gaucher disease: Efficacy and tolerability over 24 months of treatment. Clin Ther 27: 1215–1227. 526. Weinreb NJ, Barranger JA, Charrow J, Grabowski GA, Mankin HJ, Mistry P. (2005) Giudance on the use of miglustat for treating patients with type 1 Gaucher disease. Am J Hematol 80: 223–229. 527. McCormack PL, Goa KL. (2003) Miglustat. Drugs 63: 2427–2434.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

158

Page 158

Bioactive Natural Products

Brahmachari

528. Cox TM, Aerts JM, Andria G, Beck M, Belmatoug N, Bembi B, Chertkoff R, Vom Dahl S, Elstein D, Erikson A, Giralt M, Heitner R, Hollak C, Hrebicek M, Lewis S, Mehta A, Pastores GM, Rolfs A, Miranda MC, Zimran A. (2003) The role of the iminosugar n-butyldeoxinojirimycin (miglustat) in the management of type I (nonneuronopathic) gaucher disease: A position statement. J Inherited Metab Dis 26: 513–526. 529. van Giersbergen PL, Dingemanse J. (2007) Influence of food intake on the pharmacokinetics of miglustat, an inhibitor of glucosylceramide synthase. J Clin Pharmacol 47: 1277–1282. 530. Elstein D, Hollak C, Aerts JMFG, Weely SV, Maas M, Cox TM, Lachmann RH, Hrebicek M, Platt FM, Butters TD, Dwek RA, Zimran A. (2004) Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I gaucher disease. J Inherit Metab Dis 27: 757–766. 531. For further information: http://en.wikipedia.org/wiki/Miglustat (accessed on 14.12.2010). 532. Bardsley-Elliot A, Noble S, Foster RH. (1999) Mycophenolate mofetil: A review of its use in the management of solid organ transplantation. Bio Drugs 12: 363–410. 533. Curran MP, Keating GM. (2005) Mycophenolate sodium delayed release: Prevention of renal transplant rejection. Drugs 65: 799–805. 534. Moore RA, Derry S. (2006) Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Res Ther 8: R182. 535. Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR. (2007) Mycophenolate mofetil for induction therapy of lupus nephritis: A systematic review and meta-analysis. Clin J Am Soc Nephrol 2: 968–975. 536. Knight SR, Russell NK, Barcena L, Morris PJ. (2009) Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: A systematic review. Transplantation 87: 785–794. 537. Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thorne JE, Nousari HC. (2003) Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil. Arch Dermatol 139: 739–742. 538. Diamond MS, Zachariah M, Harris E. (2002) Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. Virology 304: 211–221.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 159

Bioactive Natural Products

Natural Products in Drug Discovery

159

539. Takhampunya R, Ubol S, Houng HS, Cameron CE, Padmanabhan R. (2006) Inhibition of dengue virus replication by mycophenolic acid and ribavirin. J Gen Virol 87: 1947–1952. 540. Ransom JT. (1995) Mechanism of action of mycophenolate mofetil. Therap Drug Monitor 17: 681–684. 541. Gabardi S, Tran JL, Clarkson MR. (2003) Enteric-coated mycophenolate sodium. Ann Pharmacother 37: 1685–1693. 542. Salvadori M, Holzer H, de Mattos A, Sollinger H, Arns W, Oppenheimer F, Maca J, Hall M. (2004) Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 4: 231–236. 543. Kobashigawa JA, Relund DG, Gerosa G, Almenar L, Eisen HJ, Keogh AM, Lehmkuhl HB, Livi U, Ross H, Segovia J, Yonan N. (2006) Similar efficacy and safety of enteric-coated mycophenolate sodium (ec-mps, myfortic) compared with mycophenolate mofetil (mmf) in de novo heart transplant recipients: results of a 12-month, single-blind, randomized, parallel-group, multicenter study. J Heart Lung Transplant 25: 935–941. 544. Perry TW, Trotter JF, Christians U, Bendrick-Peart J. (2006) A single-dose pharmacokinetic study of enteric coated mycophenolate sodium, ec-mps, in liver transplant recipients. Transplantation 82: 719–720. 545. Budde K, Glander P, Diekmann F, Waiser J, Fritsche L, Dragun D, Neumayer H-H. (2004) Review of the immunosuppressant enteric-coated mycophenolate sodium. Expert Opin Pharmacother 5: 1333–1345. 546. Ingle GR, Shah T. (2005) Enteric-coated mycophenolate sodium for transplant immunosuppression. Am J Health-System Pharm (AJHP) 62: 2252–2259. 547. Solinger HW. (2004) Mycophenolates in transplantation. Clin Transplant 18: 485–492. 548. Behrend M, Braun F. (2005) Enteric-coated mycophenolate sodium: Tolerability profile compared with mycophenolate mofetil. Drugs 65: 1037–1050. 549. Morris RE. (1995) Mechanisms of action of new immunosuppressive drugs. Ther Drug Monitor 17: 564–569. 550. Hale MD, Nicholls AJ, Bullingham RES, Hené R, Hoitsma A, Squifflet J-P, Weimar W, Vanrenterghem Y, Van de Woude FJ, Verpooten GA. (1998) The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther 64: 672–683.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

160

Page 160

Bioactive Natural Products

Brahmachari

551. Shaw LM, Holt DW, Oellerich M, Meiser B, van Gelder T. (2001) Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monitor 23: 305–315. 552. Shaw LM, Korecka M, De Nofrio D, Brayman KL. (2001) Pharmacokinetic, pharmacodynamic and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal and heart transplant patients. Clin Biochem 34: 17–22. 553. Perez-Aytes A, Ledo A, Boso V, Carey JC, Castell M, Vento M. (2010) Immunosuppressive drugs and pregnancy: Mycophenolate mofetil embryopathy. NeoReviews 11: 578–589. 554. Budde K, Glander P, Grohmann J, Bauer S, Hambach P, Hepburn H, Mai I, Sandau K, Fischer W, Neumayer HH. (2004) Pharmacokinetic and pharmacodynamic comparison of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) in maintenance renal transplant patients with tacrolimus as basic immunosuppression (P736). Transplantation 78: 459–460. 555. Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E, Remuzzi G, Perico N. (2005) Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transplant 5: 2937–2944. 556. Tredger JM, Brown NW. (2006) Mycophenolate: Better value through monitoring? Transplantation 81: 507–508. 557. Meier-Kriesche H-U, Davies NM, Grinyó J, Heading R, Mamelok R, Wijngaard P, Oellerich M, Maes B. (2005) Mycophenolate sodium does not reduce the incidence of GI adverse effects compared with mycophenolate mofetil. Am J Transplant 5: 1164. 558. Calvo N, Sanchez-Fructuoso AI, Conesa J, Moreno A, Barrientos A. (2006) Renal transplant patients with gastrointestinal intolerability to mycophenolate mofetil: Conversion to enteric-coated mycophenolate sodium. Transplant Proc 38: 2396–2397. 559. Loupy A, Anglicheau D, Mamzer-Bruneel M-F, Martinez F, Legendre C, Serpaggi J, Pol S. (2006) Mycophenolate sodiuminduced hepatotoxicity: First report. Transplantation 82: 581. 560. Chan L, Mulgaonkar S, Walker R, Arns W, Ambuhl P, Schiavelli R. (2006) Patient-reported gastrointestinal symptom burden and health-related quality

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 161

Bioactive Natural Products

Natural Products in Drug Discovery

561.

562.

563. 564.

565. 566. 567.

568.

569.

570.

161

of life following conversion from Mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplantation 81: 1290–1297. Fugi MA, Wittlin S, Dong Y, Vennerstrom JL. (2010) Probing the antimalarial mechanism of artemisinin and OZ277 (arterolane) with nonperoxidic isosteres and nitroxyl radicals. Antimicrob Agents Chemother 54: 1042–1046. Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MCY, Withers ST, Shiba Y, Sarpong R, Keasling JD. (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440: 940–943. Jefford CW. (2007) New developments in synthetic peroxidic drugs as artemisinin mimics. Drug Discovery Today 12: 487–495. Snyder C, Chollet J, Santo-Tomas J, Scheurer C, Wittlin S. (2007) In vitro and in vivo interaction of synthetic peroxide RBx11160 (OZ277) with piperaquine in Plasmodium models. Exp Parasitol 115: 296–300. Ranbaxy: Press release 4 May 2009. Available at http://www.ranbaxy.com/. Pan H, Lundgren LN, Andersson R. (1994) Triterpene caffeates from bark of Betula pubescens. Phytochemistry 37: 795–799. Fujioka T, Kashiwada Y, Kilkuskie RE, Cosentino LM, Ballas LM, Jiang JB, Janzen WP, Chen IS, Lee K-H. (1994) Anti-AIDS agents, 11. betulinic acid and platanic acid as anti-HIV principles from syzigium claviflorum, and the anti-HIV activity of structurally related triterpenoids. J Nat Prod 57: 243–247. Ganguly A, Das B, Roy A, Sen N, Dasgupta SB, Mukhopadhayay S, Majumder HK. (2007) Betulinic acid, a catalytic inhibitor of topoisomerase I, inhibits reactive oxygen species-mediated apoptotic topoisomerase IDNA cleavable complex formation in prostate cancer cells but does not affect the process of cell death. Cancer Res 67: 11848–11858. Kashiwada Y, Hashimoto F, Cosentino LM, Chen C-H, Garrett PE, Lee K-H. (1996) Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents. J Med Chem 39: 1016–1017. Hashimotof F, Kashiwadaf Y, Cosentino LM, Chen C-H, Garrett PE, Lee K-H. (1997) Anti-AIDS agents XXVII: Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives. Bioorg Med Chem 5: 2133–2143.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

162

Page 162

Bioactive Natural Products

Brahmachari

571. Martin DE, Blum R, Wilton J, Doto J, Galbraith H, Burgess GL, Smith PC, Ballow C. (2007) Safety and pharmacokinetics of bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers. Antimicrob Agents Chemother 51: 3063–3066. 572. Bullock P, Larsen D, Press R, Wehrman T, Martin DE. (2008) The absorption, distribution, metabolism and elimination of bevirimat in rats. Biopharm Drug Dispos 29: 396–405. 573. Myriad Pharmaceuticals: Press release 21 January 2009. Available at http://investor.myriad.com/. 574. Pisha E, Chai H, Lee I-S, Chagwedera TE, Farnsworth NR, Cordell GA, Beecher CWW, Fong HHS, Kinghorn AD, Brown DM, Wani MC, Wall ME, Hieken TJ, Das Gupta TK, Pezzuto JM. (1995) Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1: 1046–1051. 575. Sami A, Taru M, Salme K, Jari Y-K. (2006) Pharmacological properties of the ubiquitous natural product betulin. Eur J Pharm Sci 29: 1–13. 576. Chintharlapalli S, Papineni S, Ramaiah SK, Safe S. (2007) Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res 67: 2816–2823. 577. Hohenschutz LD, Bell EA, Jewess PJ, Leworthy DP, Pryce RJ, Arnold E, Clardy J. (1981) Castanospermine, a 1,6,7,8-tetrahydroxyoctahydroindolizine alkaloid, from seeds of Castanospermum australe. Phytochemistry 20: 811–814. 578. Whitby K, Pierson TC, Geiss B, Lane K, Engle M, Zhou Y, Doms RW, Diamond MS. (2005) Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo. J Virol 79: 8698–8706. 579. Whitby K, Taylor D, Patel D, Ahmed P, Tyms AS. (2004) Action of celgosivir (6-O-butanoyl castanospermine) against the pestivirus BVDV: Implications for the treatment of hepatitis C. Antiviral Chem Chemother 15: 141–151. 580. Durantel D, Alotte C, Zoulim F. (2007) Glucosidase inhibitors as antiviral agents for hepatitis B and C. Curr Opin Invest Drugs 8: 125–129. 581. MIGENIX: Press release 3 April 2009. Available at http://www.biowestinc. com/. 582. Further information on 4-methylumbelliferone clinical trial: http://www. clinicaltrial.gov/ct2/show/NCT00225537/ (accessed on 14.12.2010).

