Current Bioactive Compounds 2007, 3, 37-66
37
Podophyllotoxin: Current Perspectives Ying-Qian Liu1, Liu Yang2 and Xuan Tian1* 1
State Key Laboratory of Applied Organic Chemistry, Lanzhou Universitry, Lanzhou, 730000, P.R.China, 2Analytic Center of Environment Engineering, Environmental and Municipal Engineering School, Lanzhou Jiaotong Universtitry, Gansu Lanzhou, 730000, P.R.China Abstract: Podophyllotoxin is a naturally occurring lignan with important antineoplastic and antiviral properties and supported by detailed understanding of their mechanism of action, and facilitated by chemical manipulations that have amplified their bioactivity, the podophyllotoxin analogues have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of podophyllotoxin-based multidrug regimens, which are showing important activity in several malignancies, and many of its related analogues will complement conventional pharmaceuticals in treatment, prevention and diaganosis of disease, while at the same time adding value to agriculture. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of etoposide-based multidrug regimens, which are showing important activity in several malignancies. Extensive structural modifications of podophyllotoxin have been performed in order to obtain more potent and less toxic antitumour agents, which resulted in the widespread clinical introduction of two semisynthetic glucoconjugate analogues of etoposide and teniposide and newer agents with promising preclinical activity are in various stages of clinical assessment. As knowledge of molecular and biochemical mechanisms of action and resistance continues to expand, newer and better podophyllotoxin-based strategies for treatment of malignant disease are likely to evolve. This review provides a detailed discussion of research advances in the synthetic and medicinal chemistry of podophyllotoxin, and addresses the short history and pharmacological action of these compounds and further outlines the preclinical development and clinical trials of drugs in the pipeline and marketing approval. Finally, a systemic evaluation of novel and important analogues of podophyllotoxin and their contribution to the current structure-activity profile are considered. It is hoped that this review will be able to address the contributions of podophyllotoxin-related research to overall drug discovery and development and the role that this field will play in future.
Keywords: Reviews, podophyllotoxin, short chronology, biological activity, medicinal application, mechanism of actions, chemical modification, structure-activity relationships. INTRODUCTION Podophyllotoxin ( 1) is a naturally occurring aryltetralin lignan found in the roots of either the North American podophyllum peltatum Linnaeus (also referred to as American mandrake, or May apple) distributed from the Hudson Bay to Florida. The Indian species Podophyllum emodi Wall, which grows in the Himalayan region [1-9], or Chinese medicinal herb Podophyllum emodi Wall var Chinensis Sprague (Fig. 1), which is existed in the western China [10-11]. Plant containing podophyllotoxin analogues have been used as folk remedies in traditional medicinal of many diverse cultures. Especially, extract of plants with high podophyllotoxin related contents was widely used in the Chinese, Japanese and the Eastern world folk medicine (even today in China, as Bajiaolian) as remedies for gout, tuberculosis, gonorrhoea, syphilis, menstrual disorders, dropsy, cough, psoriasis, venereal warts and certain tumours [12-16]. Topical podophyllotoxin was introduced in 1942 by Kaplan who demonstrated the curative effect of podophyllin in tumorous growths (condylomata acuminata) and is still accepted today as an effective treatment for condyloma acuminata (venereal warts) [17]. The initial hopes with respect to the possible clinical utility of podophyllotoxin as an antitumour agent largely have been abandoned because of its side effects. However, the remarkable biological activity and the very extensive use in traditional medicine make podophyllotoxin an important family of starting product for the development of new therapeutic agents based on structural modifications of such compound. Extensive structural modifications of podophyllotoxin have been undertaken, which culminated in the clinical introduction of two semisynthetic glucoconjugate analogues of etoposide (2) and teniposide (3) [18], their anticancer activities opened a door to a virtually unlimited number of podophyllotoxin derivatives with various modifications. Consequently, many clinicians and research scientists have *Address correspondence to this author at the State Key Laboratory of Applied Organic Chemistry, Lanzhou Universitry, Lanzhou, 730000, P.R.China Tel: +86-931-8912410; Fax: +86-931-891-2582; E-mail:
[email protected] 1573-4072/07 $50.00+.00
Fig. (1). Chinese medicinal herb Podophyllum emodi Wall var Chinensis Sprague. continued to explore structural modifications geared at improving pharmaceutical properties of the podophyllotoxin class and a considerable number of new potential podophyllotoxin derivatives would continue to be synthesised. Therefore, it is necessary to review all the development made on podophyllotoxin to provide insight to the researchers and to delineate further work that is needed in this field. SHORT CHRONOLOGY OF DISCOVERY AND DEVELOPMENT OF PODOPHYLLUM DRUGS Podophyllum is the dried roots and rhizomes of species of podophyllum, which was described and its first modern botanical name was given by Linnaeus in 1753 [19], at that time he referred to two of his earlier works, in which he simply called it “podophyllum”. The first serious chemical investigation was carried out by Podwyssotzki in 1880 [20-22]. The correct empirical © 2007 Bentham Science Publishers Ltd.
38
Current Bioactive Compounds 2007, Vol. 3, No. 1
formula for podophyllotoxin first advanced by Borsche and Niemann [23] and later confirmed by Gensler et al. [24-25] by means of a first total synthesis and the configuration of podophyllotoxin was established by chemical methods and confirmed by the analysis of crystal structure of easily obtained 2'bromopodophyllotoxin [26]. The alcohol-soluble portion of podophyllum is named podophyllum resin, which was dropped as cathartics from the U.S. Pharmacopoeia. A report by Kaplan that the topical application of podophyllin in condyloma acuminatum (a type of venereal wart) produced very satisfactory clinical results, and subsequently by King and Sullivan [27-28], who found that podophyllin caused pronounced cytological changes in normal human and rabbit skin. These reports initiated a renewed medicinal interest in podophyllin from the standpoint of its antimitotic activity. Kaplan's work was amply confirmed until now, podophyllin is still the drug of choice in the treatment of condyloma acuminatum. The continued study of podophyllin based upon its recognition as a cytotoxic agent and the growing knowledge of the nature and biological properties of pure constituents, which involving a multitude of chemical and biological investigations conducted over a period of more than a century. Initial expectations regarding the clinical utility of podophyllotoxin were tempered largely due to its unacceptable gastrointestinal toxicity. This led the chemists in the pharmaceutical research department of Sandoz Ltd. to investigate the possibility that the podophyllum lignans might occur naturally as glycosides. Using special procedures to inhibit enzymatic degradation, these researchers indeed obtained the podophyllotoxin-ß-D-glucopyranoside as the main component and its 4'-demethyl derivative from the Indian podophyllum species, the research efforts were then focussed on a program to chemically modify both the glucosides and aglucones of a wide range of podophyllotoxin derivatives, which eventually lead to discovery of the clinically important anticancer drugs etoposide and teniposide [29-36], interestingly, it was not until 20 years later that the interaction of this drug with DNA began to be understood and was recognised that the effects were mediated by topoisomerase II. At that time, it began to become clear that etoposide induced doublestranded breaks by stabilising a complex formed between topoisomerase II and DNA that is referred to as the cleavable complex. Ross et al. demonstrated this by showing that topoisomerase II was the most likely cellular target in the doublestranded breaking activity of epipodophyllotoxin like etoposide and teniposide [37]. In parallel, Long and coworkers studied a range of related derivatives to establish a correlation between DNA cleaving or cytostatic activities of various molecules and the extent to which they inhibited topoisomerase II activity. In this way, he demonstrated that the cytotoxicity of analogues of etoposide was associated with inhibiting DNA topoisomerase II by stabilising the covalent topo II- DNA cleavable complex [38-40]. Although etoposide is active in the treatment of many cancers and is widely used in the therapy, it presents several limitations, such as moderate potency, poor water solubility, development of drug resistance, metabolic inactivation, and toxic effects [41-42]. Therefore in order to obtain better therapeutic agents, and extensive synthetic efforts have been devoted to overcome these problems cited above. As highlights, a water-soluble phosphate ester prodrug of etoposide, etopophos (8), was launched in 1996 by Bristol-Myers Squib. This prodrug was readily converted in vivo by endogenous phosphatase to the active drug 2 and exhibited similar pharmacological and pharmacokinetic profiles to those of 2. The in vivo bioavailability was increased from 0.04% to over 50% through this prodrug approach and thus constituted an improved formulation of etoposide [43-45]. With increasing the information about its structure- activity relationships wide investigations have generated exciting chemotherapeutic candidates and successful applications of drug development from podophyllotoxin-related lead, such as NK611 (4), GL-331 (5), Azatoxin (6), TOP53 (7), Tafluposide (9). A 2"-dimethylamino analogue of etoposide, NK611, was conduc-
Tian et al.
