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Podophyllotoxin: Current Perspectives

Profile image of Liu YangLiu Yang

2007, Current Bioactive Compounds

https://doi.org/10.2174/157340707780126499
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30 pages

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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.

FAQs

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What explains the decline in podophyllotoxin's use as an antitumour agent?add

The initial clinical interest was tempered due to unacceptable gastrointestinal toxicity, leading to its decline as an antitumour agent.

How did structural modifications of podophyllotoxin lead to drug development?add

Extensive modifications resulted in the synthesis of etoposide and teniposide, with etoposide showing notable anticancer activity since its introduction.

What biological activities are associated with podophyllotoxin analogues?add

Podophyllotoxin analogues exhibit diverse activities, including antiviral properties, immunomodulatory effects, and antitumour activities against various cancers.

When did the clinical use of podophyllin for venereal warts begin?add

Podophyllin was first introduced for treating condyloma acuminatum in 1942, demonstrating effective results in clinical applications.

How do modifications at the C-4 position of podophyllotoxin affect its activity?add

Modifications at the C-4 position are crucial for biological activity, as they significantly influence interactions with topoisomerases.

Figures (39)
Fig. (1). Chinese medicinal herb Podophyllum -emodi Wall var Chinensis Sprague. Keywords: Reviews, podophyllotoxin, short chronology, biological activity, medicinal application, mechanism of actions, chemicé modification, structure-activity relationships.
Fig. (1). Chinese medicinal herb Podophyllum -emodi Wall var Chinensis Sprague. Keywords: Reviews, podophyllotoxin, short chronology, biological activity, medicinal application, mechanism of actions, chemicé modification, structure-activity relationships.
Extracts of plant containing podophyllotoxin have been widely used in traditional herbal medicine of many diverse cultures from remote times to modem times as remedies for purgative, snake More recently, 2",3"-bis pentafluorophenoxyacetyl-4',6'-ethy- lidene-B-D-glucoside of 4'-phosphate -4'-demethyle-pipodophyl- lotoxin (Tafluposide, a novel catalytic inhibitor of topoisomerase | 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.
Extracts of plant containing podophyllotoxin have been widely used in traditional herbal medicine of many diverse cultures from remote times to modem times as remedies for purgative, snake More recently, 2",3"-bis pentafluorophenoxyacetyl-4',6'-ethy- lidene-B-D-glucoside of 4'-phosphate -4'-demethyle-pipodophyl- lotoxin (Tafluposide, a novel catalytic inhibitor of topoisomerase | 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.
Fig. (3). Composite pharmacophore model for expression of topoisomerase II activity. 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-4&-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].
Fig. (3). Composite pharmacophore model for expression of topoisomerase II activity. 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-4&-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].
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
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
author designed the condensed aromatic A-ring pyridazine analo- gues 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 t-stacking interactions in aqueous medium (2) a potential quaternarised aromatic nitrogen needed for an intercalation-based pathway and for water-solubility [107].
author designed the condensed aromatic A-ring pyridazine analo- gues 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 t-stacking interactions in aqueous medium (2) a potential quaternarised aromatic nitrogen needed for an intercalation-based pathway and for water-solubility [107].
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
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
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].
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].
active than etoposide in their DNA topoisomerase II inhibitory activity. Compounds 68 and 69 were much less active than etoposide, which indicated the requirement of a glycosidic ethylidene and thenylidene cyclic acetal moiety to be placed at C- 4B-position instead of an aromatic C-5 position as seen in the a- peltatin skeleton [113-114]. Nishimura et al. synthesised glycosidic substituents of 1-B-hydroxy-a-peltatin and1-B-hydroxy-5-methyl- a-peltatin (71-73) and these compounds showed weak antitumour activity in leukaemia L1210, compound 72 was found to have the superior antitumour activity to compound 71. T results indicated that 5-oxygenation of the podophy. may lead to decrease biological activity [115]. he two sets of lotoxin nucleus
active than etoposide in their DNA topoisomerase II inhibitory activity. Compounds 68 and 69 were much less active than etoposide, which indicated the requirement of a glycosidic ethylidene and thenylidene cyclic acetal moiety to be placed at C- 4B-position instead of an aromatic C-5 position as seen in the a- peltatin skeleton [113-114]. Nishimura et al. synthesised glycosidic substituents of 1-B-hydroxy-a-peltatin and1-B-hydroxy-5-methyl- a-peltatin (71-73) and these compounds showed weak antitumour activity in leukaemia L1210, compound 72 was found to have the superior antitumour activity to compound 71. T results indicated that 5-oxygenation of the podophy. may lead to decrease biological activity [115]. he two sets of lotoxin nucleus
Justicidin A and diphyllin isolated from justicia procum are two ring- C aromatised lignan: bens, which were found to show significant inhibitory activity in vivo against P-388 lymphocyti leukaemia (T/C=150% at 50: mg/kg/day), as well as in vitrc cytotoxicity in KB cell (EDs9<1.0yg/ml each) culture assay. Kuo: Hsiung Lee et al. have synthesised several C-ring aromatisec podophyllotoxin analogues (75- and tested their ability in inhib as well as cytotoxic activity. pounds were shown to have any inhibitory activity against DNA topoisomerase II, which indicated that non-aromatised ring C i: structurally required for the potent inhibitory activity against the target enzyme and the loss of activity may be due to the loss of the axial E-ring configuration [ apopicropodophyllotoxin (79), lactone system product of podophyllotoxin, showed as poten cytotoxic activity as podophyllotoxin against P-815 cells, its B 78) according to Gensler's method iting human DNA topoisomerase I one of the ring C aromatised com. 120]. However, interestingly, B a dehydration containing cis-fusec isomer, B-apopicropodophyllotoxin (80), especially showed many folds stronger antimitotic activity than podophyllotoxin. The posi tive antimitotic activities of del that lactone ring was not need actonised products from 1 indicatec ed for antimitotic activity in podo: phyllotoxin-type compounds [121-123].