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 163

Bioactive Natural Products

Natural Products in Drug Discovery

163

583. Kakizaki I, Kojima K, Takagaki K, Endo M, Kannagi R, Ito M, Maruo Y, Sato H, Yasuda T, Mita S, Kimata K, Itano N. (2004) A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone. J Biol Chem 279: 33281–33289. 584. Gu R, Dou G, Wang J, Dong J, Meng Z. (2007) Simultaneous determination of 1,5-dicaffeoylquinic acid and its active metabolites in human plasma by liquid chromatography-tandem mass spectrometry for pharmacokinetic studies. J Chromatogr B 852: 85–91. 585. Yang B, Meng Z, Dong J, Yan L, Zou L, Tang Z, Dou G. (2005) Metabolic profile of 1,5- dicaffeoylquinic acid in rats, an in vivo and in vitro study. Drug Metab Dispos 33: 930–936. 586. Coleman BR, Ratcliffe R, Oguntayo S, Shi X, Doctor B, Gordon R, Nambiar M. (2008) [+]-Huperzine A treatment protects against N-methyld-aspartate-induced seizure/status epilepticus in rats. Chembiol Interact 175: 387–395. 587. Kozikowski AP, Tueckmantel W. (1999) Chemistry, pharmacology, and clinical efficacy of the Chinese nootropic agent huperzine A. Acc Chem Res 32: 641–650. 588. Bai DL, Tang XC, He XC. (2000) Huperzine A, a potential therapeutic agent for treatment of Alzheimers disease. Curr Med Chem 7: 355–374. 589. Zangara A. (2003) The psychopharmacology of huperzine A: An alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer’s disease. Pharmacol Biochem Behav 75: 675–686. 590. Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ. (2009) Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer’s disease: An updated meta-analysis. J Neural Transm 116: 457–465. 591. Further information: Available at http://www.alzforum.org/ (accessed on 14.12.2010). 592. Dahan A, van Dorp E, Smith T, Yassen A. (2008) Morphine-6-glucuronide (M6G) for postoperative pain relief. Eur J Pain 12: 403–411. 593. Kilpatrick GJ, Smith TW. (2005) Morphine-6-glucuronide: Actions and mechanisms. Med Res Rev 25: 521–544. For further information: PAION. Press release 3 November 2008. Available at http://www.paion.com/. 594. Marlow SP, Stoller JK. (2003) Smoking cessation. Respiratory Care 48: 1238–1256.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

164

Page 164

Bioactive Natural Products

Brahmachari

595. Buchhalter AR, Fant RV, Henningfield JE. (2008) Novel pharmacological approaches for treating tobacco dependence and withdrawal: Current status. Drugs 68: 1067–1088. 596. Zheng G, Dwoskin LP, Crooks PA. (2006) Vesicular monoamine transporter 2: Role as a novel target for drug development. AAPS J 8: E682–E692. 597. Zheng F, Zheng G, Deaciuc AG, Zhan CG, Dwoskin LP, Crooks PA. (2007) Computational neural network analysis of the affinity of lobeline and tetrabenazine analogs for the vesicular monoamine transporter-2. Bioorg Med Chem 15: 2975–2992. 598. Zheng G, Dwoskin LP, Deaciuc AG, Norrholm SD, Crooks PA. (2005) Defunctionalized lobeline analogues: Structure-affinity of novel ligands for the vesicular monoamine transporter. J Med Chem 48: 5551–5560. 599. Yaupon Therapeutics: Further information available at http://www.yaupontherapeutics.com/. 600. Anesiva: Further information available at http://www.anesiva.com/. 601. Winston Pharmaceuticals: Press Release 19 October 2009. Available at http://www.winstonlabs.com/. 602. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. (1987) Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 79: 1510–1515. 603. Oulianova N, Falk S, Berteloot A. (2001) Two-step mechanism of phlorizin binding to the SGLT1 protein in the kidney. J Membr Biol 179: 223–242. 604. White JR. (2010) Apple trees to sodium glucose co-transporter inhibitors: A review of SGLT2 inhibition. Clinical Diabetes 28: 5–10. 605. Ehrenkranz JRL, Lewis NG, Kahn CR, Roth J. (2004) Phlorizin: A review. Diabetes Metab Res Rev 21: 31–38. 606. Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN. (2008) Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 51: 1145–1149. 607. BMS: Press release 2 October 2009. Available at http://www.bms.com/. 608. Baur JA, Sinclair DA. (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5: 493–506.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 165

Bioactive Natural Products

Natural Products in Drug Discovery

165

609. Espin JC, Garcia-Conesa MT, Tomas-Barberan FA. (2007) Nutraceuticals: Facts and fiction. Phytochemistry 68: 2986–3008. 610. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191–196. 611. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430: 686–689. 612. Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A. (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16: 296–300. 613. Elliott PJ, Walpole S, Morelli L, Lambert PD, Lunsmann W, Westphal CH, Lavu S. (2009) Resveratrol/SRT-501. Drugs Fut 34: 291–295. 614. Further information: Available at http://www.sirtrispharma.com/ (accessed on 24.12.2010). 615. Lambert DM, Fowler CJ. (2005) The endocannabinoid system: Drug targets, lead compounds, and potential therapeutic applications. J Med Chem 48: 5059–5087. 616. Burstein SH, Karst M, Schneider U, Zurier RB. (2004) Ajulemic acid: A novel cannabinoid produces analgesia without a “high”. Life Sci 75: 1513–1522. 617. Burstein H, Andette CA, Breurr A, Devane WA, Colodner S, Doyle SA, Mechoulam R. (1992) Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte antiadhesion activities. J Med Chem 35: 3135–3141. 618. Further information: Available at http://www.cervelopharm.com/ (accessed on 14.12.2010). 619. RL, Wustman BA, Huertas P, Powe AC, Pine CW, Khanna R, Schlossmacher MG, Ringe D, Petsko GA. (2007) Structure of acid betaglucosidase with pharmacological chaperone provides insight into Gaucher disease. Nat Chem Biol 3: 101–107. 620. Steet R, Chung S, Lee WS, Pine CW, Do H, Kornfeld S. (2007) Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-beta-glucosidase. Biochem Pharmacol 73: 1376–1383.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

166

Page 166

Bioactive Natural Products

Brahmachari

621. Steet R, Chung S, Wustman B, Powe A, Do H, Kornfeld SA. (2006) The iminosugar isofagomine increases the activity of N370S mutant acid betaglucosidase in gaucher fibroblasts by several mechanisms. Proc Natl Acad Sci USA 103: 13813–13818. 622. Dulsat C, Mealy N. (2009) Isofagomine tartrate. Drugs Fut 34: 23. 623. Clasby MC, Chackalamannil S, Czarniecki M, Doller D, Eagen K, Greenlee W, Kao G, Lin Y, Tsai H, Xia Y, Ahn HS, Agans-Fantuzzi J, Boykow G, Chintala M, Foster C, Smith-Torhan A, Alton K, Bryant M, Hsieh Y, Lau J, Palamanda J. (2007) Metabolism-based identification of a potent thrombin receptor antagonist. J Med Chem 50: 129–138. 624. Chelliah MV, Chackalamannil S, Xia Y, Eagen K, Clasby MC, Gao X, Greenlee W, Ahn H-S, Agans-Fantuzzi J, Boykow G, Hsieh Y, Bryant M, Palamanda J, Chan T-M, Hesk D, Chintala M. (2007) Heterotricyclic himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists. J Med Chem 50: 5147–5160. 625. Xia Y, Chackalamannil S, Clasby M, Doller D, Eagen K, Greenlee WJ, Tsai H, Agans-Fantuzzi J, Ahn H-S, Boykow GC, Hsieh Y, Lunn CA, Chintala M. (2007) Himbacine derived thrombin receptor (PAR-1) antagonists: SAR of the pyridine ring. Bioorg Med Chem Lett 17: 4509–4513. 626. Clasby MC, Chackalamannil S, Czarniecki M, Doller D, Eagen K, Greenlee WJ, Lin Y, Tagat JR, Tsai H, Xia Y, Ahn H-S, Agans-Fantuzzi J, Boykow G, Chintala M, Hsieh Y, McPhail AT. (2007) Himbacine derived thrombin receptor antagonists: Discovery of a new tricyclic core. Bioorg Med Chem Lett 17: 3647–3651. 627. Seo HJ, Surh YJ. (2001) Eupatilin, a pharmacologically active flavone derived from Artemisia plants, induces apoptosis in human promyelocytic leukemia cells. Mutat Res 496: 191–198. 628. Kim DH, Na HK, Oh TY, Kim WB, Surh YJ. (2004) Eupatilin, a pharmacologically active flavones derived from Artemisia plants, induces cell cycle arrest in ras-transformed human mammary epithelial cells. Biochem Pharmacol 68: 1081–1087. 629. Dong-A Pharmaceutical: Further information: Available at http://www. donga-pharm.com (accessed on 14.12.2010). 630. Pommier Y. (2006) Topoisomerase I inhibitors: Camptothecins and beyond. Nat Rev Cancer 6: 789–802.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 167

Bioactive Natural Products

Natural Products in Drug Discovery

167

631. Teicher BA. (2008) Next generation topoisomerase I inhibitors: Rationale and biomarker strategies. Biochem Pharmacol 75: 1262–1271. 632. Grossman SA, Carson KA, Phuphanich S, Batchelor T, Peereboom D, Nabors LB, Lesser G, Hausheer F, Supko JG. (2008) Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas. Neuro-Oncology 10: 608–616. 633. Daud A, Valkov N, Centeno B, Derderian J, Sullivan P, Munster P, Urbas P, DeConti RC, Berghorn E, Liu Z, Hausheer F, Sullivan D. (2005) Phase II trial of karenitecin in patients with malignant melanoma: Clinical and translational study. Clin Cancer Res 11: 3009–3016. 634. BioNumerik Pharmaceuticals: Press release 7 February 2008. Available at http://www.bionumerik.com/. 635. Kroep JR, Gelderblom H. (2009) Diflomotecan, a promising homocamptothecin for cancer therapy. Expert Opin Inv Drugs 18: 69–75. 636. Ipsen: Further information: Available at http://www.ipsen.com (accessed on 14.12.2010). 637. Nitiss JL, Nitiss KC. (2005) Gimatecan (sigma-tau industrie farmaceutiche riunite/novartis). IDrugs 8: 578–588. 638. Sessa C, Cresta S, Cerny T, Baselga J, Rota Caremoli E, Malossi A, Hess D, Trigo J, Zucchetti M, D’Incalci M, Zaniboni A, Capri G, Gatti B, Carminati P, Zanna C, Marsoni S, Gianni L. (2007) Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors. Ann Oncol 18: 561–568. 639. Pecorelli S, Ray-Coquard I, Tredan O, Colombo N, Parma G, Tisi G, Katsaros D, Lhomme C, Lissoni AA, Vermorken JB, du Bois A, Poveda A, Frigerio L, Barbieri P, Carminati P, Brienza S, Guastalla JP. (2010) Phase II of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer, previously treated with platinum and taxanes. Ann Oncol 21: 759–765. 640. Lavergne O, Harnett J, Rolland A, Lanco C, Lesueur-Ginot L, Demarquay D, Huchet M, Coulomb H, Bigg DC. (1999) BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 9: 2599–2602. 641. Chatterjee RD, Digumarti R, Mamidi RN, Katneni K, Upreti VV, Surath A, Srinivas ML, Uppalapati S, Jiwatani S, Subramaniam S, Srinivas NR. (2004) Safety, tolerability, pharmacokinetics, and pharmacodynamics of an

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

168

642.

643. 644.

645.

646.

647. 648.

649. 650. 651. 652.

653.