ted first at the Institute of Microbial Chemistry and then was identified at Nippon-Kayaku, it was proved that NK611 improve bioavailability as a result of the molecule-altered physicochemical properties and more potent than 2 in topo II inhibition and cytotoxicity assays against a variety of human cancer lines [46-47]. Studies by Lee et al. led to the synthesis of a p-nitroanilino group at position 4β analogue GL-331, which showed topo II inhibition and caused DNA double-strand breakage and G2 phase arrest, it could induce cell death by stimulating protein tyrosine phosphatase activity and apoptotic DNA formation. GL-331 was also shown to be active in many multidrug-resistant cancer cell lines. Due to good stability and biocompatibility, and its favourable pharmacokinetic profiles similar to those of etoposide, compound 5 has completed phase I clinical trials at M.D. Anderson Cancer Center, and is currently in phase II clinical trials in Taiwan [48-50]. Structural studies of podophyllotoxin analogues based on molecular modelling techniques resulted in the rational design of a range of new chemical agents. In this way, Pomier and coworkers identified azatoxin using molecular modelling of the pharmacophore defined by topoisomerase II inhibitors. It was almost as potent as etoposide in inhibiting topoiso-merase II and showed significant promising [51-53]. In 1993, scientists at Taiho Pharmaceutical Co. Ltd. synthesised a series of 4β-alkyl amino derivatives of 4'-O-demethyl-4desoxypodophyllotoxin, from this series, TOP-53 was selected for further evaluation, TOP-53 displayed twice the inhibitory activity of etoposide against topoiso-merase II and exhibits in vivo superior antitumour activity than etoposide against several types of cancer. In view of high activity and good properties, TOP-53 has been progressed to phase II clinical trials [54-56]. Table 1. Short Chronology of Discovery and Development of Podophyllum Drugs 1753 1820 1861 1880 1942 1946 1966 1967 1971 1978 1983 1984 1986 1990
1992
1993 1996 2000
Linnaeus first described and first gave its modern botanical name Podophyllin was included in the United States Pharmacopoeia Bently mentioned local antitumour effects of podophyllin Podwyssotzki isolated and chemically investigated podophyllotoxin Kaplan described effects of podophyllin in benign tumors King and Sullivan reported the mechanism of action of podophyllotoxin Synthesis and biological evaluation of etoposide Start of clinical trials of teniposide Start of clinical trials of etoposide Sandoz handed over further development of teniposide and etoposide to Bristol-Myers Approval by the FDA of etoposide as VePesid for testicular cancer Studies on mechanism of action: inhibition of topoisomerase II by stabilisation of cleavable complex The institute of Microbial Chemistry and Nippon-Kayaku identified NK-611 Kuo-Hisiung Lee synthetised GL-331 and Genelabs Technologies. Inc had patented this technology and proceeded with phase II clinical trials in Taiwan. Pomier and coworkers identified azatoxin using molecular modelling of the pharmacophore defined by topoisomerase II inhibitors TOP53 was synthesised by scientists at the Taiho company and had been progressed to phase II clinical trials US launch of the prodrug etopophos Tafluposide, a novel catalytic inhibitor of topoisomerase I and II) had been obtained and developed in preclinical.
Podophyllotoxin
Current Bioactive Compounds 2007, Vol. 3, No. 1 39
More recently, 2",3"-bis pentafluorophenoxyacetyl-4',6'-ethylidene-β-D-glucoside of 4'-phosphate –4'-demethyle-pipodophyllotoxin (Tafluposide, a novel catalytic inhibitor of topoisomerase I and II) has been obtained [57]. The short chronology and the structures of these different compounds are shown in Table 1 and Fig. (2) respectively.
H3C
OH 5 10
O 6 A O 7
B 8
O
O
O HO
S
O
4 3 11
5' H3CO
O O
O
O O
O
OCH3
H3CO
OCH3
OCH3
H3 CO
OH
OH
Etoposide (2)
Podophyllotoxin (1) O
O
O
OCH3
4'
O HO
O
D O 12 2 1 O 1' 2' E 3'
9
O O HO
HO
C
6'
H3C
BIOLOGICAL ACTIVITY AND MEDICINAL APPLICATION OF PODOPHYLLOTOXIN AND RELATED ANALOGUES Extracts of plant containing podophyllotoxin have been widely used in traditional herbal medicine of many diverse cultures from remote times to modern times as remedies for purgative, snake
Teniposide (3)
O
O HO N
NH
O
O
NO2
O O
O
O
O
O
N
O
OCH3
H3 CO
O
O
OCH3
H3CO
OCH3
H3CO OH
OH
OH NK611(4)
GL331(5)
Azatoxin (6) F F
F
O
F F
O
O
O N
N
H3C
O
O
O HO
O O
F F O
O
F
O
F
O O
F
HO O
O O
O
2HCl
O O
O
O
O
OCH3
H3CO OH
OCH3
H3CO
ONa
O P
ONa
O TOP-53 (7)
Fig. (2).
O O
Etopophos (8)
O
OCH3
H3CO
OH
O P
OH
O Tafluposide (9)
40
Current Bioactive Compounds 2007, Vol. 3, No. 1
bites, periodontitis, skin disorders, coughs, various intestinal worm disease, veneral wart condyloma acuminatum, lymphadenopathy and certain tumours [1, 10,14,16]. Today, podophyllotoxin is still an effective, and comparatively safe drug choice in the treatment of veneral wart condyloma acuminatum. Actually, there are different biological activities in podophyllotoxin analogues that make them interesting in wide lines of research, such as reverse transcriptase inhibition and anti-HIV activity, immunomodulatory activity, effects on cardiovascular system, anti-leishmaniasis properties, 5lipoxigenase inhibition, antirheumatic, antipsoriasis, insecticidal activity, phytogrowth inhibitory activity and ichthyotoxic activity and antimalarial and antiasmatic properties [15, 58-59]. Among the plethora of physiological activities and potential medicinal and agricultural applications, the antineoplastic and antiviral properties of podophyllotoxin congeners are arguably the most eminent from a pharmacological perspectives. An alcohol extract of podophyllin was first cited in 1942 as a tropical treatment for veneral wart (Condyloma acuminatum), an ailment caused by a papilloma virus [17]. This would be one of the first reported examples of the antiviral activity of podophyllin. A crude extract of podophyllum peltatum was observed to reduce the cytopathic effect of herpes simplex type II, influenza A and vaccinia viruses, subsequently podophyllotoxin, β-peltatin, deoxypodophyllotoxin, picropodophyllotoxin and α-peltatin were tested by Markkanen et al. and were found to be active against measles and herpes simplex type I. Later in several papers, many researchers surveyed the antiviral effects of a number of podophyllotoxin against HSV-1 (a DNA virus), the measles virus, Sindbis virus (an RNA virus), murine cytomegalovirus (a herpes DNA virus), vesicular stomatitis virus and human immunodeficiency virus (HIV), and it appeared that the antiviral effect of podophyllotoxin analogues due to their ability to bind tubulin, they disrupted the cellular cytoskeleton and thus interfered with viral replication. In addition to tubulin binding, synthetic podophyllotoxin analogues show inhibition of reverse transcriptase, which may be exploited to selectively combat RNA viruses such as the human immunodeficiency virus (HIV) [60-66]. Podophyllotoxin is also effective in the treatment of anogenital warts in children and against Molluscum contagiosum that is generally a self-limiting benign skin disease that affects mostly children, young adults and HIV patients [67]. Podophyllotoxin has other uses in dermatology: it is also a useful agent in psoriasis vulgaris [68-69]. Systemic chemical modifications (including clinical application compounds, such as etoposide and teniposide) have been shown as an outstanding antitumour activity. It is effective in the treatment of Wilms tumours, different types of genital tumours and non-Hodgkin and other lymphomas and lung cancer and the studies of mechanism showed that their powerful antitumour properties have been attributed by either its binding to tubulin during mitosis and thus inhibiting microtubule assembly or acted by inhibiting the enzymatic activity of DNA-topoisomerase II [6, 70-71]. Furthermore, podophyllotoxin-related analogues have been shown to possess immunosuppressive activity and are seen as candidate for use in organ transplantation [72-73]. Studies on the penetration of podophyllotoxin into human bioengineered skin have demonstrated that podophyllotoxin analogues induced acantholysis and cytolysis in the skin-equivalent model used for a wide variety of pharmaco-toxicological trials [74]. A number of podophyllotoxin analogues have been tested by our and other research groups for insecticidal activity, phytogrowth inhibitory activity and ichthyotoxic activity, this may apply to claims of efficacy for pesticides [75-88]. Some other biological activities of podophyllotoxin analogues are now receiving an increased interest, for example, antioxidative properties of podophyllotoxin analogues may be used as antioxidants and prevent the production of carcinogens from estrogens, or they may inhibit aromatase enzymatic activity and thereby contribute to the prevention of dependent cancers [73]. The variety of biological
Tian et al.