Justicidin A and diphyllin isolated from justicia procum are two ring- C aromatised lignan: bens, which were found to show significant inhibitory activity in vivo against P-388 lymphocyti leukaemia (T/C=150% at 50: mg/kg/day), as well as in vitrc cytotoxicity in KB cell (EDs9<1.0yg/ml each) culture assay. Kuo: Hsiung Lee et al. have synthesised several C-ring aromatisec podophyllotoxin analogues (75- and tested their ability in inhib as well as cytotoxic activity. pounds were shown to have any inhibitory activity against DNA topoisomerase II, which indicated that non-aromatised ring C i: structurally required for the potent inhibitory activity against the target enzyme and the loss of activity may be due to the loss of the axial E-ring configuration [ apopicropodophyllotoxin (79), lactone system product of podophyllotoxin, showed as poten cytotoxic activity as podophyllotoxin against P-815 cells, its B 78) according to Gensler's method iting human DNA topoisomerase I one of the ring C aromatised com. 120]. However, interestingly, B a dehydration containing cis-fusec isomer, B-apopicropodophyllotoxin (80), especially showed many folds stronger antimitotic activity than podophyllotoxin. The posi tive antimitotic activities of del that lactone ring was not need actonised products from 1 indicatec ed for antimitotic activity in podo: phyllotoxin-type compounds [121-123].
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].
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].
Extensive structure-activity relationship study unambiguously noted that C-4 position was the only molecular area tolerable to significant structural diversification and resulted in a number of promisng candidates, which suggested an important role of various C-4 substitutes to the activity profiles of etoposide-related analo- gues and the feasibility of optimising podophyllotoxin class through rational C-4 modification. On the basis of this assumption, most of research efforts have been focussed on exploring different 4- substituted podophyllotoxin analogues. This section of work has been comprehensively reviewed [124-129].
Extensive structure-activity relationship study unambiguously noted that C-4 position was the only molecular area tolerable to significant structural diversification and resulted in a number of promisng candidates, which suggested an important role of various C-4 substitutes to the activity profiles of etoposide-related analo- gues and the feasibility of optimising podophyllotoxin class through rational C-4 modification. On the basis of this assumption, most of research efforts have been focussed on exploring different 4- substituted podophyllotoxin analogues. This section of work has been comprehensively reviewed [124-129].
Fig. (4). Inactive metabolites of etoposide.
Fig. (4). Inactive metabolites of etoposide.
podophyllotoxin analogues showing significant antitumour activity, 4B-(4"-aryl-amino)- 4'-O-demethyl-podophyllotoxin cyclic acetal, y¥cyclic ether, and ylactol derivatives (105-108) were prepared with aim of blocking epimerisation or the problem of metabolic inactivation and all these compounds had higher IDs9 values compared with etoposide in the KB-ATCC cell toxicity assay. Within this series of compounds, ¥-cyclic etoposide analogues were the most active, however, they were less active than their corres- ponding lactone congener. Therefore, while the lactone moiety is not an absolute requirement for antitumour activity, its alteration reduced the activity of the parent drug [135].
podophyllotoxin analogues showing significant antitumour activity, 4B-(4"-aryl-amino)- 4'-O-demethyl-podophyllotoxin cyclic acetal, y¥cyclic ether, and ylactol derivatives (105-108) were prepared with aim of blocking epimerisation or the problem of metabolic inactivation and all these compounds had higher IDs9 values compared with etoposide in the KB-ATCC cell toxicity assay. Within this series of compounds, ¥-cyclic etoposide analogues were the most active, however, they were less active than their corres- ponding lactone congener. Therefore, while the lactone moiety is not an absolute requirement for antitumour activity, its alteration reduced the activity of the parent drug [135].
hydrolytic cleavage. Several derivatives of the 2-aza compounds were prepared and biological results showed that these 2-aza- derivatives of podophyllotoxin still retain antitumour activity [136- 145].
hydrolytic cleavage. Several derivatives of the 2-aza compounds were prepared and biological results showed that these 2-aza- derivatives of podophyllotoxin still retain antitumour activity [136- 145].
with the retrolactone modification to study the influence of these compounds on the activity[148]. The number of podophyllotoxin analogues having D-ring lactone opened was limited presumably because the transfused-y- lactone was considered to be one of the essential features for podophyllotoxin-type compounds to retain their anticancer activity. However, ethyl hydrazide derivative of podophyllic acid 124 (SP-1) was found to possesss anti-mitotic activity and its clinical efficacy was examined for some time and discontinued later due to severe side effects and the importance of these compounds had once again
with the retrolactone modification to study the influence of these compounds on the activity[148]. The number of podophyllotoxin analogues having D-ring lactone opened was limited presumably because the transfused-y- lactone was considered to be one of the essential features for podophyllotoxin-type compounds to retain their anticancer activity. However, ethyl hydrazide derivative of podophyllic acid 124 (SP-1) was found to possesss anti-mitotic activity and its clinical efficacy was examined for some time and discontinued later due to severe side effects and the importance of these compounds had once again
Contd... In addition, Ma wei-yong et al. reported 3a-bromo- epipicropodophyllotoxin derivatives (155-157) and their inhibition activities against KB cells and L1210 leukaemia cells in vitro were higher than those of etoposide [159].
Contd... In addition, Ma wei-yong et al. reported 3a-bromo- epipicropodophyllotoxin derivatives (155-157) and their inhibition activities against KB cells and L1210 leukaemia cells in vitro were higher than those of etoposide [159].
Fig. (5). Proposed activation of etoposide (VP-16) to free radical state, and its implication in metabolism, and mechanism of action 0 etoposide in tumour cell kill.
Fig. (5). Proposed activation of etoposide (VP-16) to free radical state, and its implication in metabolism, and mechanism of action 0 etoposide in tumour cell kill.
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]. Contd... .
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]. Contd... .
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 [211- 212]. 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 I] interaction moiety of the epipodophyllotoxin (345- 346) 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].
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 [211- 212]. 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 I] interaction moiety of the epipodophyllotoxin (345- 346) 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].