Page 168

Bioactive Natural Products

Brahmachari

orally active novel camptothecin analog, DRF-1042, in refractory cancer patients in a phase I dose escalation study. J Clin Pharmacol 44: 723–736. Chatterjee A, Digumarti R, Katneni K, Upreti VV, Mamidi RN, Mullangi R, Surath A, Sriniva ML, Uppalapati S, Jiwatani S, Srinivas NR. (2005) Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF1042, a novel camptothecin analog, in refractory cancer patients in a bridging phase I study. J Clin Pharmacol 45: 453–460. OncoGenex Pharmaceuticals: Further information available at http://www. oncogenex.ca/. Escalona-Benz E, Jockovich ME, Murray TG, Hayden B, Hernandez E, Feuer W, Windle JJ. (2005) Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma. Invest Ophthalmol Vis Sci 46: 8–11. Aprile S, Grosso ED, Grosa G. (2010) Identification of the human UDPglucuronosyltransferases involved in the glucuronidation of combretastatin A-4. Drug Metab Dispos 38: 1141–1146. Pettit GR, Temple C, Narayanan VL, Varma R, Simpson MJ, Boyd MR, Rener GA, Bansal N. (1995) Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des 10: 299–309. Young SL, Chaplin DJ. (2004) Combretastatin A4 phosphate: Background and current clinical status. Expert Opin Invest Drugs 13: 1171–1182. Mahindroo N, Liou J-P, Chang J-Y, Hsieh H-P. (2006) Antitubulin agents for the treatment of cancer — a medicinal chemistry update. Expert Opin Ther Pat 16: 647–691. Hinnen P, Eskens FA. (2007) Vascular disrupting agents in clinical development. Br J Cancer 96: 1159–1165. Oxigene: Press release 17 November 2009. Available at http://investor.oxigene.com/. Sanofi-Aventis: Further information available at http://www.oncology. sanofiaventis.com/. Pettit GR, Lippert JW. (2000) Antineoplastic agents 429. Syntheses of the combretastatin A-1 and combretastatin B-1 prodrugs. Anti-Cancer Drug Des 15: 203–216. Salmon HW, Siemann DW. (2006) Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity. Clin Cancer Res 12: 4090–4094.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 169

Bioactive Natural Products

Natural Products in Drug Discovery

169

654. Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C. (2008) Alterations in vascular architecture and permeability following OXi4503 treatment. Anti-Cancer Drugs 19: 17–22. 655. Ye K, Ke Y, Keshava N, Shanks J, Kapp JA, Tekmal RR, Petros J, Joshi HC. (1998) Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells. Proc Natl Acad Sci USA 95: 1601–1606. 656. Aneja R, Dhiman N, Idnani J, Awasthi A, Arora SK, Chandra R, Joshi HC. (2007) Preclinical pharmacokinetics and bioavailability of noscapine, a tubulin-binding anticancer agent. Cancer Chemother Pharmacol 60: 831–839. 657. Jackson T, Chougule MB, Ichite N, Patlolla RR, Singh M. (2008) Antitumor activity of noscapine inhuman non-small cell lung cancer xenograft model. Cancer Chemother Pharmacol 63: 117–126. 658. Kingston DG, Newman DJ. (2007) Taxoids: Cancer-fighting compounds from nature. Curr Opin Drug Discovery Dev 10: 130–144. 659. Cisternino S, Bourasset F, Archimbaud Y, Semiond D, Sanderink G, Scherrmann JM. (2003) Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats. Br J Pharmacol 138: 1367–1375. 660. Engels FK, Sparreboom A, Mathot RA, Verweij J. (2005) Potential for improvement of docetaxel-based chemotherapy: A pharmacological review. Br J Cancer 93: 173–177. 661. Gelmon KA, Latreille J, Tolcher A, Genier L, Fisher B, Forand D, D’Aloisio S, Vernillet L, Daigneault L, Lebecq A, Besenval M, Eisenhauer E. (2000) Phase I dose-finding study of a new taxane, RPR 109881A, administered as a one-hour intravenous infusion days 1 and 8 to patients with advanced solid tumors. J Clin Oncol 18: 4098–4108. 662. Kurata T, Shimada Y, Tamura T, Yamamoto N, Hyodo I, Saeki T, Takashima S, Fujiwara K, Wakasugi H, Kashimura M. (2000) Phase I and pharmacokinetic study of a new taxoid, RPR 109881A, given as a 1-hour intravenous infusion in patients with advanced solid tumors. J Clin Oncol 18: 3164–3171. 663. Brooks T, Minderman H, O’Loughlin KL, Pera P, Ojima I, Baer MR, Bernacki RJ. (2003) Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Mol Cancer Ther 2: 1195–1205.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

170

Page 170

Bioactive Natural Products

Brahmachari

664. Sessa C, Cuvier C, Caldiera S, Bauer J, Van Den Bosch S, Monnerat C, Semiond D, Perard D, Lebecq A, Besenval M, Marty M. (2002) Phase I clinical and pharmacokinetic studies of the taxoid derivative RPR 109881A administered as a 1-hour or a 3-hour infusion in patients with advanced solid tumors. Ann Oncol 13: 1140–1150. 665. Bradley MO, Webb NL, Anthony FH, Devanesan P, Witman PA, Hemamalini S, Chander MC, Baker SD, He L, Horwitz SB, Swindell CS. (2001) Tumor targeting by covalent conjugation of a natural fatty acid to paclitaxel. Clin Cancer Res 7: 3229–3238. 666. Jones RJ, Hawkins RE, Eatock MM, Ferry DR, Eskens FA, Wilke H, Evans TR. (2008) A phase II openlabel study of DHA-paclitaxel (Taxoprexin) by 2-h intravenous infusion in previously untreated patients with locally advanced or metastatic gastric or oesophageal adenocarcinoma. Cancer Chemother Pharmacol 61: 435–441. 667. Ojima I, Slater JC, Kuduk SD, Takeuchi CS, Gimi RH, Sun CM, Park YH, Pera P, Veith JM, Bernacki RJ. (1997) Syntheses and structure-activity relationships of taxoids derived from 14 betahydroxy-10-deacetylbaccatin III. J Med Chem 40: 267–278. 668. Geney R, Chen J, Ojima I. (2005) Recent advances in the new generation taxane anticancer agents. Med Chem 1: 125–139. 669. Sano D, Matsuda H, Ishiguro Y, Nishimura G, Kawakami M, Tsukuda M. (2006) Antitumor effects of IDN5109 on head and neck squamous cell carcinoma. Oncol Rep 15: 329–334. 670. Spectrum: Further information available at http://www.spectrumpharm.com/ (accessed on 14.12.2010). 671. Sampath D, Discafani CM, Loganzo F, Beyer C, Liu H, Tan X, Musto S, Annable T, Gallagher P, Rios C, Greenberger LM. (2003) MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo. Mol Cancer Ther 2: 873–884. 672. Ramanathan RK, Picus J, Raftopoulos H, Bernard S, Lockhart AC, Frenette G, Macdonald J, Melin S, Berg D, Brescia F, Hochster H, Cohn A. (2008) A phase II study of milataxel: A novel taxane analogue in previously treated patients with advanced colorectal cancer. Cancer Chemother Pharmacol 61: 453–458. 673. Shionoya M, Jimbo T, Kitagawa M, Soga T, Tohgo A. (2003) DJ-927, a novel oral taxane, overcomes Pglycoprotein-mediated multidrug resistance

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 171

Bioactive Natural Products

Natural Products in Drug Discovery

674.

675.

676.

677. 678. 679.

680.

681.

682.

683.

171

in vitro and in vivo. DJ-927, a novel oral taxane, overcomes P-glycoproteinmediated multidrug resistance in vitro and in vivo. Cancer Sci 94: 459–466. Ono C, Takao A, Atsumi R. (2004) Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys. Biol Pharm Bull 27: 345–351. Roche M, Kyriakou H, Seiden M. (2006) Drug evaluation: Tesetaxel — an oral semisynthetic taxane derivative. Curr Opin Invest Drugs 7: 1092–1099. Safarpour H, Connolly P, Tong X, Bielawski M, Wilcox E. (2009) Overcoming extractability hurdles of a 14C labeled taxane analogue milataxel and its metabolite from xenograft mouse tumor and brain tissues. J Pharm Biomed Anal 49: 774–779. Genta: Further information available at http://www.genta.com/ (accessed on 14.12.2010). Tapestry Pharmaceuticals: Further information available at http://www. tapestrypharma.com/ (accessed on 14.12.2010). Advani R, Fisher GA, Lum BL, Jambalos C, Cho CD, Cohen M, Gollerkeri A, Sikic BI. (2003) Phase I and pharmacokinetic study of BMS188797, a new taxane analog, administered on a weekly schedule in patients with advanced malignancies. Clin Cancer Res 9: 5187–5194. Fishman MN, Garrett CR, Simon GR, Chiappori AA, Lush RM, Dinwoodie WR, Mahany JJ, Dellaportas AM, Cantor A, Gollerki A, Cohen MB, Sullivan DM. (2006) Phase I study of the taxane BMS-188797 in combination with carboplatin administered every 3 weeks in patients with solid malignancies. Clin Cancer Res 12: 523–528. de Bois A, Jung B, Loehr A, Schaller-Kranz T, Cohen M, Frickhofen N. (2006) A phase I and pharmacokinetic study of novel taxane BMS-188797 and cisplatin in patients with advanced solid tumours. Br J Cancer 94: 79–84. Fahy J, Duflos A, Ribet J-P, Jacquesy J-C, Berrier C, Jouannetaud MP, Zunino F. (1997) Vinca alkaloids in superacidic media: A method for creating a new family of antitumor derivatives. J Am Chem Soc 119: 8576–8577. Makarov AA, Tsvetkov PO, Villard C, Esquieu D, Pourroy B, Fahy J, Braguer D, Peyrot V, Lafitte D. (2007) Vinflunine, a novel microtubule inhibitor, suppresses calmodulin interaction with the microtubule-associated protein STOP. Biochemistry 46: 14899–14906.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

172

Page 172

Bioactive Natural Products

Brahmachari

684. Bennouna J, Campone M, Delord JP, Pinel MC. (2005) Vinflunine: A novel antitubulin agent in solid malignancies. Expert Opin Invest Drugs 14: 1259–1267. 685. Bristol-Myers Squibb: Press release 23 November 2007. Available at http:// www.bms.com/. 686. Kruczynski A, Barret JM, Etievant C, Colpaert F, Fahy J, Hill BT. (1998) Antimitotic and tubulininteracting properties of vinflunine, a novel fluorinated Vinca alkaloid. Biochem Pharmacol 55: 635–648. 687. Laboratoires Pierre Fabre: Press release 26 June 2009. Available at http:// www.pierrefabre.com/. 688. Jacquesy J-C, Berrier C, Jouannetaud M-P, Zunino F, Fahy J, Duflos A, Ribet J-P. (2002) Fluorination in superacids: A novel access to biologically active compounds. J Fluor Chem 114: 139–141. 689. Bristol-Myers Squibb: Press release 23rd November 2007. Available at http://www.bms.com/. 690. Athar M, Back JH, Tang X, Kim KH, Kopelovich L, Bickers DR, Kim AL. (2007) Resveratrol: A review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol 224: 274–283. 691. de la Lastra CA, Villegas I. (2007) Resveratrol as an antioxidant and prooxidant agent: Mechanisms and clinical implications. Biochem Soc Trans 35: 1156–1160. 692. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. (2008) Curcumin: From ancient medicine to current clinical trials. Cell Mol Life Sci 65: 1631–1652. 693. Liu J. (1995) Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 49: 57–68. 694. Ahmad R, Raina D, Meyer C, Kharbanda S, Kufe D. (2006) Triterpenoid CDDO-Me blocks the NFkappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem 281: 35764–35769. 695. RITA: Further information available at http://www.reatapharma.com/ (accessed on 14.12.2010). 696. Choi YH, Kang HS, Yoo MA. (2003) Suppression of human prostate cancer cell growth by betalapachone via down-regulation of pRB phosphorylation and induction of Cdk inhibitor p21(WAF1/CIP1). J Biochem Mol Biol 36: 223–229. 697. Pardee AB, Li YZ, Li CJ. (2002) Cancer therapy with beta-lapachone. Curr Cancer Drug Targets 2: 227–242.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 173

Bioactive Natural Products

Natural Products in Drug Discovery

173

698. Bey EA, Bentle MS, Reinicke KE, Dong Y, Yang CR, Girard L, Minna JD, Bornmann WG, Gao J, Boothman DA. (2007) An NQO1- and PARP-1mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci USA 104: 11832–11837. 699. Bentle MS, Reinicke KE, Dong Y, Bey EA, Boothman DA. (2007) Nonhomologous end joining is essential for cellular resistance to the novel antitumor agent, beta-lapachone. Cancer Res 67: 6936–6945. 700. Harmon AD, Weiss U, Silverton JV. (1979) The structure of rohitukine, the main alkaloid of Amoora Rohituka (Syn. Aphanamixis Polystachya) (meliaceae). Tetrahedron Lett 20: 721–724. 701. Patel M, Nambiar S, Vaidayanathan P, Bheemanahally TR, Gudasalamani R, Kotiganahalli NG, Ramesh V, John M, Thankayyan RS, Mishra PD, Viswakarma R, Ramanan US. (2010) Dysoxylum Binectariferum Hook.f (Meliaceae), a rich source of rohitukine. Fitoterapia 81: 145–148. 702. Sanofi-Aventis: Further information available at http://en.sanofiaventis.com/ (accessed on 14.12.2010). 703. Coward L, Barnes NC, Setchell KDR, Barnes S. (1993) Genistein, daidzein and their β-glycoside conjugates: Antitumor and isoflavones in soybean foods from American and Asian diets. J Agric Food Chem 41: 1961–1967. 704. Constantinou AI, Husband A. (2002) Phenoxodiol (2H-1-benzopyran-70,1,3-(4-hydroxyphenyl)), a novel isoflavone derivative, inhibits DNA topoisomerase II by stabilizing the cleavable complex. Anticancer Res 22: 2581–2585. 705. Constantinou AI, Mehta R, Husband A. (2003) Phenoxodiol, a novel isoflavone derivative, inhibits dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats. Eur J Cancer 39: 1012–1018. 706. Morre DJ, Chueh PJ, Yagiz K, Balicki A, Kim C, Morre DM. (2007) ECTO-NOX target for the anticancer isoflavene phenoxodiol. Oncol Res 16: 299–312. 707. Mor G, Fu HH, Alvero AB. (2006) Phenoxodiol, a novel approach for the treatment of ovarian cancer. Curr Opin Invest Drugs 7: 542–548; Marshall Edwards: http://www.marshalledwardsinc.com/ (accessed on 14.12.2010). 708. http://en.wikipedia.org/wiki/Genistein (accessed on 14.12.2010); for futher information: http://www.newsrx.com/search_results.php?doSearch=1& cat=a&search_term=Genistein&x=0&y=0 (accessed on 14.12.2010).