activities and medicinal applications exhibited by podophyllotoxin analogues are impressive. More systemic investigations of their biological activities by utilising large number of compounds should further uncover new physiological information and medicinal uses for podophyllotoxin analogues. MECHANISM OF ACTION King and Sullivan have shown that the mechanism of cytostatic action at the cellular level of podophyllin was the same as that of colchicine, i.e. an inhibition of the formation of the mitotic spindle, resulting in an arrest of the cell division process in metaphase and a clumping of the chromosomes(c-mitosis). Later it was shown that, at the subcellular level, this is due to binding of podophyllotoxin to tubulin, preventing these macromolecules to form a microtubules, which constitute the fibers of the mitotic spindle [1, 2, 3, 9, 71, 8993]. In contrast to podophyllotoxin, neither etoposide nor teniposide has any effect on tubulin assembly even at 100µM concentration. Loike et al. showed that etoposide and teniposide are not inhibitors of microtubule due to the presence of the bulky glucoside moiety, and suggested that they must be inhibiting cell proliferation by some other mechanism. It was concluded that these drugs arrested cells in either the late S or early G2 phase of the cell cycle and they detected single-stranded breaks in DNA by the interaction of drug with DNA in HeLa cells. Further research indicated that etoposide does not interact with DNA in vitro to cause cleavage but rather induces single stranded breaks in DNA only in situ. This important research led to the conclusion that a nuclear enzyme was responsible for drug-induced cellular DNA degradation. Other studies showed that intercalative antitumour agents produced an unusual type of alkali-labile DNA breakage in which the termini of the broken strands appeared to be blocked by covalently bound protein. Based on the known catalytic relaxation mechanism of topo-isomerase, they seemed likely to be involved in this process. It was then shown in a purified system that topoisomerase II strand passing reaction was interrupted by some antitumour drugs. Topoisomerases are ubiquitous enzymes charged with the task of resolving topological problems which arise during the various process of DNA metabolism, including transcription, recombination, replication and chromosome partitioning during cell division. These enzymes are classified according to their catalytic mechanism of action, type I and II, identified in all eukaryotic cells. Topo I and II catalyse the relaxation of supercoiled chromosomal DNA replication. The relaxation of DNA by topo II involves the transient double-strand breakage of DNA, followed by strand passage and religation of the DNA strands. Topo II relaxation of DNA requires ATP and results in a change in linking number by (multiples of) two. In contrast, the mechanism of DNA relaxation of topo I involves the transient single-strand cleavage of duplex DNA, unwinding and religation. Investigation pointed that the primary mechanism of action of etoposide analogues, the antitumour activity caused by etoposide or teniposide is thought to be due to its interaction with topo II [9, 15, 16, 18, 94-98]. Another related investigations of Sinha pointed to the relevance of the etoposide O-quinone in the mechanism of action. Later, a large amount of experimental evidence supported that podophyllotoxin analogues may also exert their cytotoxic effect through the metabolic activation of the dimethoxyphenol ring (Ering) to produce metabolites that can inactivate the DNA by forming chemical adducts. It has been shown that the 3',4'-catechol derivatives of etoposide can be formed in the presence of cytochrome P-450 and that this catechol can be further oxidised to the 3', 4'-ortho-quinone in the presence of oxygen or under the influence of horseradish peroxidase or prostaglandium E synthetase. Both catechol and ortho-quinone bind strongly to purified calf thymus DNA and this may contribute to the activity of these compounds, and through the formation of free radicals or even through the direct binding of the quinone to the DNA [99-
Podophyllotoxin
Current Bioactive Compounds 2007, Vol. 3, No. 1 41
101]. Therefore, better understanding of the mechanism of action of podophyllotoxin congeners may make possible design and synthesis of novel selective drugs with improved activity and fewer side effects.
16
HN
OH
17
CHEMISTRY AND CYTOTOXICITY A. Ring Modified Podophyllotoxin Derivatives In 1964, Schreier made use of boron trichloride in the selective cleavage of the methylene-dioxy A-ring of podophyllotoxin analogues to produce the 6,7-dihydroxy derivative 10, methylation on the 6,7-dihydroxy group with diazomethane to further give the 6,7-dimethoxy derivatives 11 [102]. Later on, Lee and coworkers applied the slightly modified Schreier methods and introduced the C-4ß-substituted—arylamino group into the compound 10 and 11 to produce compound 12-31 and their biological results showed that all of the A-ring opened compounds were less active than the OH H3CO
HO
18
H
>2.00
50
CH3
H
>2.00
50
H
H
>2.20
25
H
H
1.50
20
H
H
1.46
20
H
H
2.00
20
H
H
>2.10
25
H
H
>2.10
20
CH3
CH3
7.30
>100
CH3
CH3
5.50
>100
CH3
CH3
5.80
>100
CH3
CH3
7.60
>100
CH3
CH3
1.30
100
H
CH3
1.90
>100
CH3
H
>1.80
100
CH3
H
>2.00
>100
CO2C 2 H5
CN
31
HN
F
corresponding A-ring intact 4'-O-demethyl-4ß-arylamino-4desoxypodophyllotoxin in KB, DNA topo-isomerase II and proteinDNA complex formation assays, which indicated that the maintenance of an intact methylenedioxy-type ring A system, in general, appeared to be more important than a ring-A-opened system in contributing to the enhanced ability in inhibiting human DNA topoisomerase II and causing the protein-linked DNA breakage [103]. On the basis of molecular modelling studies, Mac-Donald et al. proposed a common binding mode for intercalating and nonintercalating topoisomerase II inhibitors. Superimposition of
42
Current Bioactive Compounds 2007, Vol. 3, No. 1
Tian et al.
these compounds revealed three domains that are thought to be important for DNA topoisomerase II inhibitory activity: DNA intercalating moiety, the minor groove binding site, and the molecular region that can accommodate a number of structurally diverse substituents, which might also bind to the minor groove [104] (Fig. 3). Among the three domains of this composite pharmacophore, the DNA intercalating domain is the unexplored domain of pharmacophore model, in order to understand the mechanism of enzyme inhibition and design inhibitors with clinical potential, the intercalating domain of pharmacophore model was probed by synthesis and biological evaluation of podophenazine (32), 2", 3"-dichloropodophenazine (33), benzopodophenazine (34) and their C-4ß-p-nitroaniline derivatives (35-37) and the results was found that the mechanism of enzyme inhibition of these compounds was distinct from that of etoposide and its congeners and spectrum of cytotoxic activity (against drug-resistant cells) could be improved [105].