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References (216)

  1. Ayres, D.C., Loike. J. D. (1990) Lignans, Chemical, Biological and Clinical Properties, Cambridge University Press, Cambridge. Chap 3 and 4.
  2. Jardine, I. (1980) Podophyllotoxin in Anticancer Agents Based on Natural Products Models. Academic Press Inc. New York. pp. 319-351.
  3. King, J. (1857) Discovery of Podophyllin. Coll. J. M. Sci., 2, 557-559.
  4. Hartwell, J. L., Schrecker, A.W. (1958) Chemistry of Podophyllum. Fortshr. Chem. Org. Naturst., 15, 83-166.
  5. Kelly, M.G., Hartwell, J. L. (1954) The Biological effects and Chemical composition of Podophyllin. A review. J. Natl. Cancer Inst., 14, 967-1010.
  6. Stahelin, H., von Wartburg, A. (1989) From Podophyllotoxin gluocoside to Etoposide. Prog. Drug Res., 33, 169-267.
  7. Hartwell, J. L., Schrecker, A. W. (1951) Components of podophyllin.V. The constitution of podophyllotoxin. J. Am. Chem. Soc., 73, 2909-2916.
  8. Canetta, R., Hilgard, P., Florentine, S., Bedogni, P., Lenaz, L. (1982) Current Development of Podophyllotoxins. Cancer Chemother. Pharmacol., 7, 93- 98.
  9. Imbert, T. F. (1998) Discovery of Podophyllotoxins. Biochimie, 80, 207-222.
  10. Liu, C. J., Hou, S. S. (1997) Current Research Status of Podophyllotoxin Lignans. Nat. Prod. Res. Develop., 9, 81-89.
  11. Chen, Y. H. (1979) A Study of the Resources of Chinese Podophyllin Plants. Acta Pharm. Sin., 14, 101-107.
  12. Yang, X. Z., Shao, H., Zhang, L.Q., Zhou, C., Xuan, Q., Yang, C. Y. (2001) Present Situation of Studies on Resources of Podophyllotoxin. Chin. Traditional Herbal Drugs, 32, 1042-1044.
  13. Liu, H. J., Xu, Y., Su, G. Q., Li, C.Y., Wang, L., Liu, Y. J. (2004) Research Progress in SinopPdophyllum emodi. Chin. Traditional Herbal Drugs, 35, 98-100.
  14. Macrae Donald, W., Neil Towers, G. H. (1984) Biological Activity of Lignans. Phytochemistry, 23, 1207-1220.
  15. Gordaliza, M., García, P. A., Miguel del Corral, J. M., Castro, M. A., Gómez-Zurita, M. A. (2004) Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives. Toxicon, 44, 441-459.
  16. Bohlin, L., Rosen, B. (1996) Podophyllotoxin derivatives: drug discovery and development. Drug Discov. Today, 1, 343-351.
  17. Kaplan, I. W. (1942) Codylomata acuminata. New Orleans Med. Surg. J., 94, 388.
  18. Hande, K. R. (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur. J. Cancer, 34, 1514-1521.
  19. Species Plantrum, p.505. Stockholm: salvius.1753.
  20. Podwyssotzki, V. (1881) The active constituent of podophyllin. Pharm. J. Trans., 12, 217-218.
  21. Podwyssotzki, V. (1882) On the active constituents of podophyllin. Am. J. Pharm., 12, 102-115.
  22. Podwyssotzki, V. (1884) Pharmakologische Studien uber podophyllum peltatum. Naunyn. Schmied Arch Exp. Path. Phar., 13, 29-52.
  23. Borsche, W., Niemann, J. (1932) Uder podophyllin. Liebigs Ann. Chem., 494, 126.
  24. Gensler, W. J., Samour, C.M., Wang, S.Y., (1954) Sythesis of DL- stereoisomer of Podophyllic acid. J. Am. Chem. Soc., 76, 315.
  25. Gensler, W. J., Wang, S.Y. (1954) Sythesis of Picropodophyl-lotoxin. J. Am. Chem. Soc., 76, 5890.
  26. Petcher, T. J., Weber, H. P., Kuhn, M., von Wartburg, A. J. (1973) Crystal Structure and Absolute Configuration of 2'-Bromopodo-phyllotoxin-0.5 Ehtyl Acetate. J. C. S. Perkin. II, 288-292.
  27. King, J. L., Sullivan, M. (1946) The similarity of the effects of podophyllin and colchicines and their use in the treatment of Codylomata acuminata. Science, 104, 244-245.
  28. Sullivan, B. J., Weshler, H. J. (1947) The cytological effects of podophyllin. Science, 105, 433.
  29. Stoll, A., Renz, J., Wartburg, A. V. (1954) The isolation of podophyllotoxin gluooside. J. Am. Chem. Soc., 76, 3103-3104.
  30. Stoll, A., von Wartburg, A., Angliker, E., Renz, J. (1954) The isolation of 4'- Demethylpodophyllotoxin gluooside from rhizomes podophyllum emodi wall. J. Am. Chem. Soc., 76, 5004-5005.
  31. Emmenggger, H., Stahelin, H., Rutschmann, J., von Wartburg, A. (1961) Chemistry and Pharmacology of podophyllum glucosides and derivatives. I. Arzneimittel Forsch. 11, 327-333.
  32. Kuhn, M., von Wartburg, A. (1968) Mitosis-inhibiting substances. XXI. Synthesis of epipodophyllotoxin β-D-glucopyranoside. Helv. Chim. Acta, 51, 1631-1641.
  33. Kuhn, M., von Wartburg, A. (1969) Mitosis-inhibiting substances. glycosidation process.II. glycosides of 4'-demethylepipodo-phyllotoxin. Helv. Chim. Acta, 52, 948-955.
  34. Keller-Juslen, C., Kuhn, M., Von Wartburg, A., Staehelin, H. (1971) Mitosis-inhibiting natural products. 24. Synthesis and antimitotic activity of glycosidic lignan derivatives related to podophyllotoxin. J. Med. Chem. , 14, 936-940.
  35. Joel, S. (1996) The clinical pharmacology of etoposide. An update. Cancer Treat. Rev., 22, 179-221.
  36. Stahelin, H.F., von Wartburg, A. (1991) The Chemical and Biological Route from Podophyllotoxin Glucoside to Etoposide: Ninth Cain Memorial Award Lecture. Cancer Res., 51, 5-15.
  37. Ross, W., Rowe, T., Glisson, B., Yalowich, J., Liu, L. (1984) Role of topoisomerase II in mediating epipodophyllotoxin-induced DNA cleavage. Cancer Res., 44, 5857-5860.
  38. Long, B. H., Brattain, M.G. (1984) The Activity of Etoposide andTeniposide against Human Lung Tumour in vitro : cytotoxicity and DNA breakage. In: Etoposide: Current Status and New Developments. Issell BF. Muggia FM.Carter SA, eds. Academic Press, New York. pp. 223.
  39. Long, B. H., Minocha, A. (1983) Inhibition of topoisomerase II by VP-16 (etoposide), VM-26 (teniposide) and structure congeners as explanation for in vivo DNA breakage and cytotoxicitry. Proc. Am. Ass. Cancer Res., 24, 1271.
  40. Long, B. H., Musial, S. T., Brattain, M.G. (1984) Comparison of cytotoxicity and DNA breakage activity of congeners of podophyllotoxin including VP16-213 and VM26: a quantitative structure-activity relationship. Biochemistry, 23, 1183-1188.
