Current Topics in Medicinal Chemistry, 2016, Vol. 16, No. 23 1. 1568-0266/16 ... nal chemistry resulting in design of effective drugs for all main illnesses [1].
Perspectives in Medicinal Chemistry
Current Topics in Medicinal Chemistry, 2016, Vol. 16, No. 23
1
Perspectives in Medicinal Chemistry Sergey N. Mikhailov1, Luciana Scotti2, Rajeev K. Singla3 and Marcus T. Scotti 1
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Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow, Russian Federation-119991; 2Federal University of Paraíba, Health Center, 50670-910, João Pessoa, PB, Brazil; 3Division of Biotechnology, Netaji Subhas Institute of Technology, Sec-3,Dwarka, New Delhi-110078, India
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In antiquity, besides medical techniques, many poisons were discovered in nature and used for defense, hunting and even illegal purposes, such as poisons; (Conium maculatum) in the execution of prisoners, and Curare (Strych-
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nos guianensis or Chondodendron americana) before that on indigenous arrows. The techniques developed and used in Egypt to conserve mummies remain a challenge for modern chemistry. For centuries, only crude and semipure extracts of plants, animals, microbes and minerals represented the only medications available to treat human and domestic animal illnesses. The second half of the 20th century witnessed revolutionary development of medicinal chemistry resulting in design of effective drugs for all main illnesses [1].
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Natural products (NPs) (secondary metabolites) have been the most successful source of drug. An analysis of the sources of new drugs from 1981 – 2010 indicated that only 36% of the new chemical entities were discovered without inspiration from a natural product. In 21th century, natural products continue to provide unique structural diversity in comparison to standard combinatorial chemistry. Less than 10% of the world’s biodiversity was evaluated for potential biological activity. Despite the obvious importance, interest in natural product isolation by the pharmaceutical industry has declined in recent years [2,3]. On the other hand, the quantity of published papers about NPs are still increasing (According to Web of Science (Search topic: natural product or natural product) in 2000-2015 years 90185 papers were published (see Table 1). The same tendency was confirmed by the search in Google Scholar (In title of publication: natural products) in 2000-2015 13200 papers were published. Table 1.
Number of published papers concerning natural products in 2000-2015. Source Web of Science (Search topic: natural product or natural products).
2000
2001
2002
2003
2004
2005
2006
2007
2625
2714
3031
3348
3564
4209
4406
5002
2008
2009
2010
2011
2012
2013
2014
2015
5732
6238
6463
7167
8021
8706
9150
9800
While there are today different strategies and methodologies available to synthesize and discover new drugs, natural products chemistry is historically privileged as one of the successful alternatives. Many secondary or special metabolites are noteworthy as valuable raw materials for the production of numerous contemporary medicines, proving the strategic partnership between medicinal and natural chemical products for the discovery of innovative drugs. The influence of molecular biology on drug discovery changed the place of chemists, where they solely designed new drugs but with close a cooperation between biologists and chemists [4]. This dialogue based on the biochemical mechanisms, understanding of biological structure and functions result in the creation of novel chemical lead structures. Research involving natural products for the discovery and development of new medicines is made in several areas of medicinal chemistry; such as semi-synthesis, new targets research, evaluation of biological activities, analytical methods and /or theoretical approaches, structure-based approaches, SAR, QSAR, docking and several chemometric tools [5]. One line of scientific research is the treatment of diseases caused by metabolic disorders in modern society, for example bowel disease, obesity, diabetes and cancer [6,7]. Nucleoside area is one of the most fruitful field of natural compounds, on their basis about 100 nucleoside-based drugs were developed. One-half of the antiviral drugs and a quarter of antitumor drugs are derived from nucleosides. Natural nucleosides were found in DNA, RNA, nucleotides and coenzymes. More than 100 minor tRNA nucleosides and about 200 disaccharide nucleosides and nucleoside antibiotics have been isolated from various natural sources and have additional functional groups 1568-0266/16 $58.00+.00
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2 Current Topics in Medicinal Chemistry, 2016, Vol. 16, No. 23
Perspectives in Medicinal Chemistry
and hydrophobic residues in their structure. Nucleoside library consists of about 400 compounds and is a promising pool for the fishing out new biologically active compounds [8]. For example, during 1956-1974, 2,020 nucleoside analogs were screened for anticancer activity. About 400 of the nucleoside analogs (20%) were active in the screen, and 20 (1%) were introduced to clinical study (Table 2) [9]. From this list, five compounds reached pharmaceutical market and some drugs are still used. To the best of our knowledge, this is unbeatable record in medicinal chemistry. At that time, the total average cost per approved new drug was $109 million and, the present total capitalized cost in constant dollars increased to $2558 million [10]. Table 2.