NO2 OH HN
N O N
N O
O N O
OCH3
H3CO OCH3
OCH3
H3 CO 34
OH 35 NO2
NO2
HN
HN
Variable Substituent Cl
N
N O
Cl
O
N
N
O
O
OCH3
H3 CO
OCH3
H3CO
OH
OH
36
Intercalation or "Intercalation-like" in Ternary Complex
OCH3
H3CO XH
Groove Binding(minor) and Protein-Associated in Ternary Complex
Fig. (3). Composite pharmacophore model for expression of topoisomerase II activity. Claude Monneret et al. prepared the A-ring pyridazine analogue of podophyllotoxin (38) with the aim of creating basic site which enhance interaction with tubulin and potentially easier drug formation via water–soluble salts and this compound displayed no inhibition of tubulin polymerisation and microtubulin assembly, such results clearly indicated that the importance of the methylenedioxy A-ring for binding to tubulin [106]. Furthermore, the same
37
author designed the condensed aromatic A-ring pyridazine analogues of etoposide (39-41) that provides: (1) a planar chromophore with two to four fused aromatic rings, as in the case of DNA intercalating agents: extension of the aromatic surface area should enhance π-stacking interactions in aqueous medium (2) a potential quaternarised aromatic nitrogen needed for an intercalation-based pathway and for water-solubility [107]. In view of naturally occurring justicidin B (42) and diphyllin (43) having been shown to be much more effective against sindbis virus than podophyllotoxin itself, Lee et al. investigated the antiHIV activities of the A-ring opened C-4ß-substituted—arylaminopodophyllotoxin analogues and Compound 44-50 with the A-ring opened, methylated and the 4'-position demethylated analogues had EC50's less than 0.001µM and therapeutic index greater than 120 and the data for Compound 44-50 was encouraging and warranted further structural modification to both decrease cytotoxicity and increase antiviral inhibitory activity [108].
H3C OH
OH
N
Cl
OCH3
32
O
N O
OCH3 OCH3
OCH3
n
O
H3CO H3CO
O
N
O Cl
O
O
N O
N
N
O N
O HO
N OH
O O HO
OCH3
H3CO OCH3 33
38
OCH3
H3CO OCH3 39 40 41
n=1 n=2 n=3
Podophyllotoxin
Current Bioactive Compounds 2007, Vol. 3, No. 1 43 N
OH
O
N
HO
H3CO
H3CO
H3COOC
O
O H3CO
O
O
HO
COOCH3
O
COOCH3
H3CO O
O OCH3
H3CO
OCH3
H3CO
OR
O
H3CO
OR
O
H3CO
51 52
O
O
R=H R=OCH3
O
O
O
Recently, several isoxazole derivatives of podophyllotoxin with A-ring opened or with different functionalisation in the A-ring of the podophyllotoxin skeleton (51-58) have been prepared by Gordaliza et al. with the aim of analysing the influence on cytotoxicity, simultaneously modified in A-ring and D-ring part of the podophyllotoxin skeleton and they were transformed into five– or six– membered rings with different substituents by condensation with dihalogenated substrates. These tested derivatives showed
R=H R=OCH3
N
O
N
43
42
53 54
O
COOCH3
OCH3
H3CO
COOCH3
O
OCH3
H3CO OR
OR 55 56
57 58
R=H R=OCH3
R=H R=OCH3
R1
cytotoxicity levels, which are two or three orders of magnitude lower than those of the parent compound of podophyllotoxin, and elimination of the methylenedioxy group which led to less cytotoxic compounds, however, the cytotoxicity remained at the micromolar level [109].
R3O O R3O O
OCH3
H3CO OR 2 Compound
R1
R2
R3
44
OH
H
H
H
CH3
45
HN
CN
B. Ring Modified Podophyllotoxin Derivatives Not many literatures available on the modifications of the structure of the B-ring were reported, α-peltatin (59) and β-peltatin (60) were isolated from natural resources and the two compounds exhibited significant antitumour and antiviral activity through antimitotic mechanisms [110-112]. In order to investigate the influence of the nature and size of the substituent, a series of αpeltatin esters and ethers (including its glucosidic ethylidene and thenylidene cyclic acetals) had been prepared by Kuo-Hsiung Lee and coworkers and all these compounds (61-70) were found less OH O
46
H HN
O
CH3 O
CO2C 2 H5
O
47
H HN
CH3
NO 2
OCH3
H3CO
48
CH3 HN
OH
CH3
59
F OH
49
HN
F
H
CH3
O O O
50
H HN
O
H
F
OCH3
H3 CO OCH3 60
44
Current Bioactive Compounds 2007, Vol. 3, No. 1
Tian et al.
OR
H3C
O
O
O
O HO
H3C
O
O
HO OH
O
O
R OCH3
O
O
O
O HO O
O
O
O
O
O O
O
OCH3
H3CO
OCH3
H3 CO
OH Compound
R
Cytotoxicity:ED50 KB (mg/mL)
DNA Topoisomerase II act: % Inhibition
59
H
0.09
++++
61
COOCH2C6H5
0.01
-
62
COCH3
0.01
+
63
COCH2CH2COOH
0.01
-
64
COCH2CH2CH3
0.004
-
65
COCH2CH3
0.005
+
66
COCH2C6H5
0.01
+
67
CH3
0.001
ND
2.0
+
2.0
+
1.1
+
68
H3C
O
O
O HO
O
HO
69
O S
O
O HO
O
HO
70
HO HO HO
O
OCH3
H3CO
OH
OH 72 R=OH 73 R=NH2
71
with selenium dioxide [118]. Recently dehydropodophyllotoxin has been obtained with improved yields by applying a novel enzymatic dehydrogenation of podophyllotoxone and its stereoisomer in presence of yeast [119]. Justicidin A and diphyllin are two ring- C aromatised lignans isolated from justicia procumbens, which were found to show significant inhibitory activity in vivo against P-388 lymphocytic leukaemia (T/C=150% at 50mg/kg/day), as well as in vitro cytotoxicity in KB cell (ED50200
175
100
200
50
242
160
125
>180
145
>100
216
>160
105
>140
115
>180
125
>120
145
>180
110
>120
165
>200
240
NOCH 3 H3 CO
HO
NOCH3
O O
173
O O
NOCH3
H3 CO
O
R
H3CO
174 OH NOCH2Ph
R
Dose mg/kg/inj
P-388 Max% T/C
158
-NH2
60
288
159
-NO2
140
>140
160
-NHCH3
140
170
161
-NHAc
70
135
162
-NH(CO)N(CH2)2Cl
>160
110
163
-NHCOCH2Ph
>160
110
164
-NH(SO2)CH3
140
150
165
-N=CHPh
>200
230
166
-N=CH(Ph-p-OCH3)
70-140
175
167
-N=CH(Ph-m-NO2)
>200
235
>200
225
H3 CO
O
175 O
H3 COCHN O
176 H3 CO
N
N CH2 Ph CH 2Ph
177 H3 CO
NH2 N H2
178 168
OCH3
N=HC
OCH3 OCH3
169
H3CO
NHAc NHAc
179 >140
N=HC
N
H3 CO
195
N
S
180 170
>120
N=HC
H3 CO
200
N N
N
O
181 H3 CO
H3C
O
O
O HO
N N P S
H3 CH2 CO
O
182
HO O
H3 CO
O
N N
O O
183
R
R
171 H3CO
NOCH2 Ph NOCH3
Dose mg/kg/inj
P-388 Max% T/C
100
126
N
H3 CO
O
184 H3 CO
N2 O
50
Current Bioactive Compounds 2007, Vol. 3, No. 1
aromatic and hetero ring systems, had been explored and all of these compounds were less active in vivo against P388 leukaemia than etoposide [168-169]. Furthermore, a series of 3', 4'-Odidemethylepipodophyllotoxins and 3', 4'-O-didemethoxy-3',4'dioxoepipodophyllotoxins with various C-4ß-aniline moieties (185198) have been synthesised by the group of Lee and evaluated for their inhibitory activity against human DNA topoisomerase II and their activity in causing cellular protein-linked DNA breakage as well as their cytotoxicity against KB cells, and the biological evaluation results showed that 3', 4'-O-didemethoxy-3',4'-dioxoepipodophyllotoxins (the ortho-quinone compounds) were, in most cases, less potent than their congeners of 3', 4'-O-didemethylepipodophyllotoxins, which in turn were less potent than those of 4'-O-demethylepipodophyllotoxins and it was likely that the cytotoxic action of the 4'-O-demethyl compounds is still primarily a result of interaction with DNA topoisomerase [170-171]. Other modifications performed in the E-ring imply changes in the degree of oxygenation. Thus, podophyllotoxin analogues in which one, two or all three methoxy groups on the phenyl ring were replaced by hydrogen atoms or an alky group (199-202) and the activity results showed that some of them were almost as potent as the parent compound, suggesting that the presence of the three oxygenated functions in the E-ring of podophyllotoxin was not a strong determinant of cytotoxicity [172-174]. Previously, the configuration of podophyllotoxin was established by chemical method and was confirmed by analysis of the crystal structure of easily obtained 2'-bromopodophyllotoxin (203). Later, Ayres et al. had showed that bromide and chloride could be introduced at the 2'-position with phosphorus pentahalides [175]. The introduc-tion of a chloro atom into the C-2' position of podophyl-lotoxin was found to increase the stability to epimerisation at C-2 by bases, the physiologically active translactone configuration was retained even in the presence of alkoxide ions [176]. On the basis of this finding, Lee and coworkers synthesised and evaluated the 2'-chloro derivatives of etoposide and 4ß-(arylamino)-4'-O-demethylpodophyllotoxins via Nchlorosuccinimide chlorination of etoposide and 4ß-(arylamino)-4'O-demethylpodophyllotoxins, respectively. All of the 2'-chloro compounds (204-212) showed not only no significant cytotoxicity against KB cells but also much less activity in inhibiting the human DNA topoiso-merase II and essentially no activity in causing the cellular protein-DNA strand breakage. The introduction of chloro group into 2'-position would lead to steric hindrance to the free rotation of E-ring and to a decrease in the rate of the ortho-quinone production. Therefore, the difficulty of ortho-quinone formation or / and the steric hindrance to the free rotation of E-ring was more likely to be responsible for the lack of significant activity of the 2'chloro derivatives [177]. Systemic cytotoxic drugs rely primarily for their therapeutic effects on cytokinetic differences between cancer and normal cells. One promising strategy is the use of less toxic prodrugs that can be selectively activated in tumour tissue after administration, either by metabolism or by spontaneous chemical breakdown, to form a pharmacologically active species. Therefore one potential strategy aimed at providing substantial increase in the clinical efficacy of etoposide is the design and synthesis of prodrug of etoposide. Thus, E-ring modification also has been focussed on the design and synthesis of prodrug of etoposide and some other 4'-acyl derivatives. Extensive systemic modification of 4'-position have been performed by Bristol-Myers company and these compounds included 4'-acyl derivatives (213-240) and phosphorus- containing derivatives (241-250) and most of them retained significant antitumour activity in vivo against P388 leukaemia and some were even more active than etoposide. As highlights, a water- soluble etoposide prodrug, etoposide phosphate 243 (BMY-404811), was developed and this prodrug could be administrated in higher doses than etoposide as a short intravenous injection, whereafter it was
Tian et al.