  41. Zhu, X. K., Guan, J., Tachibana, Y., Bastow, K. F., Cho, S. J., Cheng, H. H., Cheng, Y. C., Gurwith, M., Lee, K. H. (1999) Antitumour Agents. 194. Synthesis and Biological Evaluations of 4-β-Mono-, -Di-, and -Trisubstituted Aniline-4'-O-demethyl-podo-phyllotoxin and Related Compounds with Improved Pharma-cological Profiles. J. Med. Chem., 42, 2441-2446.
  42. Xiao, Z., Bastow, K. F., Vance, J. R., Sidwell, R. S., Wang, H.-K., Chen, M. S., Shi, Q., Lee, K. H. (2004) Antitumour Agents. 234. Design, Synthesis, and Biological Evaluation of Novel 4β-[(4' '-Benzamido)-Amino]-4'-O- Demethyl-Epipodophyllotoxin Derivatives. J. Med. Chem., 47, 5140-5148.
  43. Schacter, L. P., Igwemezie, L. N., Seyedsadr, M. (1994) Clinical and pharmacokinetic over view of parental etoposide phosphate. Cancer Chemother. Pharmacol., 34 (Suppl), s58-s63.
  44. Budman, D.R. (1996) Early studies of etoposide phosphate, a water prodrug. Semin. Oncol., 23(suppl), 8-14.
  45. Greco, F. A., Hainsworth, J. D. (1996) Clinical Studies of Etoposide phosphate. Semin. Oncol., 23 (suppl), 45-50.
  46. Saito, H., Yoshikawa, H., Nishimura, Y., Kondo, S., Takeuchi, T., Umezawa, H. (1986) Studies on Lignan Lactone Antitumour Agents.II. Synthesis of N- Alkylamino-and 2,6-Dideoxy-2-Aminoglycosidic Lignan Variants Related to Podophyllotoxin. Chem. Pharm. Bull., 34, 3741-3746.
  47. Pagani, O., Zucchetti, M., Sessa, C., De Jong, J., D' Incalci, M., De Fusco, M., Kaeser-Froehlich, A., Hanauske, A., Cavalla, F. (1996) Clinical and Pharmacokinetic Study of Oral NK611, a New Podophyllotoxin Derivatives. Cancer Chemother. Pharmacol., 38, 541-547.
  48. Lee, K. H. (1999) Novel Antitumour Agents from Higher Plants. Med. Res. Rev., 19, 569-596.
  49. Lee, K. H., Beers, S. A., Mori, M., Wang, Z. Q., Kuo, Y. H., Li, L., Liu, S. Y., Chang, J. Y., Han, F. S., Cheng, Y. C. (1990) Antitumour agents. 111. New 4-hydroxylated and 4-halogenated anilino derivatives of 4'- demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomerase II. J. Med. Chem., 33, 1364-1368.
  50. Wang, Z. Q., Kuo, Y. H., Schnur, D., Bowen, J. P., Liu, S. Y., Han, F. S., Chang, J. Y., Cheng, Y. C., Lee, K. H. (1990) Antitumour agents. 113. New 4.beta.-arylamino derivatives of 4'-O-demethylepipodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II. J. Med. Chem., 33, 2660-2666.
  51. Leteurtre, F., Madalengoitia, J., Orr, A., Cuzi, T. J., Lehnert, E., Macdonald, T., Prommier, Y. (1992) Rational Design and Molecular Effects of a new Topoisomerase II inhibitor, azatoxin. Cancer Res., 52, 4478-4483.
  52. Tomioka, K., Kubuta, Y., Koga, K. (1989) Synthesis and Antitumour Activity of Podopyllotoxin aza-analogues. Tetradron Lett., 30, 2953-2954.
  53. Solary, E., Leteurture, F., Paull, K. D., Scudiero, D., Hamel, E., Prommier, Y. (1993) Dual Inhibition of Topoisomerase II and Tubulin Polymerization by azatoxin, a novel cytotoxic agent. Biochem. Pharmacol., 45, 2449-2456.
  54. Terada, T., Fujimoto, K., Nomura, M., Yamashita, J., Wierzba, K., Yamazaki, R., Shibata, J., Sugimoto, Y., Yamada, Y. (1993) Antitumour agents. 3. Synthesis and biological activity of 4.beta.-alkyl derivatives containing hydroxy, amino, and amido groups of 4'-O-demethyl-4- desoxypodophyllotoxin as antitumour agents. J. Med. Chem., 36, 1689-1699.
  55. Kobunai, T., Saito, H., Yoshida, M., Toko, T., Takeda, S., Unemi, N. (1994) in vitro and in vivo Antitumour Activity against lung cancer of TOP53, a novel podophyllotoxin derivative. Proc. Am. Assoc. Cancer Res., 35, Abst 2154.
  56. Kobunai, T., Saito, H., Yoshida, M., Utsugi, T., Takeda, S., Yamada, Y. (1996) Antitumour Activity of TOP53, a novel podophyllotoxin derivative. Proc. Am. Assoc. Cancer Res., 37, Abst 22914.
  57. Cragg, G. M., Newman, D. J. (2004) A Tale of Two Tumour Targets: Topoisomerase I and Tubulin. The Wall and Wani Contribution to Cancer Chemotherapy. J. Nat. Prod., 67, 232-244.
  58. Maria, D. P., Manel, R. and Isabel, S. (2005) Synthesis and Biological Activity of New Class of Dioxygenated Anticancer Agents. Anti-Cancer Agents Med. Chem., 5, 215-237.
  59. Gordaliza, M., Castro, M.A., Miguel del Corral, J.M., Feliciano A. S. (2000) Antitumour Properties of Podophyllotoxin and Related Compounds. Curr. Pharm. Des., 6, 1811-1839.
  60. Bedows, E., Hatfield, G. M. (1982) An Investigation of the Antiviral Activity of Podophyllum peltatum. J. Nat. Prod., 45, 725-729.
  61. Gordaliza, M., Castro, M.A., Garcia-Gracalos, M.D., Ruiz, P., Miguel del Corral, J.M., Feliciano A. S. (1994) Antineoplastic and antiviral activities of podophyllotoxin. Arch. Pharm (Weinheim)., 327, 175-179.
  62. Hammonds, T. R., Denyer, S. P., Jackson, D. E., Irving, W. L. (1996) Studies to show that with podophyllotoxin the early replicative stages of herpes simplex virus type I depend upon functional cytoplasmic microtubules. J. Med. Microbiol., 45, 167-172.
  63. Broomhead, A. J., Dewick, P. M. (1990) Aryletralin Lignans from Linum Flavum and Linum Capitatum. Phytochemistry, 29, 3839-3844.
  64. Canel, C., Moraes, R. M., Dayan, F. E., Ferreira, D. (2000) Podophyllotoxin. Phytochemistry, 54, 115-120.
  65. Charlton, J. L. (1998) Antiviral Activity of Lignans. J. Nat. Prod., 61, 1447- 1451. Tian et al.
  66. Gordaliza, M., Miguel del Corral, J. M., Castro, M. A., García-García, P. A., San Feliciano, A. (2001) Cytotoxic cyclolignans related to podophyllotoxin. IL FARMACO, 56, 297-304.
  67. Markos, A. R. (2001) The Successful Treatment of molluscum contagiosum with Podophyllotoxin(0.5%) self-application. Int. J. STD. AIDS, 12, 833.
  68. Leander, K., Rosen, B. (1988) Medicinal used for podophyllotoxin. US patent, 4,788,216.
  69. Schwartz, J., Norton, S. A. (2002) Useful plants of dermatology.VI. The mayapple (podophyllum). J. Am. Acad. Dermatol., 47, 774-775.
  70. You, Y. J. (2005) Podophyllotoxin Derivatives: Current Synthetic Approaches for New Anticancer Agents. Curr. Pharm. Des., 11, 1695-1717.
  71. Mukherjee, A. K., Basu, S., Sarkar, N., Ghosh, A. C. (2001) Advances in Cancer Therapy with Plant Based Natural Products. Curr. Med. Chem., 8, 1467-1486.