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

174

Page 174

Bioactive Natural Products

Brahmachari

709. Rewcastle GW, Atwell GJ, Baguley BC, Calveley SB, Denny WA. (1989) Potential antitumor agents. 58. Synthesis and structure-activity relationships of substituted xanthenone-4-acetic acids active against the colon 38 tumor in vivo. J Med Chem 32: 793–799. 710. Rewcastle GW, Atwell GJ, Zhuang L, Baguley BC, Denny WA. (1991) Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9Hxanthene-4-acetic acids. J Med Chem 34: 217–222. 711. Wallace A, LaRosa DF, Kapoor V, Sun J, Cheng G, Jassar A, Blouin A, Ching LM, Albelda SM. (2007) The vascular disrupting agent, DMXAA, directly activates dendritic cells through a MyD88-independent mechanism and generates antitumor cytotoxic T lymphocytes. Cancer Res 67: 7011–7019. 712. McKeage MJ. (2008) The potential of DMXAA (ASA404) in combination with docetaxel in advanced prostate cancer. Expert Opin Invest Drugs 17: 23–29. 713. Antisoma: Further information available at http://www.antisoma.com/ (accessed on 14.12.2010). 714. Provinciali M, Papalini F, Orlando F, Pierpaoli S, Donnini A, Morazzoni P, Riva A, Smorlesi A. (2007) Effect of the silybin-phosphatidylcholine complex (IdB 1016) on the development of mammary tumors in HER-2/neu transgenic mice. Cancer Res 67: 2022–2029. 715. Gazak R, Walterova D, Kren V. (2007) Silybin and silymarin — new and emerging applications in medicine. Curr Med Chem 14: 315–338. 716. Mokhtari MJ, Motamed N, Shokrgozar MA. (2008) Evaluation of silibinin on the viability, migration and adhesion of the human prostate adenocarcinoma (PC-3) cell line. Cell Biol Int 32: 888–892. 717. Bhatia N, Zhao J, Wolf DM, Agarwal R. (1999) Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: Comparison with silymarin. Cancer Lett 147: 77–84. 718. Hogan FS, Krishnegowda NK, Mikhailova M, Kahlenberg MS. (2007) Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer. J Surg Res 143: 58–65. 719. Sharma G, Singh RP, Chan DC, Agarwal R. (2003) Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells. Anticancer Res 23: 2649–2655.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 175

Bioactive Natural Products

Natural Products in Drug Discovery

175

720. Youngren JF, Gable K, Penaranda C, Maddux BA, Zavodovskaya M, Lobo M, Campbell M, Kerner J, Goldfine ID. (2005) Nordihydroguaiaretic acid (NDGA) inhibits the IGF-1 and cerbB2/HER2/neu receptors and suppresses growth in breast cancer cells. Breast Cancer Res Treat 94: 37–46. 721. Khanna N, Dalby R, Tan M, Arnold S, Stern J, Frazer N. (2007) Phase I/II clinical safety studies of terameprocol vaginal ointment. Gynecol Oncol 107: 554–562. 722. Hwu JR, Tseng WN, Gnabre J, Giza P, Huang RC. (1998) Antiviral activities of methylated nordihydroguaiaretic acids. 1. Synthesis, structure identification, and inhibition of tat-regulated HIV transactivation. J Med Chem 41: 2994–3000. 723. Chen H, Teng L, Li JN, Park R, Mold DE, Gnabre J, Hwu JR, Tseng WN, Huang RC. (1998) Antiviral activities of methylated nordihydroguaiaretic acids. 2. Targeting herpes simplex virus replication by the mutation insensitive transcription inhibitor tetra-O-methyl-NDGA. J Med Chem 41: 3001–3007. 724. Chang CC, Heller JD, Kuo J, Huang RC. (2004) Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression. Proc Natl Acad Sci USA 101: 13239–13244. 725. Lopez RA, Goodman AB, Rhodes M, Blomberg JA, Heller J. (2007) The anticancer activity of the transcription inhibitor terameprocol (meso-tetraO-methyl nordihydroguaiaretic acid) formulated for systemic administration. Anti-Cancer Drugs 18: 933–939. 726. Smolewski P. (2008) Terameprocol, a novel site-specific transcription inhibitor with anticancer activity. IDrugs 11: 204–214. 727. Barret JM, Kruczynski A, Etievant C, Hill BT. (2002) Synergistic effects of F 11782, a novel dual inhibitor of topoisomerases I and II, in combination with other anticancer agents. Cancer Chemother Pharmacol 49: 479–486. 728. Sargent JM, Elgie AW, Williamson CJ, Hill BT. (2003) Ex vivo effects of the dual topoisomerase inhibitor tafluposide (F11782) on cells isolated from fresh tumor samples taken from patients with cancer. Anti-Cancer Drugs 14: 467–473. 729. Kluza J, Mazinghien R, Irwin H, Hartley JA, Bailly C. (2006) Relationships between DNA strand breakage and apoptotic progression upon treatment of HL-60 leukemia cells with tafluposide or etoposide. Anti-Cancer Drugs 17: 155–164.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

176

Page 176

Bioactive Natural Products

Brahmachari

730. Gotta H, Adolf W, Opferkuch HJ, Hecker E. (1984) On the active principles of the Euphorbiaceae, IX. Ingenane type diterpene esters from five Euphorbia species. Z Naturforsch B 39: 683–694; Hohmann J, Evanics F, Berta L, Bartok T. (2000) Diterpenoids from Euphorbia peplus. Planta Med 66: 291–294; Ivanova A, Khozin-Goldberg I, Kamenarska Z, Nechev J, Cohen Z, Popov S, Stefanov K. (2003) Lipophylic compounds from Euphorbia peplis L. — a halophytic plant from the Bulgarian black sea coast. Z. Naturforsch 58c: 783–788. 731. Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, McAlpine J, Johns TM, Scott KP, Sutherland JM, Gardner TTT, Le A, Lenarczyk D, Aylward JH, Parsons PG. (2004) Antitumor activity of 3ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res 64: 2833–2839. 732. Challacombe JM, Suhrbier A, Parsons PG, Jones B, Hampson P, Kavanagh D, Rainger GE, Morris M, Lord JM, Le TTT, Hoang-Le D, Ogbourne SM. (2006) Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol 177: 8123–8132. 733. Ogbourne SM, Hampson P, Lord JM, Parsons P, De Witte PA, Suhrbier A. (2007) Proceedings of the First International Conference on PEP005. AntiCancer Drugs 18: 357–362; Ersvaer E, Kittang AO, Hampson P, Sand K, Gjertsen BT, Lord JM, Bruserud Ø. (2010) The protein kinase-c agonist pep005 (ingenol 3-angelate) in the treatment of human cancer: A balance between efficacy and toxicity. Toxins 2: 174–194. 734. Michel S, Gaslonde T, Tillequin F. (2004) Benzo[b]acronycine derivatives: A novel class of antitumor agents. Eur J Med Chem 39: 649–655. 735. Garrett CR, Fishman MN, Rago RR, Williams CC, Dellaportas AM, Mahany JJ, Lush RM, Dalton WS, Gollerkeri A, Cohen MB, Sullivan DM. (2005) Phase I study of a novel taxane BMS-188797 in adult patients with solid malignancies. Clin Cancer Res 11: 3335–3341. 736. Tillequin F. (2007) Rutaceous alkaloids as models for the design of novel antitumor drugs. Phytochem Rev 6: 65–79. 737. Leonce S, Kraus-Berthier L, Golsteyn RM, David-Cordonnier MH, Tardy C, Lansiaux A, Poindessous V, Larsen AK, Pierre A. (2006) Generation of replication-dependent double-strand breaks by the novel N2-G-alkylator S23906-1. Cancer Res 66: 7203–7210.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 177

Bioactive Natural Products

Natural Products in Drug Discovery

177

738. Quintas-Cardama A, Kantarjian H, Garcia-Manero G, O’Brien S, Faderl S, Estrov Z, Giles F, Murgo A, Ladie N, Verstovsek S, Cortes J. (2007) Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer 109: 248–255. 739. ChemGenex: Press release 23 March 2010. Available at http://www. chemgenex.com/. 740. Hebeisen P, Heinze-Krauss I, Angehrn P, Hohl P, Page MGP, Then RL. (2001) In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillinresistant Staphylococci. Antimicrob Agents Chemother 45: 825–836. 741. Bush K, Heep M, Macielag MJ, Noel GJ. (2007) Anti-MRSA β-lactams in development, with a focus on ceftobiprole: The first anti-MRSA β-lactam to demonstrate clinical efficacy. Expert Opin Invest Drugs 16: 419–429. 742. Yun HC, Ellis MW, Jorgensen JH. (2007) Activity of ceftobiprole against community-associated methicillin-resistant Staphylococcus Aureus isolates recently recovered from US military trainees. Diagn Microbiol Infect Dis 59: 463–466. 743. Widmer AF. (2008) Ceftobiprole: A new option for treatment of skin and soft-tissue infections due to methicillin-resistant Staphylococcus Aureus. Clin Infect Dis 46: 656–658. 744. Noel GJ, Bush K, Bagchi P, Ianus J, Strauss RS. (2008) A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skinstructure infections. Clin Infect Dis 46: 647–655. 745. Ishikawa T, Matsunaga N, Tawada H, Kuroda N, Nakayama Y, Ishibashi Y, Tomimoto M, Ikeda Y, Tagawa Y, Iizawa Y, Okonogi K, Hashiguchi S, Miyake A. (2003) TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: Synthesis, physiochemical and pharmacological properties. Bioorg Med Chem 11: 2427–2437. 746. Iizawa Y, Nagai J, Ishikawa T, Hashiguchi S, Nakao M, Miyake A, Okonogi K. (2004) In vitro antimicrobial activity of T-91825, a novel anti-MRSA cephalosporin, and in vivo anti-MRSA activity of its prodrug, TAK-599. J Infect Chemother 10: 146–156. 747. Talbot GH, Thye D, Das A, Ge Y. (2007) Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother 51: 3612–3616.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

178

Page 178

Bioactive Natural Products

Brahmachari

748. Parish D, Scheinfeld N. (2008) Ceftaroline fosamil, a cephalosporin derivative for the potential treatment of MRSA infection. Curr Opin Invest Drugs 9: 201–209. 749. Hikida M, Itahashi K, Igarashi A, Shiba T, Kitamura M. (1999) In vitro antibacterial activity of LJC 11,036, an active metabolite of L-084, a new oral carbapenem antibiotic with potent antipneumococcal activity. Antimicrob Agents Chemother 43: 2010–2016. 750. Liu C-X, Kato N, Watanabe K, Sakata T, Kaneko T. (2000) Impact of a new quinolone, DU-6859a, and two oral carbapenems, CS-834 and L-084, on the rat and mouse caecal microflora. J Antimicrob Chemother 46: 823–826. 751. Kobayashi R, Konomi M, Hasegawa K, Morozumi M, Sunakawa K, Ubukata K. (2005) In vitro activity of tebipenem, a new oral carbapenem antibiotic, against penicillin-nonsusceptible Streptococcus Pneumoniae. Antimicrob Agents Chemother 49: 889–894. 752. Thomson KS, Moland ES. (2004) CS-023 (R-115685), a novel carbapenem with enhanced in vitro activity against oxacillin-resistant Staphylococci and Pseudomonas aeruginosa. J Antimicrob Chemother 54: 557–562. 753. Kawamoto I, Shimoji Y, Kanno O, Kojima K, Ishikawa K, Matsuyama E, Ashida Y, Shibayama T, Fukuoka T, Ohya S. (2003) Synthesis and structureactivity relationships of novel parenteral carbapenems, CS-023 (R-115685) and related compounds containing an amidine moiety. J Antibiot 56: 565–579. 754. Macgowan AP, Bowker KE, Noel AR. (2008) Pharmacodynamics of the antibacterial effect and emergence of resistance to tomopenem, formerly RO4908463/CS-023, in an in vitro pharmacokinetic model of Staphylococcus aureus infection. Antimicrob Agents Chemother 52: 1401–1406. 755. Ueda Y, Kanazawa K, Eguchi K, Takemoto K, Eriguchi Y, Sunagawa M. (2005) In vitro and in vivo antibacterial activities of SM-216601, a new broad-spectrum parenteral carbapenem. Antimicrob Agents Chemother 49: 4185–4196. 756. Ueda Y, Itoh M, Sasaki A, Sunagawa M. (2005) SM-216601, a novel parenteral 1betamethylcarbapenem: Structure-activity relationships of antibacterial activity and neurotoxicity in mice. J Antibiot 58: 118–140. 757. Kurazono M, Ida T, Yamada K, Hirai Y, Maruyama T, Shitara E, Yonezawa M. (2004) In vitro activities of ME1036 (CP5609), a novel parenteral

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 179

Bioactive Natural Products

Natural Products in Drug Discovery

758.