rapidly converted to the parent compound by plasma phosphatases, and thus constituted an improved formulation of etoposide [178179]. Recently, Doron Shabat et al. reported a chemo-therapeutic strategy based on catalytic antibody-mediated prodrug activation and the prodrug incorporated a trigger portion designed to be released by sequential retro-aldol/retro-Michael reactions catalysed by aldolase antibody 38C2 and this unique prodrug (251) was greater than 10 2-fold less toxic than etoposide in vivo assay against the NXS2 neuroblas-toma cell line and drug activity was restored after activation by antibody 38C2 [180] and later they reported the preparation of a novel catalytic antibody-polymer conjugation for selective prodrug activation and demonstrated that the antibody retained its catalytic activity after conjugation to the HPMA copolymer. Furthermore, a cell growth inhibition assay demonstrated that the conjugate retained its catalytic activity and was capable of activating prodrug in a manner analogues to the free antibody [181]. Wolf Wrasidlo and coworkers synthesised two 4'-propylcarbonoxy derivatives of etoposide (252-253) through the hydrolytic activation approach and these two drugs significantly decreased the activity/ toxicity of the drug, which could be restored via hydrolysis mechanism [182]. It is shown by enzyme histochemistry that necrotic areas in human cancers are the site in which lysosomal β-glucuronidase is liberated extracellularly in high local concentration and further investigation has demonstrated that extracellular β-glucuronidase originated from monocytes and granulocytes concentrated within necrotic areas. Based on these facts, glucuronide-based prodrug of etoposide (254) has been synthesised with the aim of selectively liberating the active compound by β-glucuronidase already present in necrotic tumours. In vitro, the prodrug was shown to be less cytotoxic and more water-soluble than etoposide and the cleavage of the prodrug with complete release of the active drug in the presence of the β-D- glucuronidase has been observed [183]. One direct strategy proposed to overcome the immunogenicity issue of the drug-activating enzyme is to use endogenous enzymes specifically expressed by tumours and H.N.Lode et al. selected tyrosine hydroxylase as endogenous tumour catalyst since it is highly expressed in neuroblastoma and designed the prodrug of etoposide (255) activated by tyrosine hydroxylase to yield free etoposide thereby providing proof of concept for neuroblastoma directed enzyme prodrug therapy (NDEPT)[184-185]. Recently, Peter D. Senter et al. described a new anticancer prodrug activation strategy based on the 1,6-elimination reaction of P-aminobenzyl ether, the phenolic anticancer drug of etoposide was attached to the Z-val-cit-p-amidobenzyl alcohol through ether linkage (256) and the results showed that the released drug was 13-50 times more potent than the prodrug precursor on a panel of cancer cell lines [186], although modification of the phenol function significantly decreases not only the activity but also the toxicity, both are almost selectively restored by enzymatic cleavage. Based on 4β-arylamino substitution is regarded as a structural feature critical for improved activity profiles and several 4'-ester epipodophyllotoxin derivatives (257–264) were designed and synthesised with the aim to overcome drug resistance and improve water-solubility simultaneously. These compounds were superior to etoposide in causing cellular protein linked DNA breaks and inhibiting KB and 1-resistant KB-7d cell replication. Unexpectedly, the ester remained as the major component and no visible hydrolysis (metabolite) was detected after incubation. These results indicated that these compounds were an enzyme inhibitor in vitro and the intact esters were the active form responsible for in vitro activity. These results, especially the in vitro topo II inhibition, challenged the long standing structure–activity relationships (SAR) premise that a free
Podophyllotoxin
Current Bioactive Compounds 2007, Vol. 3, No. 1 51
R
R O
O
O
O O
O
O
O
O
H3CO O (A)
OH (B) Cytotoxicity ID50 KB (µM)
Compound 185
R
HN
N O2
186 HN
187
OH
H3 CO
Inhibition of DNA Topoisomerase II activity, ID50 (µM)
Cellular Protein-DNA Complex Formation (%)
(A)
(B)
(A)
(B)
(A)
(B)
1.3
1.3
10
10
128
200
1.4
-
25
-
110
-
1.3
1.5
25
10
92
117
6.5
-
25
-
51
-
1.8
-
50
-
32
-
1.6
-
100
-
50
--
1.2
-
100
-
29
-
2.0
-
50
-
57
-
1.9
-
100
25
47
-
1.2
2.3
100
-
67
94
CO2C 2 H5
HN
F
188 HN
CF3
189
N O2 HN NO2
190
F HN
191
F HN
F
192 HN
F
193
OH HN
194
CO2 CH3
CO2 CH3 HN
52
Current Bioactive Compounds 2007, Vol. 3, No. 1
Tian et al. Contd…. Cytotoxicity ID50 KB (µM)
Compound
R
195
C2 H5 O2C
Inhibition of DNA Topoisomerase II Activity, ID50 (µM)
Cellular Protein-DNA Complex Formation (%)
(A)
(B)
(A)
(B)
(A)
(B)
7.0
-
100
-
4
-
5.5
-
>100
-
>100
-
>2.0
1.8
50
50
18
146
>2.0
1.8
25
25
32
128
HN
CF3
196 HN
CF3
197 HN
198
CN
HN
OH OH O O
O O
O
O
O
Br O 199 R1=OCH3 200 R1=OCH3 201 R1=H 202 R1=OCH3
R3
R1
R2=H R2= OCH3 R2=H R2=OAc
R2
R3=OH R3=H R 3=OH R3 =OAc
OCH3
H3CO OCH3 203
R1 O O O R2
O
OCH3
H3 CO OH R1
203 H3 C
O
O
O HO
R2
Cytotoxicity ID50 KB (µM)
Inhibition of DNA Topoisomerase II Activity, ID50 (µM)
Cellular Protein-DNA Complex Formation (%)
H
0.2
>50
100
Cl
>6.4
>50
6.1
O
HO
204 H3 C
O
O
O HO HO
O
Podophyllotoxin
Current Bioactive Compounds 2007, Vol. 3, No. 1 53
Contd….