  72. Pugh, N. I., Khan, I., Moraes, R. M., Pasco, D. (2001) Podophyllotoxin lignans enhance IL-1E but suppress TNF-a mRNA expression in LPS-treated monocytes. Immunopharmacol. Immunotoxicol., 23, 83-95.
  73. Botta, B., Monache, G. D., Misiti, D., Vitali, A., Zappia, G. (2001) Aryltetralin Lignans: Chemistry, Pharmacology and Biotrans-formations. Curr. Med. Chem., 8, 1363-1381.
  74. Hermanns, L.T., Arrese, J. E., Goffin, V., Pierard, G. E. (1998) Podophyllotoxin-induced acantholysis and cytolysis in a skin equivalent model. Eur. J. Morphol., 36, 183-187.
  75. Inamori, Y., Kato, Y., Kubo, M., Waku, Y., Hayashiya, K., Sakai, M. (1984) Mechanisms of insecticidal action of deoxypodophyl-lotoxin (Anthricin). II. Histopathological studies on tissues of silkworm larvae intoxicated by deoxypodophyllotoxin. Chem. Pharm. Bull., 32, 2015-2019.
  76. Kozawa, M., Baba, K., Matsuyama, Y., Kido, T. (1982) Components of the root of Anthriscus sylvestris Hoffm II. Insecticidal activity. Chem. Pharm. Bull., 30, 2885-2888.
  77. Inamori, Y., Kubo, M., Tsujibo, H.,Ogawa, M., Baba, K., Kozawa, M., Fujita, E. (1986) The biological activities of podophyllotoxin compounds. Chem. Pharm. Bull., 34, 3928-3932.
  78. Inamori, Y., Kubo, M., Tsujibo, H., Oki, S., Kodama, Y. (1986) Mechanisms of insecticidal action of deoxypodophyllotoxin (Anthricin). III. The mode of delayed insecticidal action of deoxypodophyllotoxin. Chem. Pharm. Bull., 34, 2247-2250.
  79. Gao, R., Tian, X., Zhang, X. (2000) A study on the relationship between structure and insecticidal activity of podophyllotoxin analogues I. The synthesis of podophyllotoxin analogues and their insecticidal activities. Acta Universitatis agriculturalis Boreali-occidentalis, 28, 8-13.
  80. Gao, R., Tian, X., Zhang, X. (2001) Study on insecticidal activities of three podophyllotoxin analogues. Acta Univeristaties Agriculturalis Boreali- occidentalis, 29, 71-74.
  81. Xu, H., Zhang, X., Tian, X., Lu, M., Wang, Y.G. (2002) Synthesis and insecticidal activity of novel 4 β-halogenated benzoylaminopo- dophyllotoxins against Pieris rapae Linnaeus. Chem. Pharm. Bull., 50,399- 402.
  82. Gao, R., Gao, C. F., Tian, X., Yu, X. Y., Di, X. D., Xiao, H., Zhang, X. (2004) Insecticidal activity of deoxypodophyllotoxin, isolated from Juniperus sabina L, and related lignans against larvae of Pieris rapae L. Pest Manag. Sci., 60, 1131-1136.
  83. Tian, X., Gao, R., Zhang, X. (2000) Study on the relationship between structure and insecticidal activity of podophyllotoxin analogues II. Analysis of structure-activity relationship and prediction of optimal structure. Acta Universitatis Agriculturalis Boreali-occidentalis., 28, 19-24.
  84. Gao, R., Tian, X., Zhang, X. (2002) A brief review on podophyllotoxin analogues. Chin. J. Pest. Sci., 2, 1-6.
  85. Xu, D. M., Xu, X. Y., Liu, Y. Q., Feng, J. T., Pan, L. G., Liu, X. J., He, J., Zhang, X. (2005) Development of an enzyme-linked immunosorbent assay for podophyllotoxin. Int. Immunopharmacol., 5, 1583-1592.
  86. Wang, M. H., Yang, C. L., Jiang, M. G. (2002) the recent progress in pesticides. World Pest., 24, 13-15.
  87. Oliva, A., Moraes, R. M., Watson, S. B., Duke, S. O., Dayan, F. E. (2002) Aryltetralin Lignans Inhibit Plant Growth by Affecting the Formation of Mitotic Microtubular Organizing Centers. Pest. Biochem. Phys. 72, 45-54.
  88. Garcia, E. S., Azambuja, P. (2004) Lignoids in insects: chemical probes for the study of ecdysis, excretion and Trypanosoma cruzi-triatomine interactions. Toxicon, 44, 431-440.
  89. Wilson, L., Friedkin, M. (1967) the Biochemical Events of Mitosis. II. The in vivo and in vitro Binding of Colchicine in Grasshopper Embryos and Its Possible Relation to Inhibition of Mitosis. Biochemistry, 6, 3126-3135.
  90. Cortese, F., Bhattacharyya, B., Wolf, B. (1977) Podophyllotoxin as a probe for the colchicines binding site of tubulin. J. Biol. Chem., 252, 1134-1140.
  91. ter Haar, E., Rosenkranz, H. S., Hamel, E., Day, B. W. (1996) Computational and molecular modeling evaluation of the structural basis for tubulin polymerization inhibition by colchicine site agents. Bioorg. Med. Chem., 4, 1659-1671.
  92. Desbène, S., Giorgi-Renault, S. (2001) Drugs that Inhibit Tubulin Polymerization: The Particular Case of Podophyllotoxin and Analogues. Curr. Med. Chem. Anti-Cancer Agents, 1, 71-90.
  93. Islam, M. N., Iskander, M. N. (2004) Microtubulin Binding Sites as Target for Developing Anticancer Agents. Mini-Rev. Med. Chem., 4, 1077-1104.
  94. Osheroff, N. (1998) DNA topoisomerases. Biochim. Biophys. Acta, 1400, 1- 2.
  95. Champoux, J. J. (2001) DNA topoisomerases: structure, function, and mechanism. Annu. Rev. Biochem., 70, 369-413.
  96. Burden, D.A., Osheroff, N. (1998) Mechanism of action of eukaryotic topoisomerase II and drug targeted to the enzyme. Biochim. Biophys. Acta, 1400, 139-154.
  97. Berger, J. M., Gambin, S. J., Harrison S. C., Wang, J.C. (1996) Structure and Mechanism of DNA Topoisomerase II. Nature, 379, 225-232.
  98. Pommier,Y. (1997) DNA topoisomerase II inhibitors. In: Cancer Therapeutic: Experimental and Clinical Agents. Teacher BA, Eds, Human Press, Taotowa, New Jersey. pp. 153-174.
  99. Haim, N., Nemec, J., Roman, J., Sinha, B. K. (1986) Peroxidative free radical formation and O-demethylation of etoposide and teniposide. Biochem. Biophys. Res. Commun., 135, 215-220.
  100. Haim, N., Nemec, J., Roman, J., Sinha, B. K. (1987) peroxidase-catalyzed metabolism of etoposide and covalent binding of reactive intermediates to cellular macromolecules. Cancer Res., 47, 5835-5840.
  101. Sinha, B. K. (1989) Free radicals in anticancer drug pharmacology. Chem. Biol. Interact., 69, 293-317.
  102. Schreier, E. (1964) Partialsynthese der 6, 7-Dimethoxy-Analogen von Podophyllotoxin, Epi-, Neo-, und Desoxy-podophyllotoxin. Helv. Chim. Acta, 47, 1529-1554.