759.

760.

761.

762. 763.

764. 765.

766.

767.

768.

179

carbapenem, against methicillin-resistant Staphylococci. Antimicrob Agents Chemother 48: 2831–2837. Sader HS, Fritsche TR, Jones RN. (2008) Antimicrobial activities of ceftaroline and ME1036 tested against clinical strains of community-acquired methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 52: 1153–1155. Gootz T, Girard D, Schelkley W, Tensfeldt T, Foulds G, Kellogg M, Stam J, Campbell B, Jasys J, Kelbaugh P, Volkmann R, Hamanaka E. (1990) Pharmacokinetic studies in animals of a new parental penem CP-65,207 and its oral prodrug ester. J Antibiot 43: 422–432. Volkmann RA, Kelbaugh PR, Nason DM, Jasys VJ. (1992) 2-Thioalkyl Penems: An efficient synthesis of sulopenem, a (5R, 6S)-6-(1 (R)hydroxyethy1)-2-[(cis-1-oxo-3-thiolanyl)thioI-2-penem antibacterial. J Org Chem 57: 4352–4361. Minamimura M, Taniyama Y, Inoue E, Mitsuhashi S. (1993) In vitro antibacterial activity and betalactamase stability of CP-70,429 a new penem antibiotic. Antimicrob Agents Chemother 37: 1547–1551. Gettig JP, Crank CW, Philbrick AH. (2008) Faropenem medoxomil. Ann Pharmacother 42: 80–90. Schurek KN, Wiebe R, Karlowsky JA, Rubinstein E, Hoban DJ, Zhanel GG. (2007) Faropenem: Review of a new oral penem. Expert Rev Anti-Infect Ther 5: 185–198. Dalhoff A, Janjic N, Echols R. (2006) Redefining penems. Biochem Pharmacol 71: 1085–1095. Malabarba A, Ciabatti R, Kettenring J, Ferrari P, Scotti R, Goldstein BP, Denaro M. (1994) Amides of de-acetylglucosaminyl-deoxy teicoplanin active against highly glycopeptide-resistant Enterococci. J Antibiot 47: 1493–1506. Sosio M, Donadio S. (2006) Understanding and manipulating glycopeptide pathways: The example of the dalbavancin precursor A40926. J Ind Microbiol Biotechnol 33: 569–576. Billeter M, Zervos MJ, Chen AY, Dalovisio JR, Kurukularatne C. (2008) Dalbavancin: A novel onceweekly lipogylcopeptide antibiotic. Clin Infect Dis 46: 577–583. Kim A, Kuti JL, Nicolau DP. (2007) Review of dalbavancin, a novel semisynthetic lipoglycopeptide. Expert Opin Invest Drugs 16: 717–733;

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

180

769. 770.

771. 772. 773. 774. 775. 776.

777. 778.

779. 780. 781.

Page 180

Bioactive Natural Products

Brahmachari

Chen AY, Zervos MJ, Vazquez JA. (2007) Dalbavancin: A novel antimicrobial. Int J Clin 61: 853–863. For further information: http://www.pfizer.com/ (accessed on 14.12.2010). Coyle EA, Rybak MJ. (2010) Activity of oritavancin (ly333328), an investigational glycopeptide, compared to that of vancomycin against multidrug-resistant Streptococcus Pneumoniae in an in vitro pharmacodynamic model. Antimicrob Agents Chemother 45: 706–709; Kim SJ, Cegelski L, Stueber D, Singh M, Dietrich E, Tanaka KSE, Parr Jr TR, Far AR, Schaefer J. (2008) Oritavancin exhibits dual mode of action to inhibit cell-wall biosynthesis in Staphylococcus Aureus. J Mol Biol 377: 281–293; for further information: http://www.targanta.com/ (accessed on 14.12.2010). Theravance: Press release 7 July 2007. Available at http://investor. theravance.com/. Farver DK, Hedge DD, Lee SC. (2005) Ramoplanin: A lipoglycodepsipeptide antibiotic. Ann Pharmacother 39: 863–868. Fang X, Tiyanont K, Zhang Y, Wanner J, Boger D, Walker S. (2006) The mechanism of action of ramoplanin and enduracidin. Mol BioSyst 2: 69–76. Breukink E, De Kruijff B. (2006) Lipid II as a target for antibiotics. Nat Rev Drug Discov 5: 321–332. Fulco P, Wenzel RP. (2006) Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent. Expert Rev Anti-Infect Ther 4: 939–945. Scheinfeld N. (2007) A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus Aureus and enterococcus. J Drugs Dermatol 6: 97–103. Gerding DN, Muto CA, Owens RC. (2008) Treatment of Clostridium difficile infection. Clin Infect Dis 46: S32–S42. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J. (2009) Bad bugs, No drugs: no ESKAPE! an update from the infectious diseases society of america. Clin Infect Dis 48: 1–12. Vannuffel P, Cocito C. (1996) Mechanism of action of streptogramins and macrolides. Drugs 51: 20–30. Johnston NJ, Mukhtar TA, Wright GD. (2002) Streptogramin Antibiotics: Mode of action and resistance. Curr Drug Targets 3: 335–344. Pankuch GA, Kelly LM, Lin G, Bryskier A, Couturier C, Jacobs MR, Appelbaum PC. (2003) Activities of a new oral streptogramin, XRP

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 181

Bioactive Natural Products

Natural Products in Drug Discovery

782.

783.

784.

785.

786.

787.

788.

789.

790. 791.

181

2868, compared to those of other agents against Streptococcus pneumoniae and Haemophilus species. Antimicrob Agents Chemother 47: 3270–3274. Mabe S, Champney WS. (2005) A comparison of a new oral streptogramin XRP 2868 with quinupristindalfopristin against antibiotic-resistant strains of Haemophilus Influenzae, Staphylococcus Aureus, and Streptococcus Pneumoniae. Curr Microbiol 51: 363–366. Dupuis M, Leclercq R. (2006) Activity of a new oral streptogramin, XRP2868, against gram-positive Cocci harboring various mechanisms of resistance to Streptogramins. Antimicrob Agents Chemother 50: 237–242. Wecke T, Zuhlke D, Mader U, Jordan S, Voigt B, Pelzer S, Labischinski H, Homuth G, Hecker M, Mascher T. (2009) Daptomycin versus friulimicin B: In-depth profiling of Bacillus subtilis cell envelope stress responses. Antimicrob Agents Chemother 53: 1619–1623. Aretz W, Meiwes J, Seibert G, Vobis G, Wink J. (2000) Friulimicins: novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes Friuliensis sp nov. J Antibiot 53: 807–815. Vertesy L, Ehlers E, Kogler H, Kurz M, Meiwes J, Seibert G, Vogel M, Hammann P. (2000) Friulimicins: Novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes Friuliensis sp nov. J Antibiot 53: 816–827. Shotwell OL, Stodola FH, Michael WR, Lindenfelser LA, Dworschack RG, Pridham TG. (1958) Antibiotics against plant disease. III. Duramycin, a new antibiotic from Streptomyces Cinnamomeus forma Azacoluta. J Am Chem Soc 80: 3912–3915. Hayashi F, Nagashima K, Terui Y, Kawamura Y, Matsumoto K, Itazaki H. (1990) The structur of PA48009: The revised structure of duramycin. J Antibiot 43: 1421–1430. Grasemann H, Stehling F, Brunar H, Widmann R, Laliberte TW, Molina L, Doring G, Ratjen F. (2007) Inhalation of Moli1901 in patients with cystic fibrosis. Chest 131: 1461–1466. Lawrence LE. (2001) ABT-773 (Abbott Laboratories). Curr Opin Invest Drugs 2: 766–772. Dougherty TJ, Barrett JF. (2001) ABT-773: A new ketolide antibiotic. Expert Opin Inv Drugs 10: 343–351.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

182

Page 182

Bioactive Natural Products

Brahmachari

792. Zhanel GG, Hisanaga T, Nichol K, Wierzbowski A, Hoban DJ. (2003) Ketolides: An emerging treatment for macrolide-resistant respiratory infections, focusing on S. pneumoniae. Expert Opin Emerg Drugs 8: 297–321. 793. Reinert RR. (2004) Clinical efficacy of ketolides in the treatment of respiratory tract infections. J Antimicrob Chemoth 53: 918–927. 794. Hammerschlag MR, Sharma R. (2008) Use of cethromycin, a new ketolide, for treatment of communityacquired respiratory infections. Expert Opin Inv Drugs 17: 387–400. 795. Advance Life Sciences: Press release 3 December 2008. Available at http://ir.advancedlifesciences.com/; for further information: http://www. medicalnewstoday.com/articles/131707.php. 796. Wang G, Niu D, Qiu Y-L, Phan LT, Chen Z, Polemeropoulos A, Or YS. (2004) Synthesis of novel 6,11-O-bridged bicyclic ketolides via a palladiumcatalyzed bis-allylation. Org Lett 6: 4455–4458. 797. Xiong L, Korkhin Y, Mankin AS. (2005) Binding site of the bridged macrolides in the Escherichia coli ribosome. Antimicrob Agents Chemother 49: 281–288. 798. Stucki A, Gerber P, Acosta F, Cottagnoud M, Cottagnoud P, Jiang L, Nguyen P, Wachtel D, Wang G, Phan LT. (2008) Effects of EDP-420 on penicillin-resistant and quinolone- and penicillinresistant pneumococci in the rabbit meningitis model. J Antimicrob Chemother 61: 665–669. 799. Dreier J, Amantea E, Kellenberger L, Page MGP. (2007) Activity of the novel macrolide BAL19403 against ribosomes from erythromycinresistant Propionibacterium acnes. Antimicrob Agents Chemother 51: 4361–4365. 800. Heller S, Kellenberger L, Shapiro S. (2007) Antipropionibacterial activity of BAL19403, a novel macrolide antibiotic. Antimicrob Agents Chemother 51: 1956–1961. 801. Wind M, Gebhardt K, Grunwald H, Spickermann J, Donzelli M, Kellenberger L, Muller M, Fullhardt P, Schmitt-Hoffmann A, Schleimer M. (2007) Elucidation of the in vitro metabolic profile of stable isotope labeled BAL19403 by accurate mass capillary liquid chromatography/quadrupole time-of-flight mass spectrometry and isotope exchange. Rapid Commun Mass Spectrom 21: 1093–1099. 802. Shi J, Montay G, Bhargava VO. (2005) Clinical pharmacokinetics of telithromycin, the first ketolide antibacterial. Clin Pharmacokinet

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 183

Bioactive Natural Products

Natural Products in Drug Discovery

803.

804. 805. 806.

807. 808.

809.

810. 811.

812.

813.

814.

183

44: 915–934; for further information: http://www.ketek.com/ (accessed on 14.12.2010). Hochlowski JE, Swanson SJ, Ranfranz LM, Whittern DN, Buko AM, McAlpine JB. (1987) Tiacumicins, a novel complex of 18-membered macrolides II isolation and structure determination. J Antibiot 40: 575–588. Revill P, Serradell N, Bolos J. (2006) Tiacumicin B. Drugs Fut 31: 494–497. Johnson AP. (2007) OPT-80, a narrow-spectrum macrocyclic antibiotic. Curr Opin Invest Drugs 8: 168–173. Shue YK, Sears PS, Walsh RB, Lee C, Gorbach SL, Okumu F, Preston RA. (2008) Safety, tolerance and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses. Antimicrob Agents Chemother 52: 1391–1395. Sergio S, Pirali G, White R, Parenti F. (1975) Lipiarmycin, a new antibiotic from actinoplanes III mechanism of action. J Antibiot 28: 543–549. Gualtieri M, Villain-Guillot P, Latouche J, Leonetti JP, Bastide L. (2006) Mutation in the Bacillus subtilis RNA polymerase β ′ subunit confers resistance to lipiarmycin. Antimicrob Agents Chemother 50: 401–402. Gerber M, Ackermann G. (2008). OPT-80, a macrocyclic antimicrobial agent for the treatment of Clostridium difficile infections: A review. Expert Opin Inv Drugs 17: 547–553. Novartis: Press release 8 October 2009. Available at http://www.novartis. com/. Hawkins LD, Christ WJ, Rossignol DP. (2004) Inhibition of endotoxin response by synthetic TLR4 antagonists. Curr Top Med Chem 4: 1147–1171. Mullarkey M, Rose JR, Bristol J, Kawata T, Kimura A, Kobayashi S, Przetak M, Chow J, Gusovsky F, Christ WJ, Rossignol DP. (2003) Inhibition of endotoxin response by E5564, a novel tolllike receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther 304: 1093–1102. Qureshi N, Takayama K, Kurtz R. (1991) Diphosphoryl lipid A obtained from the nontoxic lipopolysaccharide of Rhodopseudomonas Sphaeroides is an endotoxin antagonist in mice. Infect Immun 59: 441–444. Kaltashov IA, Doroshenko V, Cotter RJ, Takayama K, Qureshi N. (1997) Confirmation of the structure of lipid A derived from the lipopolysaccharide

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

184

815. 816.