205
R1
R2
Cytotoxicity ID50 KB (µM)
Inhibition of DNA Topoisomerase II Activity, ID50 (µM)
Cellular Protein-DNA Complex Formation (%)
OH
Cl
>22.3
>50
15.6
Cl
>7.2
>100
0
Cl
>7.2
>100
0
Cl
5.7
>100
0
Cl
>7.0
>100
0
Cl
>7.5
>100
0
Cl
>7.3
>100
0
Cl
>6.8
>100
0
206 HN
207
NO2
NO2 HN
208
OH HN
209
O HN
O
HN
F
HN
Cl
HN
Br
210
211
212
4'-phenol group is essential for 2-related topo II inhibitors, and in addition, suggested that the 4'-position might tolerate chemical modifications such as esterification [187-188]. Moreover, the esters of 4'-demethyl-4-deoxypodophyl-lotoxin with alkyl acid, unsaturated fatty acids and amino acids (265-292) have been prepared by the groups of Byung-Zun Ahn and most of esters showed significant in vivo antitumour activity despite the lower in vitro than 4'-demethyl-4-deoxypodophyllotoxin [189-191]. SPIN LABELLED PODOPHYLLOTOXIN DERIVATIVES Research into free radical compounds of the stable nitroxide type and their application in biological studies has become increasingly frequent in recent years and the stable nitroxides have a wide range of activities in biology. A number of studies have shown that the introduction of nitroxyl moiety into the bioactive molecules can lead to a fast decomposition, higher alkylating, lower carbamoylating activity, better antimelanomic activity, lower general toxicity, and recently it has been found that the nitroxyl radicals can normalise the level of the oxidised form of p-450 cytochrome which has been brought down by the injection of cytostatic agents of lethal doses and the nitroxyl moiety serves as a transportant vehicle through cell membranes. Therefore nitroxyl radicals can be considered as biological response modifiers and some researchers introduced a stable nitroxyl radical into some antitumour drugs, (such as thio-TEPA, 5-fluorouracil, nitrosourea, rubromycin and 6-mercaptopurine etc.) [192] which could result in compounds with superior pharmacological properties to those of the parent compounds and these nitroxyl-labelled compounds have another advantage that they can be monitored by ESR technique in pharmacokinetic experiments, which can be readily accomplished
than radiolabelling of the parent compounds. In order to find compounds with superior bioactivity and less toxicity, our group has been involved for many years in isolation and the chemical transformation of podophyllotoxin and its analogues and we have especially prepared a large number of podophyllotoxin derivatives by the introduction of a stable nitroxyl radical into different positions in the podophyllotoxin skeleton and proved to have significant antitumour activity against several mouse transplantable tumours with a marked decrease in toxicity (293-318), we found that the introduction of a stable nitroxyl radical into the molecule of podophyllotoxin could result in new compounds which have significant antitumour activity with marked decrease in toxicity compared with the parent compounds. Among these, those analogues modified at the C-rings or D-rings with the nitroxyl radical structures are particularly worthy of note, in particular, GP-7 (298) showed lower toxicity but equivalent activity both in vivo (mouse solid tumours S180 and HePA) and in vitro (mouse leukaemia L1210 and human stomach carcinoma SGC-7901) in comparison with etoposide and GP-11 (299) was reported as low immunosuppressive antitumour agent, which increased the mitotic index and resulted in G2/M phase, and to a lesser extent, S arrest. It has the possibility of becoming a promising new antitumour drug [193-205]. PODOPHYLLOTOXIN-BIOLOGICALLY ACTIVE MOIETY CONJUGATES AS NOVEL CYTOTOXIC AGENTS The use of conjugates has emerged as a frequent strategy in efforts to optimise therapeutically beneficial properties of podophyllotoxin analogues, including an increase in the minor groove binding ability of the epipodophyllotoxin derivatives and on
54
Current Bioactive Compounds 2007, Vol. 3, No. 1
H3C
O
O
O HO
Tian et al.
O
H3 C
O
O
O HO
HO
O
HO
O O
O
O
O
O
O
O R OCH3
H3 CO
R
R
O
Dose mg/kg/dose
P-388 Max % T/C
140(50)
363(256)
125(100)
306(369)
200(100)
225(269)
240(60)
165(250)
200(100)
155(270)
240(100)
250(260)
150(100)
217(267)
120(40)
>544(>45)
200(60)
285(280)
160(60)
305(280)
O
R
213
-CH=CH2
Dose mg/kg/dose
P-388 Max % T/C
40(80)
205(>370)
OCH3
H3CO
OR 1
241
ONa P
R 1=
214
-CH2Br
50(40)
225(365)
215
-CH2(CH2)5CH3
100(40)
235(365)
216
-OCH3
70(40)
235(365)
P
217
-phenyl
60(60)
330(260)
O
218
-benzyloxy
120(60)
355(260)
242
219
-N(CH2CH2Cl)2
100(60)
ONa
O
OH OH
243
O Na P
210(260)
ONa
S
220
-NHNH2
280(100)
225(295)
221
-O(CH2)2N(CH3)2
280(100)
225(295)
222
-NH(CH2)2N(CH3)2
140(100)
190(295)
223
-S(CH2)2N(CH3)2
280(100)
230(295)
244
NEt2 P
NEt2
O Cl
245
P
224
-O(CH2)2N(CH3)2 HCl
70(100)
263(338)
225
-NH(CH2)2N(CH3)2 HCl
35(100)
175(338)
226
-S(CH2)2N(CH3)2 HCl
70(100)
256(338)
P
227
-N(CH3)2
300(120)
170(>510)
O
228
-NH2
300(120)
285(>510)
CH2 CH2Cl
O
246
OPh
247
OCH2 CCl3 P
229
-NHCH3
300(150)
OPh
OCH2 CCl3
165(>480) O
230
231
-CH2(CH2)6CH=CHCH2CH= CH(CH2)4CH3
200(60)
-(CH2)2S(CH2)2N(CH3)2 HCl
200(60)
290(250) 248 215(250)
O
H3 CO O
232
-CH2(CH2)2N(CH3)2 HCl
180(80)
>335(260)
233
-CH2(CH2)2N(CH3)2
90(60)
245(260)
234
4-Pyridyl HCl
180(60)
210(260)
235
4-Pyridyl
160(60)
180(260)
236
-CH(CH2)2Br
45(60)
165(260)
237
-CH2(CH2)2I
45(80)
205(295)
238
-CH2(CH2)2N3
160(80)
335(295)
239
p-nitrobenzyloxy
180(80)
335(295)
240
anthraquinone-2-methyloxy
80(80)
165(295)
P
Et Et
Et
249 O
H3 CO O
CH2CN
P
NCH2 C
CH2CN
250 O
H3CO O
P O
CH
CH2 OH CH2OH
Podophyllotoxin
Current Bioactive Compounds 2007, Vol. 3, No. 1 55
H3 C
O
O
O HO
O
HO O O O O
OCH3
H3CO O R Compound
R O
251
O
HO
N
O
N O 252
OH OH
O O 253
H3C
CH3
O O
O O
254 O N HOOC O
HO HO
NO2
O
HO O
255
OCH3 N
O
N O
256
O
O NH
N H
O
N H
O
O NH
C
NH2
basis of the combination therapy theory, solubility/lipophilicity, tumour cell recognition and sequence specificity of DNA damage. Two predominant methodologies have been utilised for the synthesis of conjugates. The first relies on the utilisation of the C-4 position as the site for conjugation. The second involves biologically active moiety conjugate with podophyllotoxin through different reactive functional groups, for example, amino, hyroxyl, imine, carboxylic acid groups, on modified podophyllotoxin analogues. Since the nucleoside substituent itself is a biologically active moiety and two of novel derivatives of podophyllo-toxin and 4'demethylepipodophyllotoxin in which the nucleoside thymidine (319-320) have been conjugated at the C-4 position and the observed cross-resistance patterns of the thymidine derivatives suggested that these compounds displayed podophyllotoxin-like activity and showed no etoposide-like activity. These thymidine derivatives exhibi-ted much lower activity in comparison to podophyllotoxin and 4'-demethylepipodophyllotoxin, suggesting that the thymidine moiety interferes with the interaction of these compounds with the receptor site on the tubulin molecule [206]. It has been demonstrated that the specific minor groove-binding agents such as distamycin interfering with the catalytic activity of topo II and inhibit DNA-protein cross links and DNA double-strand breaks induced by teniposide and these results indicated that the minor groove of duplex DNA may be involved in the molecular recognition and action of this enzyme. Three 4'-demethylpodophyllotoxin –lexitropsin conjugates (321-323) were synthesised with aim to confer higher affinity for DNA, improved cellular uptake and higher metabolic stability and further investigated the biological effects of such bifunctional hybrids, the results demonstrated that conjugation with the minor groove-binding moieties could alter or increase the number of topoisomerase II–induced cleavable sites. Following novel water-soluble 4β-amino-4'-Odemethylepipodophyllotoxin derivatives (324-325) were also designed by Lee et al. to enhance minor groove binding ability and compounds exhibited a superior activity profile compared to that of etoposide against DNA topoisomerase II [207]. The idea of some severe side effects in the most current chemotherapy regimes for cancer were optimal for chemical and biochemical modulations by combinations of 5-fluorouracil with other anticancer agents. Moreover, according to the principle of drug design, combinations of antimetabolite 5-fluorouracil and topoisomerase inhibitor etoposide may circumvent some faults and lead to decreased repair of etoposide-induced DNA damage and increase induction of apoptosis, or increase DNA adduct formation in cancer cells. A series of 4β-5-fluorouracil substituted-4'demethylepipodophyllotoxin (326-334) and five novel bimolecular structures composed of etoposide and 5-fluorouracil derivatives (335-339) joined by suitable amino acid spacers have been synthesised and the cytotoxicity assay for most of these analogues demonstrated many folds increase of activity in comparison to etoposide, these testing results indicated that the design and synthesis of these compounds were beneficial for therapeutic values of etoposide [208-210]. A major problem in cancer chemotherapy is the development of acquired multiple drug resistance (MDR) in tumour cells after drug treatment, which calls for the development of new anticancer compounds with broader sensitivity profile against resistant cells. One way of improving cancer therapy is to develop new anticancer agents which are able to overcome the resistance mechanisms, retaining their activity against MDR cells. Based on such facts, several conjugates composed of 4'-demethyl-epipodophyllotoxin and camptothecin (340-341) or paclitaxel derivatives (342-344) joined by an imine linkage were respectively prepared with the aim to develop etoposide analogues with multiple antitumour mechanisms or improved activity against drug resistant cells and the
56
Current Bioactive Compounds 2007, Vol. 3, No. 1
Tian et al.