  103. Wang, Z. Q., Hu, H., Chen, H. X., Cheng, Y. C., Lee, K. H. (1992) Antitumour agents. 124. New 4.beta.-substituted aniline derivatives of 6,7- O,O-demethylene-4'-O-demethylpodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II. J. Med. Chem., 35, 871- 877.
  104. Cho, S. J., Tropsha, A., Suffness, M., Cheng, Y.C., Lee, K. H. (1996) Antitumour Agents. 163. Three-Dimensional Quantitative Structure-Activity Relationship Study of 4'-O-Demethyl-epipodophyllotoxin Analogs Using the Modified CoMFA/q 2 -GRS Approach. J. Med. Chem., 39, 1383-1395.
  105. Cho, S. J., Kashiwada, Y., Bastow, K. F., Cheng, Y.C., Lee, K. H. (1996) Antitumour Agents. 164. Podophenazine, 2'',3''-Dichloropo-dophenazine, Benzopodophenazine, and Their 4β-p-Nitroaniline Derivatives as Novel DNA Topoisomerase II Inhibitors. J. Med. Chem., 39, 1396-1402.
  106. Bertounesque, E., Imbert, T., Monneret, C. (1996) Synthesis of podophyllotoxin A-ring pyridazine analogue. Tetrahedron, 52, 14235-14246.
  107. Meresse, P., Bertounesque, E., Imbert, T., Monneret, C. (1999)Synthetic approaches to condensed aromatic analogues from etoposide. Synthesis of A- ring pyridazine picroetoposide. Tetrahedron, 55, 12805-12818.
  108. Lee, C. T. L., Lin, V. C. K., Zhang, S. X., Zhu, X. K., VanVliet, D., Hu, H., Beers, S. A., Wang, Z. Q., Cosentino, L. M., Morris-Natschke, S. L., Lee, K. H. (1997) Anti-AIDS agents. 29. Anti-HIV activity of modified podophyllotoxin derivatives. Bioorg. Med. Chem. Lett., 7, 2897-2902.
  109. Castro, A., Miguel del Corral, J. M., Gordaliza, M., Grande, C., Gómez- Zurita, A., García-Grávalos, D., San Feliciano, A. (2003) Synthesis and cytotoxicity of podophyllotoxin analogues modified in the A ring. Eur. J. Med. Chem., 38, 65-74.
  110. Hartwell, J. L. (1947) α-Peltatin, a New compound Isolated from podophyllum peltatum. J. Am. Chem. Soc., 69, 2918-2918.
  111. Stoll, A., von Wartburg, A., Renz, J. (1955) The isolation of α-peltatin glucoside from the rhizomes of Podophyllum peltatum L. J. Am. Chem. Soc., 77, 1710-1711.
  112. Bedows, E., Hatfield, G. M. (1982) An Investigation of the Antiviral Activity of Podophyllum peltatum. J. Nat. Prod., 45, 725-729.
  113. Thurston, L.S., Irie, H., Tani, S., Han, F. S., Liu, Z. C., Cheng, Y. C., Lee, K. H. (1986) Antitumour agents. 78. Inhibition of human DNA topoisomerase II by podophyllotoxin and alpha-peltatin analogs. J. Med. Chem., 29, 1547- 1550.
  114. Thurston, L. S., Imakura, Y., Haruna, M., Li, D. H., Liu, Z. C., Liu, S. Y., Cheng, Y. C., Lee, K. H. (1989) Antitumour agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and .alpha.-peltatin. J. Med. Chem., 32, 604-608.
  115. Saito, H., Nishimura, Y., Kondo, S., Takeuchi, T., Umezawa, H. (1988) Studies on Lignan Lactone Antitumour Agents.IV. Synthesis of Glycosidic Lignan Variants Related to α-peltatin. Bull. Chem. Soc. Jpn., 61, 1259-1263.
  116. Schrecker, A. W., Hartwell, J. L. (1952) Components of Podophyllin. IX. The Structure of the Apopicropodophyllins. J. Am. Chem. Soc., 74, 5676- 5683.
  117. Gensler, W. J., Ahmed, Q. A., Muljiani, Z., Gatsonis, C. D. (1971) Ultraviolet irradiation of .alpha.-apopicropodophyllin. J. Am. Chem. Soc., 93, 2515-2522.
  118. Gensler, W. J., Johnson, F., Sloan, A. D. B. (1960) Compounds Related to Podophyllotoxin. XII. Podophyllotoxone, Picropo-dophyllone and Dehydropodophyllotoxin. J. Am. Chem. Soc., 82, 6074-6081.
  119. Kamal, A., Damayanthi, Y. (1997) A novel enzymatic dehydrogenation of podophyllotoxin congeners by yeast cells. Bioorg. Med. Chem. Lett., 7, 657- 662.
  120. Beers, S. A., Imakura, Y., Dai, H. J., Li, D. H., Cheng, Y. C., Lee, K. H. (1988) Antitumour Agents, 99. Synthetic Ring C Aromatized Podophyllotoxin Analogues as Potential Inhibitors of Human DNA Topoisomerase II. J. Nat. Prod., 51, 901-905.
  121. Canjanamurthy, K., Lokanatharai, M. (1985) Synthesis of Podophyllotoxin & related analogues: part II-Synthesis of ß-apopicrophyllin analogues with modified Hydroaromatic ring-B. Indian J. Chem., 24B, 505-508.
  122. Canjanamurthy, K., Lokanatharai, M. (1987) Synthesis of Podophyllotoxin & related analogues: part III-Synthesis of ß-apopicrophyllin analogues with modified lactone ring. Indian J. Chem., 26B, 131-135.
  123. He, Y., Ma, W.Y., Zhang, C. N. (2001) The effects of unsaturated factors on ring C to chemical Properties of podophyllotoxin analogues. J. Chin. Pharm. Sci., 10, 81-84.
  124. Damayanthi, Y., Lown, J. W. (1998) Podophyllotoxins: Current Status and Recent Developments. Curr. Med. Chem., 5, 205-252.
  125. Zhang, Y. L., Lee, K. H. (1994) Recent progress in the development of novel antitumour etoposide analogues. Chin. Pharm. J., 46, 319-369.
  126. Ma, W. Y., Zhang, C. N. (1997) Progress of antitumour drugs of podophyllotoxins. Chin. J. Pharm., 28, 65-69.
  127. Lee, K. H. (2004) Current Developments in the Discovery and Design of New Drug Candidates from Plant Natural Product Leads. J. Nat. Prod., 67, 273-283.
  128. Srivastava, V., Negi, A. S., Kumar, J.K., Gupta, M.M., Khanuja, S. P.S. (2005) Plant-based anticancer molecules: A chemical and biological profile of some important leads. Bioorg. Med. Chem., 13, 5892-5908.
  129. Walter, J., Gensler, C. D., Murthy, M. H. T. (1977) Nonenolizable podophyllotoxin derivatives. J. Med. Chem., 20, 635-644.
  130. Glinski, M.B., Freed, J. C., Durst, T. (1987) Preparation of 2-substituted podophyllotoxin derivatives. J. Org. Chem., 52, 2749-2753.
  131. VanVliet, D.S., Lee, K. H. (1999) A high yield preparation of 2- fluoropodophyllotoxin. Tetrahedron Lett., 40, 2259-2262.
  132. VanVliet, D. S., Tachibana, Y., Bastow, K. F., Huang, E. S., Lee, K.- H.(2001) Antitumour Agents. 207. Design, Synthesis, and Biological Testing of 4β-Anilino-2-fluoro-4'-demethylpodophyllo-toxin Analogues as Cytotoxic and Antiviral Agents. J. Med. Chem., 44, 1422-1428.
  133. Laatsch, H., Ernst, B. P., Noltemeyer, M. (1996) Synthesis of Sterically Fixed Podophyllotoxin. Liebigs Ann., 731-737.