817.

818.

819.

820.

821.

822.

823.

Page 184

Bioactive Natural Products

Brahmachari

of Rhodobacter Sphaeroides by a combination of MALDI, LSIMS and tandem mass spectrometry. Anal Chem 69: 2317–2322. Rossignol DP, Lynn M. (2005) TLR4 antagonists for endotoxemia and beyond. Curr Opin Invest Drugs 6: 496–502. Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, Enkhbayar P, Matsushima N, Lee H, Yoo OJ, Lee J-O. (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist eritoran. Cell 130: 906–917. Rossignol DP, Wasan KM, Choo E, Yau E, Wong N, Rose J, Moran J, Lynn M. (2004) Safety, pharmacokinetics, pharmacodynamics and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers. Antimicrob Agents Chemother 48: 3233–3240. Bennett-Guerrero E, Grocott HP, Levy JH, Stierer KA, Hogue CW, Cheung AT, Newman MF, Carter AA, Rossignol DP, Collard CD. (2007) A phase II, double-blind, placebo-controlled, ascendingdose study of eritoran (E5564), a lipid A antagonist, in patients undergoing cardiac surgery with cardiopulmonary bypass. Anesth Analg 104: 378–383. Robertson GT, Bonventre EJ, Doyle TB, Du Q, Duncan L, Morris TW, Roche ED, Yan D, Lynch AS. (2008) In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: Studies of the mode of action in Staphylococcus aureus. Antimicrob Agents Chemother 52: 2313–2323. Robertson GT, Bonventre EJ, Doyle TB, Du Q, Duncan L, Morris TW, Roche ED, Yan D, Lynch AS. (2008) In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: Microbiology profiling studies with Staphylococci and Streptococci. Antimicrob Agents Chemother 52: 2324–2334. Kato A, Nakaya S, Ohashi Y, Hirata H. (1997) WAP-8294A2, a novel anti-MRSA antibiotic produced by Lysobacter sp. J Am Chem Soc 119: 6680–6681. Kato A, Nakaya S, Kokubo N, Aiba Y, Ohashi Y, Hirata H, Fujii K, Harada K. (1998) A new anti-MRSA antibiotic complex, WAP-8294A. J Antibiot 51: 929–935. Harad KI, Suzuki M, Kato A, Fujii K, Oka H, Ito Y. (2001) Separation of WAP-8294A components, a novel anti-methicillin-resistant Staphylococcus

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 185

Bioactive Natural Products

Natural Products in Drug Discovery

824. 825.

826.

827.

828.

829. 830. 831.

832.

833.

834.

185

Aureus antibiotic, using high-speed countercurrent chromatography. J Chromatogr A 932: 75–81. aRigen Pharmaceuticals: Press release 17 August 2009. Available at http://www.arigen.jp/. Mukhopadhyay T, Roy K, Bhat RG, Sawant SN, Blumbach J, Ganguli BN, Fehlhaber HW, Kogler H. (1992) Deoxymulundocandin — a new echinocandin type antifungal antibiotic. J Antibiot 45: 618–623. Brzankalski GE, Najvar LK, Wiederhold NP, Bocanegra R, Fothergill AW, Rinaldi MG, Pattterson TF, Graybill JR. (2008) Evaluation of aminocandin and caspofungin against Candida glabrata including isolates with reduced caspofungin susceptibility. J Antimicrob Chemother 62: 1094–1100. Cateau E, Levasseur P, Borgonovi M, Imbert C. (2007) The effect of aminocandin (HMR 3270) on the in vitro adherence of Candida Albicans to polystyrene surfaces coated with extracellular matrix proteins or fibronectin. Clin Microbiol Infec 13: 311–315. Kakeya H, Miyazaki Y, Senda H, Kobayashi T, Seki M, Izumikawa K, Yanagihara K, Yamamoto Y, Tashiro T, Kohno S. (2008) Efficacy of SPK843, a novel polyene antifungal, in comparison with amphotericin B, liposomal amphotericin B, and micafungin against murine pulmonary aspergillosis. Antimicrob Agents Chemother 52: 1868–1870. Kaken Pharmaceutical: Annual Report 2007. Available at http://www.kaken. co.jp/. Kasanah N, Hamann MT. (2005) SPK-843 (Aparts/Kaken). Curr Opin Invest Drugs 6: 845–856. Bruzzese T, Rimaroli C, Bonabello A, Ferrari E, Signorini M. (1996) Amide derivatives of partricin A with potent antifungal activity. Eur J Med Chem 31: 965–972. Rimaroli C, Bonabello A, Sala P, Bruzzese T. (2002) Pharmacokinetics and tissue distribution of a new partricin A derivative (N-dimethylaminoacetylpartricin A 2-dimethylaminoethylamide diaspartate) in mice. J Pharm Sci 91: 1252–1258. Mozzi G, Benelli P, Bruzzese T, Galmozzi MR, Bonabello A. (2002) The use of lipid emulsions for the iv administration of a new water soluble polyene antibiotic, SPK-843. J Antimicrob Chemother 49: 321–325. Aparts BV: Further information available at http://www.apartsbv.com/.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

186

Page 186

Bioactive Natural Products

Brahmachari

835. Borel JF. (2002) History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 114: 433–437. 836. Flisiak R, Dumont J-M, Crabbe R. (2007) Cyclophilin inhibitors in hepatitis C viral infection. Expert Opin Invest Drugs 16: 1345–1354. 837. Watashi K, Shimotohno K. (2007) Chemical genetics approach to hepatitis C virus replication: Cyclophilin as a target for anti-hepatitis C virus strategy. Rev Med Virol 17: 245–252. 838. Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M. (2007) The way forward in HCV treatment — finding the right path. Nat Rev Drug Discov 6: 991–1000. 839. Ma S, Boerner JE, TiongYip C, Weidmann B, Ryder NS, Cooreman MP, Lin K. (2006) NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother 50: 2976–2982. 840. Hansson MJ, Mattiasson G, Mansson R, Karlsson J, Keep MF, Waldmeier P, Ruegg UT, Dumont J-M, Besseghir K, Elmer E. (2004) The nonimmunosuppressive cyclosporine analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr 36: 407–413. 841. Hayakawa Y, Nakagawa M, Kawai H, Tanabe K, Nakayama H, Shimazu A, Seto H, Otake N. (1983) Studies on the differentiation inducers of myeloid leukemic cells III. Spicamycin, a new inducer of differentiation of HL-60 human promyelocytic leukemia cells. J Antibiot 36: 934–937. 842. Hayakawa Y, Nakagawa M, Kawai H, Tanabe K, Nakayama H, Shimazu A, Seto H, Otake N. (1985) Spicamycin, a new differentiation inducer of mouse myeloid leukemia cells (M1) and human promyelocytic leukemia cells (HL-60). Agric Biol Chem 49: 2685–2691. 843. Kobierski LA, Abdi S, DiLorenzo L, Feroz N, Borsook D. (2003) A single intravenous injection of krn5500 (antibiotic spicamycin) produces longterm decreases in multiple sensory hypersensitivities in neuropathic pain. Anesth Analg 97: 174–182. 844. DARA BioSciences: Further information available at http://www.darabio sciences.com/. 845. Miyake Y, Ebata M. (1988) Inhibition of β-galactosidase by galactostatin, galactostatin-lactam, and 1-deoxygalactostatin. Agric Biol Chem 52: 1649–1654.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 187

Bioactive Natural Products

Natural Products in Drug Discovery

187

846. For further information: http://www.amicustherapeutics.com/ (accessed on 14.12.2010). 847. Jirousek MR, Gillig JR, Gonzalez CM, Heath WF, McDonald JH, Neel DA, Rito CJ, Singh U, Stramm LE, Melikian-Badalian A, Baevsky M, Ballas LM, Hall SE, Winneroski LL, Faul MM. (1996) (S)-13-[(dimethylamino) methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13Hdibenzo[e,k] pyrrolo[3,4-h] [1,4,13] oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and related analogues: Isozyme selective inhibitors of protein kinase C beta. J Med Chem 39: 2664–2671. 848. Engel GL, Farid NA, Faul MM, Richardson LA, Winneroski LL. (2000) Salt form selection and characterization of LY333531 mesylate monohydrate. Int J Pharm 198: 239–247. 849. Joy SV, Scates AC, Bearelly S, Dar M, Taulien CA, Goebel JA, Cooney MJ. (2005) Ruboxistaurin, a protein kinase-c beta inhibitor, as an emerging treatment for diabetes microvascular complications. Ann Pharmacother 39: 1693–1699. 850. Gardner TW, Antonetti DA. (2006) Ruboxistaurin for diabetic retinopathy. Ophthalmology 113: 2135–2136. 851. Clarke M, Dodson PM. (2007) PKC inhibition and diabetic microvascular complications. Best Pract Res Clin Endocrinol Metab 21: 573–586. 852. Yasuzawa T, Iida T, Yoshida M, Hirayama N, Takahashi M, Shirahata K, San H. (1986) The structures of the novel protein kinase C inhibitors K252a, b, c and d. J Antibiot 39: 1072–1078. 853. Kase H, Iwahashi K, Matsuda Y. (1986) K-252a, a potent inhibitor of protein kinase c from microbial origin. J Antibiot 39: 1059–1065. 854. Anglade E, Yatscoff R, Foster R, Grau U. (2007) Next-generation calcineurin inhibitors for ophthalmic indications. Expert Opin Invest Drugs 16: 1525–1540. 855. Lux Biosciences: Press release 30 March 2010. Available at http://www. luxbio.com/. 856. For further information: http://www.isotechnika.com/ (accessed on 14.12.2010). 857. Sakai T, Sameshima T, Matsufuji M, Kawamura N, Dobashi K, Mizui Y. (2004) Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. I. Taxonomy, fermentation, isolation and screening. J Antibiot (Tokyo) 57: 173–179.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

188

Page 188

Bioactive Natural Products

Brahmachari

858. Sakai T, Asai N, Okuda A, Kawamura N, Mizui Y. (2004) Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. II. Physico-chemical properties and structure elucidation. J Antibiot (Tokyo) 57: 180–187. 859. Mizui Y, Sakai T, Iwata M, Uenaka T, Okamoto K, Shimizu H, Yamori T, Yoshimatsu K, Asada M. (2004) Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. III. In vitro and in vivo antitumor activities. J Antibiot (Tokyo) 57: 188–196. 860. Kotake Y, Sagane K, Owa T, Mimori-Kiyosue Y, Shimizu H, Uesugi M, Ishihama Y, Iwata M, Mizui Y. (2007) Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat Chem Biol 3: 570–575. 861. Konishi M, Sugawara K, Kofu F, Nishiyama Y, Tomita K, Miyaki T, Kawagushi H. (1986) Elsamicins, new antitumor antibiotics related to chartreusin. I. Production, isolation, characterization and antitumor activity. J Antibiot (Tokio) 39: 784–791. 862. Callisto Pharmaceuticals: Further information available at http://www. callistopharma.com/. 863. Trevino AV, Woynarowska BA, Herman TS, Priebe W, Woynarowski JM. (2004) Enhanced topoisomerase II targeting by annamycin and related 4-demethoxy anthracycline analogues. Mol Cancer Ther 3: 1403–1410. 864. Brooks TA, O’Loughlin KL, Minderman H, Bundy BN, Ford LA, Vredenburg MR, Bernacki RJ, Priebe W, Baer MR. (2007) The 4′-Obenzylated doxorubicin analog WP744 overcomes resistance mediated by P-glycoprotein, multidrug resistance protein and breast cancer resistance protein in cell lines and acute myeloid leukemia cells. Invest New Drugs 25: 115–122. 865. Bos AM, de Vries EG, Dombernovsky P, Aamdal S, Uges DR, Schrijvers D, Wanders J, Roelvink MW, Hanauske AR, Bortini S, Capriati A, Crea AE, Vermorken JB. (2001) Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours. Cancer Chemother Pharmacol 48: 361–369. 866. Caponigro F, Willemse P, Sorio R, Floquet A, van Belle S, Demol J, Tambaro R, Comandini A, Capriati A, Adank S, Wanders J. (2005) A phase II study of sabarubicin (MEN-10755) as second line therapy in patients with locally advanced or metastatic platinum/taxane resistant ovarian cancer. Invest New Drugs 23: 85–89.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 189