HN
R
O O O O
OCH3
H3CO O
R' ED50 (mg/mL)
R 257
R´
NO2
%PLDB formation
KB
KB-7d
219
0.4
8
156
8
20
199
0.35
10
172
1
9
165
0.4
8
102
0.9
10
116
0.5
4
161
0.2
2
228
0.33
2
N O
258
NO2 N
HCl
O
259
F NH 2 O
260
F N H O
261
F N O
262
F N
H Cl
O
263
F NH2 O
H N
264
N
O 5
O
NO2
results showed that cytotoxic activity and selectivity were largely retained through conjugation and conjugation afforded a broader spectrum of cytotoxic activity against drug-resistant cells [211212]. Later, Line Rothenborg-Jensen et al. aimed at overcoming the development of acquired multiple drug resistance in tumour cells after drug treatment and generated new structures comprising the
topoisomerase II interaction moiety of the epipodophyllotoxin (345346) and the DNA intercalating acridine moiety via different length spacers and these compounds were capable of circumventing the MDR phenotype of cancer cells comprising different resistance mechanisms, involving over-expression of membrane transporters as well as down regulation of topoisomerase II [213].
Podophyllotoxin
Current Bioactive Compounds 2007, Vol. 3, No. 1 57 O O O O
OCH3
H3CO O R'
ED50 (µg/mL) R
A-549
SKMEL-2
265
Acetyl
0.003
0.006
266
Propanoyl
0.004
0.010
267
Butanoyl
0.005
0.017
268
3-Methylbytanoyl
0.006
0.089
269
Heptanoyl
0.013
0.078
270
Octanoyl
0.009
0.030
271
Decanoyl
0.027
0.004
272
Dodecanoyl
0.030
0.025
273
Tetradecanoyl
0.041
0.050
274
Hexadecanoyl
0.268
0.290
275
cis-9-Hexadecenoyl
0.733
0.065
276
Octadecanoyl
2.670
>5
277
cis-9-Octadecenoyl
0.179
0.159
278
trans-9-Octadecenoyl
0.367
0.550
279
cis-11-Octadecenoyl
0.335
0.057
280
trans-11-Octadecenoyl
1.010
0.253
281
All-cis-9,12-Octadecanedienoyl
0.090
0.030
282
All-trans-9,12-Octadecanedienoyl
0.259
0.110
283
All-cis-9,12,15-Octadecantrienoyl
0.084
0.048
284
All-cis-6,9,12-Octadecantrienoyl
0.085
0.041
285
Eicosanoyl
>5
>5
286
cis-11-Eicosenoyl
>5
>5
287
trans-11-Eicosenoyl
1.660
1.130
288
All-cis-11,14-Eicosadienoyl
0.870
0.347
289
All-cis-5,8,11,14-Eicosateraenoyl
0.910
0.184
290
Docosanoyl
>5
>5
291
cis-13-Docosenoyl
2.170
0.561
292
All-cis-4,7,10,13,16,19docosahexaenoyl
0.119
0.035
2
VP-16(etoposide)
1.102
-
DDPT
0.023
0.015
In the light of current interest in dimeric analogues of lipophilic, neutral, DNA mono- intercalating agents as potential antitumour drugs. Ahmed Kamal et al. reported bisepipodophyllotoxin congers by linking two 4β-amino podophyllotoxin moieties with suitable aryl spacers (347-353) and most of these analogues have exhibited promising in vitro anticancer activity against different human tumour cell lines [214]. Recently a dynamic combinatorial library of thiocolchicine-podophyllotoxin derivatives (354-357) based on the disulfide bond exchange reaction was described and the results of the in vitro biological tests provided evidence that the formation of divalent compound gave a new chemical entity whose activity was not predicted by the sum of the single ligands activities, thus reflecting a different interaction with the putative biological target [215]. In addition, polymer-podophyllotoxin conjugates with unique physical properties or biological activity were particularly worthy of note, such as 4-poly (ethylene glycol) derivatives of podophyllotoxin (358-362) were also described [216]. STRUCTURE-ACTIVITY RELATIONSHIPS The development of these synthetic and semi-synthetic strategies has facilitated the study of podophyllotoxinmechanism, as well as the identification of analogues with improved properties. Likewise, the availability of topo II-DNA and inhibiting tubulin polymerisation mechanism analysis and the composite pharmacophore model proposed by different research groups provided insight regarding the mechanisms of action of podophyllotoxin analogues, alth-ough a number of questions remain unanswered. Especially in the absence of the 3D-structure of topo II active site for conducting rational drug design, two models have been built to provide insight about key structural parameters required for optimum biological efficacy. First, the composite pharmacophore model based upon various Topo II inhibitors that contain three structurally distinct domains: intercalation, groove binding, and variable substituent. Second, the CoMFA model (site receptor model) [104,152,217] that represented the 3-D steric and electrostatic fields of a set of superimposed 4'-O-demethyl-4substituted epipodophyllotoxin derivatives. These fields are compatible with stereochemical properties of the DNA backbone. The latter include an understanding of the exact mode and the specific roles of various structural features of podophyllotoxin in some critical mechanism studies. Further, it is important to gain an understanding of how systemic modifications in the podophyllotoxin skeleton may enhance or suppress the effect of the type of drug in a biological context. Numerous studies exploring the structure-activity relationships (SARs) of podophyllotoxin derivatives have provided novel insights and contributed to the clinical successes. The present discussion of podophyllotoxin derivatives focusses basically upon substitutions, additions and different configurations of the C-4 position, the A, B, C, D, and the E ring of the podophyllotoxin skeleton and can be summarised (Fig. 6). In general, the design of novel podophyllotoxin analogues rests upon a few important working assumptions. These assumptions have revealed structural features critical for their biological activity: (a) the 4 β - configuration is essential with various substitution accommodated at C-4 position; (b) the free 4' - hydroxy is crucial; (c) the trans-lactone D ring with 2 α, 3 β configuration is very important; (d) the dioxolane A ring is optimal; and (e) the free rotation of ring E is required. CONCLUSIONS AND PERSPECTIVES Plants containing podophyllotoxin have been a prime source of highly effective folk remedies for the treatment of many forms of diseases. Among the plethora of physiological activities and potential medicinal and other applications, the antineoplastic and antiviral properties of podophyllotoxin congeners and their
58
Current Bioactive Compounds 2007, Vol. 3, No. 1
Tian et al.