  134. Zhou, X. M., Lee, K. J. H., Cheng, J., Wu, S. S., Chen, H. X., Guo, X., Cheng, Y. C., Lee, K. H. (1994) Antitumour agents. 144. New .gamma.- lactone ring-modified arylamino etoposide analogs as inhibitors of human DNA topoisomerase II. J. Med. Chem., 37, 287-292.
  135. Tomioka, K., Kubota, Y., Koga, K. (1989) Synthesis and antitumour activity of podophyllotoxin aza-analogues. Tetrahedron Lett., 30, 2953-2954.
  136. Van der Eycken, J., Bosmans, J. P., Van Haver, D., Vandewalle, M., Hulkenberg, A., Veerman, W., Nieuwenhuizen, R. (1989) The synthesis of 4- desoxy-2-azapodophyllotoxins. Tetrahedron Lett., 30, 3873-3876.
  137. Bosmans, J. P., Van der Eycken, J. Vandewalle, M., Hulkenberg, A., Van Hes, R. Veerman, W. (1989) The synthesis of 2-azapodophyllotoxins. Tetrahedron Lett., 30, 3877-3880.
  138. Tomioka, K., Kubota, Y., Koga, K. (1993) Design, synthesis, and antitumour activity-absolute configuration relationships of podophyllotoxin aza- analogues. Tetrahedron, 49, 1891-1900.
  139. Hitotsuyanagi, Y., Ichihara, Y., Takeya, K., Itokawa, H. (1994) Synthesis of 4-Oxa-2-azapodophyllotoxin, a novel analog of the antitumour lignan podophyllotoxin. Tetrahedron Lett., 35, 9401-9402.
  140. Hitotsuyanagi, Y., Yamagami, K., Fujii, A., Naka, Y., Ito, Y., Tahara, T. (1995) Syntheses and biological properties of novel aza-podophyllotoxin analogs prossessing pronounced antitumour activity. Bioorg. Med. Chem. Lett., 5, 1039-1042.
  141. Iida, A., Kano, M., Kubota, Y., Koga, K., Tomioka, K. (1997) Targeting DNA topoisomerase II with podophyllotoxin aza-analogue. Bioorg. Med. Chem. Lett., 7, 2565-2566.
  142. Hitotsuyanagi, Y., Kobayashi, M., Morita, H., Itokawa, H., Takeya, K. (1999) Synthesis of (-)-4-aza-4-deoxypodophyllotoxin from (-)- podophyllotoxin. Tetrahedron Lett., 40, 9107-9110 .
  143. Marcantoni, E., Petrini, M., Profeta, R. (2004) Synthesis of advanced intermediates for the preparation of aza-analogues of podophyllotoxin. Tetrahedron Lett., 45, 2133-2136.
  144. Kadow, J.F., Vyas, D.M., Doyle, D. M. (1989) Synthesis of etoposide Lactam via Mitsunobu reaction sequence. Tetrahedron Lett., 30, 3299-3302.
  145. Meresse, P., Monneret, C., Bertounesque, E. (2004) Synthesis of podophyllo- toxin analogues: δ-lactone-containing picropodophyllin, podophyllotoxin and 4´-demethyl-epipodophyllotoxin derivatives. Tetrahedron, 60, 2657-267.
  146. Meresse, P., Magiatis, P., Bertounesque, E., Monneret, C. (2003) Synthesis and antiproliferative activity of retroetoposide. Bioorg. Med. Chem. Lett., 13, 4107-4109.
  147. Duca, M., Guianvarc'h, D., Meresse, P., Bertounesque, E., Dauzonne, D., Kraus-Berthier, L., Thirot, S., Leonce, S., Pierre, A., Pfeiffer, B., Renard, P., Arimondo, P. B., Monneret, C. (2005) Synthesis and Biological Study of a New Series of 4'-Demethylepipodophyllotoxin Derivatives. J. Med. Chem., 48, 593-603.
  148. Gordaliza, M., Faircloth, G. T., Castro, M. A., Miguel del Corral, J. M., Lopez-Vazquez, M. L., San Feliciano, A. (1996) Immunosuppressive Cyclolignans. J. Med. Chem., 39, 2865-2868.
  149. Subrahmanyam, D., Renuka, B., Laxmana Rao, C. V., Sangeeta Sagar, P., Deevi, D. S., Babu, J. M., Vyas, K. (1998) Novel D-ring analogues of podophyllotoxin as potent anti-cancer agents. Bioorg. Med. Chem. Lett., 8, 1391-1396.
  150. Subrahmanyam, D., Renuka, B., Sunil Kumar, G., Vandana, V., Deevi, D. S. (1999) 9-Deoxopodophyllotoxin derivatives as anti-cancer agents. Bioorg. Med. Chem. Lett., 9, 2131-2134.
  151. López-Pérez, J. L., del Olmo, E., de Pascual-Teresa, B., Merino, M., Barajas, M., San Feliciano, A (2000)A role for dipole moment in the activity of cyclolignans. J. Mol. Structure: THEOCHEM, 504, 51-57.
  152. Gordaliza, M., Castro, M. A., Miguel del Corral, J. M, López-Vázquez, M. L., García, P. A., San Feliciano, A., García-Grávalos, M.D., Broughton, H. (1997) Preparation and cytotoxicity of podophyllotoxin derivatives lacking the lactone ring. Tetrahedron, 53, 15743-15760.
  153. Gordaliza, M., Castro, M. A., Miguel del Corral, J. M., López-Vázquez, M. L., García, P. A., García-Grávalos, M. D., San Feliciano, A. (2000) Synthesis and antineoplastic activity of cyclolignan aldehydes. Eur. J. Med. Chem., 35, 691-698.
  154. Gordaliza, M., Miguel del Corral, J. M,, Castro, M. A., López-Vázquez, M, L., García, P. A., Feliciano, A. S., García-Grávalos M. D. (1995) Selective cytotoxic cyclolignans. Bioorg. Med. Chem. Lett., 5, 2465-2468.
  155. Gordaliza, M., Castro, M., Miguel del Corral, J., López-Vázquez, M., García, P. A., Feliciano, A. S., García-Grávalos, M., Broughton, H. (1997) Preparation and cytotoxicity of podophyl-lotoxin derivatives lacking the lactone ring. Tetrahedron, 53, 15743-15760.
  156. Castro, M. A., Miguel del Corral, J. M., Gordaliza, M., Garcia, P. A.; Gomez-Zurita, M. A., Garcia-Gravalos, M. D., de la Iglesia-Vicente, J., Gajate, C., An, F., Mollinedo, F., San Feliciano, A. (2004) Synthesis and Biological Evaluation of New Selective Cytotoxic Cyclolignans Derived from Podophyllotoxin. J. Med. Chem., 47, 1214-1222.
  157. Xiao, Z. Y., Han, S. Q., Bastow, K. F., Lee, K. H. (2004) Anti-tumour agents. Part 232: Synthesis of cyclosulfite podophyllotoxin analogues as novel prototype antitumour agents. Bioorg. Med. Chem. Lett., 14, 1581-1584.
  158. He, Y., Ma, W. Y., Zhang, C. N. (2001) 3 α-Bromo-epipicropo-dophyllin and Its Derivatives: Novel Analogues of Podophyllotoxin with Antitumour Activities. J. Chin. Pharm. Sci., 10, 75-80.
  159. Long, B. H., Stringfellow, D.A. (1988) Inhibitors of Topoiso-merase II: Structure-activity relationships and Mechanism of Action of podophyllin Congeners. Adv. Enz. Regul., 27, 223-256.
  160. Van Maanen, J. M. S., Retel, J., de Vries, J., Pinedo, H. M. (1988) Mechanism of Action of Antitumour Drug Etoposide: A Review. J. Natl. Cancer Inst., 80, 1526-2533.
  161. Sinha, B. K., Trush, M. A. (1983) Free Radical Metabolism of VP-16 and inhibition of anthracycline-induced lipid peroxidation. Biochem. Pharmacol., 32, 3495-3498.