Bioactive Natural Products

Natural Products in Drug Discovery

189

867. Fraier D, Frigerio E, Brianceschi G, James CA. (2002) LC-MS-MS determination of nemorubicin (methoxymorpholinyldoxorubicin, PNU-152243A) and its 13-OH metabolite (PNU-155051A) in human plasma. J Pharm Biomed Anal 30: 377–389. 868. Quintieri L, Geroni C, Fantin M, Battaglia R, Rosato A, Speed W, Zanovello P, Floreani M. (2005) Formation and antitumor activity of PNU159682, a major metabolite of nemorubicin in human liver microsomes. Clin Cancer Res 11: 1608–1617. 869. Bellorini M, Moncollin V, D’lncalci M, Mongelli N, Mantovani R. (1995) Distamycin A and tallimustine inhibit TBP binding and basal in vitro transcription. Nucleic Acids Res 23: 1657–1663. 870. Geroni C, Marchini S, Cozzi P, Galliera E, Ragg E, Colombo T, Battaglia R, Howard M, D’Incalci M, Broggini M. (2002) Brostallicin, a novel anticancer agent whose activity is enhanced upon binding to glutathione. Cancer Res 62: 2332–2336. 871. Cozzi P, Beria I, Caldarelli M, Capolongo L, Geroni C, Mongelli N. (2000) Cytotoxic halogenoacrylic derivatives of distamycin A. Bioorg Med Chem Lett 10: 1269–1272. 872. Cozzi P, Beria I, Caldarelli M, Geroni C, Mongelli N, Pennella G. (2000) Cytotoxic alpha-bromoacrylic derivatives of distamycin analogues modified at the amidino moiety. Bioorg Med Chem Lett 10: 1273–1276. 873. Cozzi P. (2003) The discovery of a new potential anticancer drug: A case history. Farmaco 58: 213–220. 874. Broggini M, Marchini S, Fontana E, Moneta D, Fowst C, Geroni C. (2004) Brostallicin: A new concept in minor groove DNA binder development. Anti-Cancer Drugs 15: 1–6. 875. Leahy M, Ray-Coquard I, Verweij J, Le Cesne A, Duffaud F, Hogendoorn PC, Fowst C, de Balincourt C, di Paola ED, van Glabbeke M, Judson I, Blay JY. (2007) European Organisation for research and treatment of cancer soft tissue and bone sarcoma group. Eur J Cancer 43: 308–315. 876. Cell Therapeutics: Further information available at http://www.celltherapeutics. com/. 877. DeBoer C, Meulman PA, Wnuk RJ, Peterson DH. (1970) Geldanamycin, a new antibiotic. J Antibiot 23: 442–447.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

190

Page 190

Bioactive Natural Products

Brahmachari

878. Bedin M, Gaben AM, Saucier C, Mester J. (2004) Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest. Int J Cancer 109: 643–652. 879. Schnur RC, Corman ML, Gallaschun RJ, Cooper BA, Dee MF, Doty JL, Muzzi ML, Moyer JD, DiOrio CI, Barbacci EG, Miller PE, Pollalk VA, Savage DM, Sloan DE, Pustilnik LR, Moyer MP. (1995) Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives. J Med Chem 38: 3806–3812. 880. Modi S, Stopeck AT, Gordon MS, Mendelson D, Solit DB, Bagatell R, Ma W, Wheler J, Rosen N, Norton L, Cropp GF, Johnson RG, Hannah AL, Hudis CA. (2007) Combination of trastuzumab and tanespimycin (17-AAG, KOS953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: A phase I dose-escalation study. J Clin Oncol 25: 5410–5417. 881. Neckers L. (2006) Using natural product inhibitors to validate Hsp90 as a molecular target in cancer. Curr Top Med Chem 6: 1163–1171. 882. Waza M, Adachi H, Katsuno M, Minamiyama M, Sang C, Tanaka F, Inukai A, Doyu M, Sobue G. (2005) 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med 11: 1088–1095. 883. Jez JM, Chen JC, Rastelli G, Stroud RM, Santi DV. (2003) Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem Biol 10: 361–368. 884. Hanson BE, Vesole DH. (2009) Retaspimycin hydrochloride (IPI-504): A novel heat shock protein inhibitor as an anticancer agent. Expert Opin Inv Drugs 18: 1375–1383. 885. Infinity Pharmaceuticals: Further information available at http://www.infi. com/ (accessed on 14.12.2010). 886. Elit L. (2006) Drug evaluation: AP-23573 — an mTOR inhibitor for the treatment of cancer. IDrugs 9: 636–644. 887. Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F. (2008) Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opin Inv Drugs 17: 1947–1954. 888. Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW. (2008) Phase Itrial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669)

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 191

Bioactive Natural Products

Natural Products in Drug Discovery

889. 890.

891.

892. 893.

894.

895. 896.

897. 898.

191

administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 26: 361–367. ARIAD Pharmaceuticals: Press release 17 December 2009. Available at http://www.ariad.com/. Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W. (2003) Salinosporamide A: A highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 42: 355–357. Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M, Mitsiades C, Mitsiades N, Yasui H, Letai A, Ovaa H, Berkers C, Nicholson B, Chao TH, Neuteboom ST, Richardson P, Palladino MA, Anderson KC. (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8: 407–419. Nereus Pharmaceuticals: Further information available at http://www. nereuspharm.com/. Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchiya H, Takahashi Y, Masuma R. (1977) A new alkaloid AM-2282 of Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J Antibiot 30: 275–282. Wang Y, Yin OQ, Graf P, Kisicki JC, Schran H. (2008) Dose- and timedependent pharmacokinetics of midostaurin in patients with diabetes mellitus. J Clin Pharmacol 48: 763–775. Chen YB, LaCasce AS. (2008) Enzastaurin. Expert Opin Inv Drugs 17: 939–944. Robertson MJ, Kahl BS, Vose JM, de Vos S, Laughlin M, Flynn PJ, Rowland K, Cruz JC, Goldberg SL, Musib L, Darstein C, Enas N, Kutok JL, Aster JC, Neuberg D, Savage KJ, LaCasce A, Thornton D, Slapak CA, Shipp MA. (2007) Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 25: 1741–1746. Eli Lilly: Further information available at http://www.lilly.com/ (accessed on 14.12.2010). Propper DJ, McDonald AC, Man A, Thavasu P, Balkwill F, Braybrooke JP, Caponigro F, Graf P, Dutreix C, Blackie R, Kaye SB, Ganesan TS, Talbot DC, Harris AL, Twelves C. (2001) Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol 19: 1485–1492.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

192

Page 192

Bioactive Natural Products

Brahmachari

899. Knapper S, Burnett AK, Littlewood T, Kell WJ, Agrawal S, Chopra R, Clark R, Levis MJ, Small D. (2006) A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108: 3262–3270. 900. Revill P, Serradell N, Bolos J, Rosa E. (2007) Lestaurtinib. Drugs Fut 32: 215–222. 901. Press release 6th June 2009. Available at http://www.cephalon.com/. 902. Takahashi I, Saitoh Y, Yoshida M, Sano H, Nakano H, Morimoto M, Tamaoki T. (1989) UCN-01 and UCN-02, new selective inhibitors of protein kinase C. II. Purification, physico-chemical properties, structural determination and biological activities. J Antibiot 42: 571–576. 903. Fuse E, Kuwabara T, Sparreboom A, Sausville EA, Figg WD. (2005) Review of UCN-01 development: A lesson in the importance of clinical pharmacology. J Clin Pharmacol 45: 394–403. 904. Tse AN, Carvajal R, Schwartz GK. (2007) Targeting checkpoint kinase 1 in cancer therapeutics. Clin Cancer Res 13: 1955–1960. 905. Charan RD, Schlingmann G, Janso J, Bernan V, Feng X, Carter GT. (2004) Diazepinomicin, a new antimicrobial alkaloid from a marine Micromonospora sp. J Nat Prod 67: 1431–1433. 906. McAlpine JB, Banskota AH, Charan RD, Schlingmann G, Zazopoulos E, Piraee M, Janso J, Bernan VS, Aouidate M, Farnet CM, Feng X, Zhao Z, Carter GT. (2008) Biosynthesis of diazepinomicin/ECO-4601, a Micromonospora secondary metabolite with a novel ring system. J Nat Prod 71: 1585–1590. 907. Gourdeau H, McAlpine JB, Ranger M, Simard B, Berger F, Beaudry F, Falardeau P. (2008) Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand. Cancer Chemother Pharmacol 61: 911–921. 908. Campas C. (2009) Diazepinomicin. Drugs Fut 34: 349–351. 909. Thallion Pharmaceuticals: Further information available at http://www. thallion.com/. 910. Bennett JW, Bentley R. (2000) Seeing red: The story of prodigiosin. Adv Appl Microbiol 47: 1–32. 911. Gemin X: Further information available at http://www.geminx.com/. 912. Galmarini CM, Dumontet C. (2003) EPO-906 (Novartis). Idrugs 6: 1182–1187.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 193

Bioactive Natural Products

Natural Products in Drug Discovery

193

913. Rothermel J, Wartmann M, Chen T, Hohneker J. (2003) EPO906 (epothilone B): A promising novel microtubule stabilizer. Semin Oncol 30: 51–55. 914. Alexander EJ, Rosa E, Bolos J, Castaner R. (2008) Sagopilone. Drugs Fut 33: 496–506. 915. Klar U, Buchmann B, Schwede W, Skuballa W, Hoffmann J, Lichtner RB. (2006) Total Synthesis and Antitumor Activity of ZK-EPO: The first fully synthetic epothilone in clinical development. Angew Chem Int Ed 45: 7942–7948. 916. Bayer schering pharma: Further information available at http://www. bayerscheringpharma.de/. 917. White JD, Sundermann KF, Wartmann M. (2002) Synthesis, conformational analysis, and bioassay of 9,10-didehydroepothilone D. Org Lett 4: 995–997. 918. Kanoh K, Kohno S, Katada J, Takahashi J, Uno I. (1999) (–)-Phenylahistin arrests cells in mitosis by inhibiting tubulin polymerization. J Antibiot 52: 134–141. 919. Nicholson B, Lloyd GK, Miller BR, Palladino MA, Kiso Y, Hayashi Y, Neuteboom ST. (2006) NPI-2358 is a tubulin-depolymerizing agent: In vitro evidence for activity as a tumor vasculardisrupting agent. Anticancer Drugs 17: 25–31. 920. Nereus Pharmaceuticals: Press release 23 November 2009. Available at http://www.nereuspharm.com/. 921. McMorris TC, Kelner MJ, Wang W, Estes LA, Montoya MA, Taetle R. (1992) Structure-activity relationships of illudins: Analogs with improved therapeutic index. J Org Chem 57: 6876–6883. 922. Kelner MJ, McMorris TC, Estes L, Wang W, Samson KM, Taetle R. (1996) Efficacy of HMAF (MGI-114) in the MV522 metastatic lung carcinoma xenograft model nonresponsive to traditional anticancer agents. Invest New Drugs 14: 161–167. 923. Wang Y, Wiltshire T, Senft J, Reed E, Wang W. (2007) Irofulven induces replication-dependent CHK2 activation related to p53 status. Biochem Pharmacol 73: 469–480. 924. Escargueil AE, Poindessous V, Soares DG, Sarasin A, Cook PR, Larsen AK. (2008) Influence of irofulven, a transcription-coupled repair-specific antitumor agent, on RNA polymerase activity, stability and dynamics in living mammalian cells. J Cell Sci 121: 1275–1283.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

194

Page 194

Bioactive Natural Products

Brahmachari

925. Moneo V, Serelde BG, Leal JFM, Blanco-Aparicio C, Diaz-Uriarte R, Aracil M, Tercero JC, Jimeno J, Carnero A. (2007) Levels of p27(kip1) determine Aplidin sensitivity. Mol Cancer Ther 6: 1310–1316. 926. Kem WR. (1971) A study of the occurrence of anabaseine in Paranemertes and other nemertines. Toxicon 9: 23–32. 927. Kem W, Soti F, Wildeboer K, LeFrancois S, MacDougall K, Wei D-Q, Chou K-C, Arias HR. (2006) The nemertine toxin anabaseine and its derivative DMXBA (GTS-21): Chemical and pharmacological properties. Mar Drugs 4: 255–273. 928. Kem WR, Mahnir VM, Papke RL, Lingle CJ. (1997) Anabaseine is a potent agonist on muscle and neuronal α-Bungarotoxin-sensitive nicotinic receptors. J Pharmacol Exp Ther 283: 979–992. 929. Martin LF, Kem WR, Freedman R. (2004) α-7 nicotinic receptor agonists: Potential new candidates for the treatment of schizophrenia. Psychopharmacology 174: 54–64. 930. Olincy A, Stevens KE. (2007) Treating schizophrenia symptoms with an α7 nicotinic agonist from mice to men. Biochem Pharmacol 74: 1192–1201. 931. Kitagawa H, Takenouchi T, Azuma R, Wesnes KA, Kramer WG, Clody DE, Burnett AL. (2003) Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 28: 542–551. 932. Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R. (2006) Proof-of-concept trial of an α7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63: 630–638. 933. PharmaMar: Press release 2 June 2009. Available at http://www.pharmamar. com/. 934. Hirata Y, Uemura D. (1986) Halichondrins — antitumor polyether macrolides from a marine sponge. Pure Appl Chem 58: 701–710. 935. Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK. (1992) Total synthesis of halichondrin B and norhalichondrin B. J Am Chem Soc 114: 3162–3164. 936. Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, DiPietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA. (2001) In vitro and in vivo anticancer activities of synthetic

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 195

Bioactive Natural Products

Natural Products in Drug Discovery

937.