OH
OH
O
OH NH N
O
N O
O
OH
O
NH NH
O
O
O
OCH3
H3CO
N
OCH3
H3CO OCH3
OCH3
293
294
OH
OH
O
OH
O
S
NHNHCNH
O
OH
NHNHC NH
O
O
OH
N
O O
N
O
OCH3
H3CO
OCH3
N
O
OCH3
H3CO
OCH3
295
O
OCH3
296
297
OH
N O
NH
S
NHNHC NH
O
OCH3
H3CO
O
S
O
O
OH
O O
O
O
NHNHC HN
O
O
N O
OCH3
H3 CO
OCH3
H3CO OCH3
OH
299
298
H3C
O
H3C
O
O HO
O
O
O
O HO
O
HO
HO
O
O
OH NH N
O
N O
OH NH N
O
O
OCH3
H3CO
O
OCH3
H3CO
OH 300
OH 301
N O
Podophyllotoxin
R
Current Bioactive Compounds 2007, Vol. 3, No. 1 59
O
O
H 3C
O
O HO
O
O
O HO
R
O R
HO
HO
O
O O
O
302 O
O N
O
304
O
N
O OCH3
H3CO
O
303
OCH3
H3CO
OH
O
N
R
O
O O
R
305 N O
O 307
306
O O
N
N
O
O
O O
308
309 N
N O
O
OCH3
H3CO OH
O HN
R 311
310 O O O
N
N
O
O
O 313
312
N O
N O OCH3
H3CO OH
O
O
O
CH3
H N
O
N O
O
R
CH3
HN
O
O
O
HO
HN N
O HO
O
O
N O
O O
O OCH3
H3 CO
O
O
O O
OCH3
O R 314
H
315
CH3
316
CH2SCH3
317
CH(CH3)CH2CH3
O
OCH3
H3CO OH 319
318
CH2Ph
O O O
OCH3
H3 CO OCH3 320
60
Current Bioactive Compounds 2007, Vol. 3, No. 1
Tian et al.
H N H N
O
n
329
CH2Ph
4
330
CH(CH3)CH2CH3
4
331
CH2SCH3
4
332
CH2Ph
5
333
CH(CH3)CH2CH3
5
334
CH2SCH3
5
N
N O CH3 O O O O O 321 322 323
OCH3
H3 CO
n=1 n= 2 n=3
H3C
O
O
O HO
O
HO
OH
O
NO2
O
H N
O
N
O
H N
O N O
CH3
n
H3CO
CH3
HN
OCH3 R
O
CH2
N H
O
F
O
O NH
O
O O
N O
335-339 O
R OCH3
H3 CO
324 n=0 325 n=1
OH
F R N HN
n O
O NH
O
335
H
336
CH3
337
CH(CH3)2
338
CH2Ph
339
CH(OH)CH3
O O O O
OCH3
H3CO OH 326-334
R
n
326
CH2Ph
3
327
CH(CH3)CH2CH3
3
328
CH2SCH3
3
derivatives are arguably the most eminent from a pharmacological perspective. Although semisynthetic derivatives of etoposide and teniposide as important cancer chemotherapeutic agents were introduced into clinical use, however, the main problem with these agents is their typical adverse effects common to most antineoplastics (such as anaemia, hair loss and severe gastrointestinal disturbances). Other than this, drug resistance is another problem, which arises after some time. Nowadays, combination therapy is used to combat this problem, which seems to be a temporary one. But this approach threatens the possibility of the development of drug resistance. Although a number of potential candidates (such as etopophos, NK611, TOP-53, GL-331, etc) have been developed from extensive chemical modifications at various sites of the podophyllotoxin backbone, development of a safe, economic and site-specific anticancer drug is still a challenge. Perhaps, with indepth studies of multiple pharmacological actions and development of new technologies making podophyllotoxin continue to be the subject of extensive research, and efforts to rationally designing a better antineoplastic drug based on the podophyllotoxin framework may be more widely developed. It can be seen that a multi-
Podophyllotoxin
Current Bioactive Compounds 2007, Vol. 3, No. 1 61
R1
O
AcO
C6H5
O
OR2
O
N H
O O
L
HO
N
C
HN
O
O
N
O
O
O
342
R1=C6H5
343
R1= C6H5
R 2=H
O
O
H
O O
O
O HO
R 2= CH3
H3C
O
C
OCH3
H3CO
O
AcO
C6 H5
O
N
O
OCH3
H3CO
OH
344
R1=C6H5
R2= O
OH
O
O
340 L= Para linkage 341 L=Ortho linkage
O
N
O OCH3
H3CO OH
O H3CO
O
352
O
O
OCH3 H N
HO
R
N H
O
OH
H3CO O O
353
O
O
OCH3
disciplinary approach can be profitably based on semisynthetic chemistry and mechanistic pharmacology, revealing novel potential perspectives.
347-353
ACKNOWLEDGEMENTS I am indebted to the excellent graduate students and research associates, whose names are given in the text and references, for their invaluable experimental and theoretical contributions to the work carried out on podophyllotoxin's chemistry and medicinal chemistry in our laboratory. I would like to thank my collaborators, which have contributed in this research in many ways, and who are cited in the accompanying references. This work was financially supported by the Natural Science Foundation of Gansu Province especially foundation (ZGS-033-A-43-013).
R 347
348
REFERENCES 349
H3CO
OCH3
[1] [2] [3] [4]
350
O
[5] [6]
351 n
Ayres, D.C., Loike. J. D. (1990) Lignans, Chemical, Biological and Clinical Properties, Cambridge University Press, Cambridge. Chap 3 and 4. Jardine, I. (1980) Podophyllotoxin in Anticancer Agents Based on Natural Products Models. Academic Press Inc. New York. pp. 319-351. King, J. (1857) Discovery of Podophyllin. Coll. J. M. Sci., 2, 557-559. Hartwell, J. L., Schrecker, A.W. (1958) Chemistry of Podophyllum. Fortshr. Chem. Org. Naturst., 15, 83-166. Kelly, M.G., Hartwell, J. L. (1954) The Biological effects and Chemical composition of Podophyllin. A review. J. Natl. Cancer Inst., 14, 967-1010. Stahelin, H., von Wartburg, A. (1989) From Podophyllotoxin gluocoside to Etoposide. Prog. Drug Res., 33, 169-267.
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O
Tian et al.
N
S
n
HN
O
O
H N
O
OCH3
H N
S
n
x OCH3
H O
O
OCH3
O
O
O
O
O O
OCH3
H3CO
SCH3
O
O
H N
O
CH2O
OCH3
H3 CO
345 n=6 346 n= 8
OH
354 355 356 357
OCH3
PEG
x=1 x=2 x=2 x=1
O
H N
OH2C
n=1 n=2 n=1 n=2
O
O
O
R
R
O
O O
O O
O
O
O
OCH3
H3CO
OCH3
H3 CO
358 R=H 359 R=CH3 360 R=CH2 SCH3 361 R= CH2 Ph 362 R= CH(CH3) 2
OCH3
OCH3
β-D-glucopyranos e is not essential 4β configuration is fundamental
5-oxygenation of B-ring may led to decrease biological activity R methylenedioxy cycle is important for optimal antitumoral activity. diaza heterocycles is important for cytotoxicity, but weak inhibition of topo II
11
O A O
trans lactone is crucial
B
4 C 3 1 2
D O O 2α configuration is very important
E OCH3
H3CO
free rotation of cycle E is essential
OH
3'and 5' E-ring hydroxy groups prepared for stabilization of topoII-DNA intermediates but low potency in vitro and in vivo
Fig. (6). Structure-activity relationship (SAR) of etoposide analogues.
4'-OH is crucial, prodrug at 4'-position is allowed, 4'-substitution is not tolerated
Podophyllotoxin [7] [8]
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Revised: September 08, 2006
Accepted: October 13, 2006