Purine and pyrimidine nucleoside analogs sponsored for clinical studies by the division of cancer treatment, NCI [9]. Purine Nucleoside Analogs
Pyrimidine Nucloside Analogs
1
Mercaptopurine ribonucleoside
5-Fluoro-2-Deoxyuridine
2
6-Methylmercaptopurine ribonucleoside
6-Azauridine
3
β-2-Deoxythioguanosine
6-Azauridine triacetate
4
α-2-Deoxythioguanosine
5-Bromo-2-deoxyuridine
5
Inosine dialdehyde
Cytosine arabinoside
6
Adenine arabinoside
Trifluoromethyl-2-deoxyuridine
7
Arabinofuranosyl-6-meraptopurine
5-Azacytidine
8
Sangivamycin
Cyclocytidine
9
Thioguanosine
Ftorafur
10
2-Fluoroadenosine
11
Toyocamycin
Many studies in the scientific literature aim to discover of natural leads that are potential new drugs against metabolic disorders. Often metabolic changes favor the spread of harmful infectious agents, but these also require research and effective treatment. Constant efforts are undertaken in order to discover new natural bioactive constituents in medicinal chemicals. The future issue; Natural Leads in Drug Discovery against Metabolic Disorders and Their Related Infectious Diseases will report scientific studies in medicinal chemistry under this line of research, aimed at solving this most modern problem through natural products; including the paper Cytokinin Nucleosides - Natural Compounds with a Unique Spectrum of Biological Activity [8] of Prof S.N. Mikhailov. ACKNOWLEDGEMENT The research was supported by the Russian Science Foundation (SNM), project No 16-14-00178. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Dias, D. A., Urban, S.; Roessner, U. A historical overview of natural products in drug discovery. Metabolites 2012, 2(2), 303-336. Maier, M. E. Design and synthesis of analogues of natural products. Org. Biomol. Chem. 2015, 13(19), 5302-5343. David, B.; Wolfender, J. L.; Dias, D. A., The pharmaceutical industry and natural products: historical status and new trends. Phytochem. Rev. 2015, 14 (2), 299-315. Scotti, M. T.; Emerenciano, V.; Ferreira, M. J. P.; Scotti, L.; Stefani, R.; da Silva, M. S.; Mendonça Júnior, F. J. B. Self-Organizing Maps of Molecular Descriptors for Sesquiterpene Lactones and Their Application to the Chemotaxonomy of the Asteraceae Family. Molecules 2012, 17(4), 46844702. Scotti, L.; Mendonca, F. J. B.; Moreira, D. R. M.; da Silva, M. S.; Pitta, I. R.; Scotti, M. T., SAR, QSAR and Docking of Anticancer Flavonoids and Variants: A Review. Curr. Top. Med. Chem. 2012, 12 (24), 2785-2809. Abente, E. J.; Subranian, M.; Ramachandran, V.; Najafi-Shoushtari, S. H. MicroRNAs in obesity-associated disorders. Arch. Biochem. Biophys. 2016, 589, 108-119. Cron, L.; Allen, T.; Febbraio, M. A. The role of gp130 receptor cytokines in the regulation of metabolic homeostasis. J. Exp. Biol. 2016, 219(2), 259265. Drenichev, M. S., Oslovsky, V. E., Mikhailov, S. N. Cytokinin nucleosides - natural compounds with a unique spectrum of biological activity. Curr. Top. Med. Chem. 2016, 16, DOI: 10.2174/1568026616666160414123717. Slavik, M. Nucleoside analogs in the treatment of neoplastic and nonneoplastic diseases. Ann. N. Y. Acad. Sci. 1975, 255, 266-268. DiMasi, J. A.; Grabowski, H. G.; Hansen, R. W. Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 2016, 47, 2033.