938.

939.

940.

941. 942.

943.

944.

945. 946.

195

macrocyclic ketone analogues of halichondrin B. Cancer Res 61: 1013–1021. Seletsky BM, Wang Y, Hawkins LD, Palme MH, Habgood GJ, DiPietro LV, Towle MJ, Salvato KA, Wels BF, Aalfs KK, Kishi Y, Littlefield BA, Yu MJ. (2004) Structurally simplified macrolactone analogues of halichondrin B. Bioorg Med Chem Lett 14: 5547–5550. Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L, Towle MJ, Salvato KA, Wels BF, Aalfs KK, Kishi Y, Littlefield BA, Yu MJ. (2004) Macrocyclic ketone analogues of halichondrin. Bioorg Med Chem Lett 14: 5551–5554. Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA. (2004) Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res 64: 5760–5766. Newman S. (2007) Eribulin, a simplified ketone analog of the tubulin inhibitor halichondrin B, for the potential treatment of cancer. Curr Opin Invest Drugs 8: 1057–1066. Eisai Pharmaceuticals: Press release 30 March 2010. Available at http://www.eisai.com/. Talpir R, Benayahu Y, Kashman Y. Pannell L, Schleyer M. (1994) Hemiasterlin and geodiamolide TA; two new cytotoxic peptides from the marine sponge Hemiasterella minor (Kirkpatrick). Tetrahedron Lett 35: 4453–4456. Anderson HJ, Coleman JE, Andersen RJ, Roberge M. (1997) Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation. Cancer Chemother Pharmacol 39: 223–226. George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F, Sigua C, Sondarva G, Moscinski L, Atadja P, Bhalla K. (2005) Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 105: 1768–1776. Revill P, Mealy N, Serradell N, Bolos J, Rosa E. (2007) Panobinostat. Drugs Fut 32: 315–322. Schaufelberger DE, Koleck MP, Beutler JA, Vatakis AM, Alvarado AB, Andrews P, Marzo LV, Muschik GM, Roach J, Ross JT, Lebherz WB,

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

196

947.

948.

949.

950. 951.

952.

953.

954.

Page 196

Bioactive Natural Products

Brahmachari

Reeves MP, Eberwein RM, Rodgers LL, Testerman RP, Snader KM, Forenza S. (1991) The large-scale isolation of bryostatin 1 from Bugula neritina following current good manufacturing practices. J Nat Prod 54: 1265–1270. Sudek S, Lopanik NB, Waggoner LE, Hildebrand M, Anderson C, Liu H, Patel A, Sherman DH, Haygood MG. (2007) Identification of the putative bryostatin polyketide synthase gene cluster from “Candidatus Endobugula sertula”, the uncultivated microbial symbiont of the marine bryozoans Bugula neritina. J Nat Prod 70: 67–74. Banerjee S, Wang Z, Mohammad M, Sarkar FH, Mohammad RM. (2008) Efficacy of selected natural products as therapeutic agents against cancer. J Nat Prod 71: 492–496. Leal JF, Garcia-Hernandez V, Moneo V, Domingo A, Bueren-Calabuig JA, Negri A, Gago F, Guillen-Navarro MJ, Aviles P, Cuevas C, GarciaFernandez LF, Galmarini CM. (2009) Molecular pharmacology and antitumor activity of zalypsis in several human cancer cell lines. Biochem Pharmacol 78: 162–170. PharmaMar: Press release 21 April 2010. Available at http://www.pharmamar. com/. Bai R, Friedman SJ, Pettit GR, Hamel E. (1992) Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia. Interaction with tubulin and effects of cellular microtubules. Biochem Pharmacol 43: 2637–2645. Ray A, Okouneva T, Manna T, Miller HP, Schmid S, Arthaud L, Luduena R, Jordan MA, Wilson L. (2007) Mechanism of action of the microtubuletargeted antimitotic depsipeptide tasidotin (formerly ILX651) and its major metabolite tasidotin C-carboxylate. Cancer Res 67: 3767–3776. Mita AC, Hammond LA, Bonate PL, Weiss G, McCreery H, Syed S, Garrison M, Chu QS, DeBono JS, Jones CB, Weitman S, Rowinsky EK. (2006) Phase I and pharmacokinetic study of tasidotin hydrochloride (ILX651), a third-generation dolastatin-15 analogue, administered weekly for 3 weeks every 28 days in patients with advanced solid tumors. Clin Cancer Res 12: 5207–5215. Watanabe J, Natsume T, Kobayashi M. (2007) Comparison of the antivascular and cytotoxic activities of TZT-1027 (Soblidotin) with those of other anticancer agents. Anti-Cancer Drugs 18: 905–911.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 197

Bioactive Natural Products

Natural Products in Drug Discovery

197

955. Sewell JM, Mayer I, Langdon SP, Smyth JF, Jodrell DI, Guichard SM. (2005) The mechanism of action of Kahalalide F: Variable cell permeability in human hepatoma cell lines. Eur J Cancer 41: 1637–1644. 956. PharmaMar: Press release 10 June 2009. Available at http://www.pharmamar. com/. 957. Hamann MT, Scheuer PJ. (1993) Kahalalide F: A bioactive depsipeptide from the sacoglossan mollusk Elysia rufescens and the green alga Bryopsis sp. J Am Chem Soc 115: 5825–5826. 958. Bonnard I, Manzanares I, Rinehart KL. (2003) Stereochemistry of kahalalide F. J Nat Prod 66: 1466–1470. 959. Suárez Y, González L, Cuadrado A, Berciano M, Lafarga M, Muñoz A. (2003) Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. Mol Cancer Ther 2: 863–872. 960. Jimeno J, Aracil M, Tercero JC. (2006). Adding pharmacogenomics to the development of new marine-derived anticancer agents. J Transl Med 4: 3–9. 961. Piggott AM, Karuso P. (2008) Rapid identification of a protein binding partner for the marine natural product kahalalide F by using reverse chemical proteomics. ChemBioChem 9: 524–530. 962. Ling YH, Aracil M, Jimeno J, Perez-Soler R, Zou Y. (2009) Molecular pharmacodynamics of PM02734 (elisidepsin) as single agent and in combination with erlotinib; synergistic activity in human non-small cell lung cancer cell lines and xenograft models. Eur J Cancer 45: 1855–1864. 963. Provencio M, Sánchez A, Gasent J, Gómez P, Rosell R. (2009) Cancer treatments: Can we find treasures at the bottom of the sea? Clin Lung Cancer 10: 295–300. 964. For more information: http://www.zeltia.com/media/docs/mizklylt.pdf (accessed on 14.12.2010). 965. For further information: http://ncit.nci.nih.gov/ConceptReport.jsp?dictionary= NCI%20Thesaurus&code=C66949 (accessed on 14.12.2010). 966. Yokoo A. (1950) Chemical studies on pufferfish toxin (3) — separation of spheroidine. J Chem Soc Jpn 71: 590–592. 967. Hagen NA, Fisher KM, Lapointe B, Souich P, Chary S, Moulin D, Sellers E, Ngoc AH. (2007) An open-label, multi-dose efficacy and safety study of intramuscular tetrodotoxin in patients with severe cancer-related pain. J Pain Symptom Manage 34: 171–182.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

198

Page 198

Bioactive Natural Products

Brahmachari

968. Hagen NA, Souich P, Lapointe B, Ong-Lam M, Dubuc B, Walde D, Love R, Ngoc AH. (2008) Tetrodotoxin for moderate to severe cancer pain: A randomized, double blind, parallel design multicenter study. J Pain Symptom Manage 35: 420–429. 969. Wex Pharmaceuticals: Further information available at http://www. wextech.ca/. 970. Sharpe IA, Gehrmann J, Loughnan ML, Thomas L, Adams DA, Atkins A, Palant E, Craik DJ, Adams DJ, Alewood PF, Lewis RJ. (2001) Two new classes of conopeptides inhibit the alpha1-adrenoceptor and noradrenaline transporter. Nat Neurosci 4: 902–907. 971. Lovelace ES, Armishaw CJ, Colgrave ML, Wahlstrom ME, Alewood PF, Daly NL, Craik DJ. (2006) Cyclic MrIA: A stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter. J Med Chem 49: 6561–6568. 972. Paczkowski FA, Sharpe IA, Dutertre S, Lewis RJ. (2007) X-Conotoxin and tricyclic antidepressant interactions at the norepinephrine iransporter define a new transporter model. J Biol Chem 282: 17837–17844. 973. Xenome: Further information available at http://www.xenome.com. 974. Rao MN, Shinnar AE, Noecker LA, Chao TL, Feibush B, Snyder B, Sharkansky I, Sarkahian A, Zhang X, Jones SR, Kinney WA, Zasloff M. (2000) Aminosterols from the dogfish shark squalus acanthias. J Nat Prod 63: 631–635. 975. Moore KS, Wehrli S, Roder H, Rogers M, Forrest JN, McCrimmon D, Zasloff M. (1993) Squalamine: An aminosterol antibiotic from the shark. Proc Natl Acad Sci USA 90: 1354–1358. 976. Ahima RS, Patel HR, Takahashi N, Qi Y, Hileman SM, Zasloff MA. (2002) Appetite suppression and weight reduction by a centrally active aminosterol. Diabetes 51: 2099–3104. 977. Chernova MN, Vandorpe DH, Clark JS, Williams JI, Zasloff MA, Jiang L, Alper SL. (2005) Apparent receptor-mediated activation of Ca2+-dependent conductive Cl– transport by shark-derived polyaminosterols. Am J Physiol Regul Integr Comp Physiol 289: R1644–R1658. 978. For further information: http://www.genaera.com/download/NAASO_ clinical_poster.pdf (accessed on 14.12.2010). 979. Isaacson RE. (2003) MBI-226 (Micrologix/Fujisawa). Curr Opin Investig Drugs 4: 999–1003.

b1214_Chapter-01.qxd

9/7/2011

4:23 PM b1214

Page 199

Bioactive Natural Products

Natural Products in Drug Discovery

199

980. Sader HS, Fedler KA, Rennie RP, Stevens S, Jones RN. (2004) Omiganan pentahydrochloride (MBI 226), a topical 12-amino-acid cationic peptide: Spectrum of antimicrobial activity and measurements of bactericidal activity. Antimicrob Agents Chemother 48: 3112–3118. 981. Melo MN, Dugourd D, Castanho MARB. (2006) Omiganan pentahydrochloride in the front line of clinical applications of antimicrobial peptides. Recent Pat Anti-Infect Drug Discov 1: 201–207. 982. Fritsche TR, Rhomberg PR, Sader HS, Jones RN. (2008) Antimicrobial activity of omiganan pentahydrochloride against contemporary fungal pathogens responsible for catheter-associated infections. Antimicrob Agents Chemother 52: 1187–1189. 983. Fritsche TR, Rhomberg PR, Sader HS, Jones RN. (2008) Antimicrobial activity of omiganan pentahydrochloride tested against contemporary bacterial pathogens commonly responsible for catheter-associated infections. J Antimicrob Chemother 61: 1092–1098.