  162. Van Maanen, J.M.S., Lafleur, M.V.M., Mans, D. R. A., Van den Akker, E., de Ruiter, C., Kootstra, P. R., Pappie, D., de Vries, J., , Retel, J., Pinedo, H. M. (1988) Effects of the ortho-quinone and catechol of the antitumour drug VP-16-213 on the biological activity of single-stranded and double-stranded ΦX174DNA. Biochem. Pharmacol., 37, 3579-3589.
  163. Haim, N., Roman, J., Nemec, J., Sinha, B. K. (1986) Peroxidative free radical formation and O-demethylation of etoposide and teniposide. Biochem. Biophys. Res. Comm., 135, 215-220.
  164. Kalyanaraman, B., Nemec, J., Sinha, B. K. (1989) Characterization of free radicals produced during oxidation of etoposide and its catechol and quinone derivatives. An ESR study. Biochemistry, 28, 4839-4846.
  165. Van Maanen, J. M. S., de Vries, J., Pappie, D., Van den Akker, E., Lafleur, M.V. M., Retel, J., van der Greef, J., Pinedo, H. M. (1987) CytochromeP- 450-mediated-O-demethylation: A route in the metabolic activation of etoposide. Cancer Res., 47, 4658-4662.
  166. Ayres, D.C., Ritchie, T. J. (1988) Lignans and related Phenols. Part 18. The synthesis of Quinones fron Podophyllotoxin and its analogues. J. Chem. Soc. Perkin. Trans. I., 2573-2578.
  167. Vyas, D. M., Saulnier, M. G., Kadow, J. F. (1989) Novel 3',4'-dinitrogen substituted epipodophyllotoxin glucoside derivatives, their preparation and use as antitumour agents. Eur. Pat. Appl. EP 0,297,594,1989.
  168. Vyas, D. M., Saulnier, M. G., Kadow, J. F. (1988) Preparation and Testing of epipodophyllotoxin glucosides as antitumour Agents. Eur.Pat.Appl.EP 291,957,1988.
  169. Zhang, Y. L., Shen, Y. C., Wang, Z. Q., Chen, H. X., Guo, X., Cheng, Y. C., Lee, K. H. (1992) Antitumour Agents 130. Novel 4β-Arylamino Derivatives of 3',4'-Didemethoxy-3',4'-dioxo-4-deoxypodophyllotoxin as Potent Inhibitors of Human DNA Topoisomerase II. J. Nat. Prod., 55, 1100-1111.
  170. Wang, Z. Q., Shen, Y. C., Chen, H. X., Chang, J.Y., Guo, X., Cheng, Y. C., Lee, K. H. (1993) Antitumour Agents 126. Novel 4β-Substituted Anilino Derivatives of 3',4'-O,O-Didemethyl-podophyl-lotoxin as Potent Inhibitors of Human DNA Topoisomerase II. Pharm. Res., 10, 343-349.
  171. Saulnier, M. G., Vyas, D. M., Langley, D. R., Doyle, T. W., Rose, W. C., Crosswell, A. R., Long, B. H. (1989) E-ring desoxy analogs of etoposide. J. Med. Chem., 32, 1418-1420.
  172. Berkowitz, D. B., Maeng, J.H., Dantzig, A. H., Shepard, R. L., Norman, B. H. (1996) Chemoenzymatic and Ring E-Modular Approach to the (-)- Podophyllotoxin Skeleton. Synthesis of 3',4',5'-Tridemethoxy-(-)- podophyllotoxin. J. Am. Chem. Soc., 118, 9426-9427.
  173. Saulnier, M. G., LeBoulleuc, K. L., Long, B. H., Vyas, D. M., Crosswell, A. R., Doyle, T. W. (1992) Synthesis of biological evaluation of 4´-deshydroxy- 4´-methyl etoposide and teniposide analogs. Bioorg. Med. Chem. Lett., 2, 1213-1218.
  174. Ayres, D. C., Lim, C. K. (1972) Lignans and related Phenols. Part XIII. Halogenated Derivatives of podophyllotoxin. J. Chem. Soc. Perkin. Trans. I, 1350-1355.
  175. Ayres, D. C., Lim, C. K. (1982) Modification of the Pendant Ring of Podophyllotoxin. Cancer Chemother. Pharmacol., 7, 99-101.
  176. Hu, H., Liu, S.Y., Cheng, Y. C., Lee, K.H., Wang, Z. Q. (1992) Antitumour agents. 123. Synthesis and human DNA topoisomerase II inhibitory activity of 2'-chloro derivatives of etoposide and 4.beta.-(arylamino)-4'-O-deme thylpodophyllotoxins. J. Med. Chem., 35, 866-871.
  177. Saulnier, M. G. (1990) Preparation of Phosphorus containing etoposide derivatives as antitumour agents. US Pat. 4916217, 1990.
  178. Saulnier, M. G., Vyas, M. D., Langley, D. R. (1989) preparation and testing of epipodophyllotoxin glucoside 4´-O-acyl derivatives as antitumour agents. Eur. Pat. Appl. EP 0,320,988,1989.
  179. Shabat, D., Lode, H. N., Pertl, U., Reisfeld, R. A., Rader, C., Lerner, R. A., Barbas, C. F. (2001) In vivo activity in a catalytic antibody-prodrug system: antibody catalyzed etoposide prodrug activation for selective chemotherapy. Proc. Nat. Acad. Sci. USA, 98, 7528-7533.
  180. Satchi-Fainaro, R., Wrasidlo, W., Lode, H. N., Shabat, D. (2002) Synthesis and characterization of a catalytic Antibody-HPMA copolymer-Conjugate as a tool for tumour selective prodrug activation. Bioorg . Med. Chem., 10, 3023-3029.
  181. Wrasidlo, W., Schröder, U., Bernt, K., Hübener, N., Shabat, D., Gaedicke, G., Lode, H. (2002) Synthesis, Hydrolytic Activation and Cytotoxicity of Etoposide Prodrugs. Bioorg. Med. Chem. Lett., 12, 557-560.
  182. Schmidt, F., Monneret, C. (2003) Prodrug Mono therapy: synthesis and biological evaluation of an etoposide glucuronide-prodrug. Bioorg. Med. Chem., 11, 2277-2283.
  183. Jikai, J., Shamis, M., Huebener, N., Schroeder, U., Wrasidlo, W., Wenkel, J., Lange, B., Gaedicke, G., Shabat, D., Lode, H. N. (2003) Neuroblastoma directed therapy by a rational prodrug design of etoposide as a substrate for tyrosine hydroxylase. Cancer Lett., 197, 219-224.
  184. Lange, B., Schroeder, U., Huebener, N., Jikai, J., Wenkel, J., Strandsby, A., Wrasidlo, W., Gaedicke, G., Lode, H. N. (2003) Rationally designed hydrolytically activated etoposide prodrugs, a novel strategy for the treatment of neuroblastoma. Cancer Lett., 197, 225-230.
  185. Toki, B. E., Cerveny, C. G., Wahl, A. F., Senter, P. D. (2002) Protease- Mediated Fragmentation of p-Amidobenzyl Ethers: A New Strategy for the Activation of Anticancer Prodrugs. J. Org. Chem., 67, 1866-1872.
  186. Han, S.Q., Xiao, Z. Y., Bastow K. F., Lee, K. H. (2004) Antitumour agents. Part 230: C4´-esters of GL-331 as cytotoxic agents and DNA topoisomerase II inhibitors. Bioorg. Med. Chem. Lett., 14, 2979-2982.
  187. Xiao, Z.Y., Vance, J. R., Bastow, K. F., Brossi, A., Wang, H. K., Lee, K. H. (2004) Antitumour agents. Part 235: Novel 4´-ester etoposide analogues as potent DNA topoisomerase II inhibitors with improved therapeutic potential. Bioorg. Med. Chem., 12, 3363-3369.
  188. Kim, Y., You, Y. J., Nam, N. H., and Ahn, B. Z. (2002) Prodrugs of 4´- demethyl-4´-deoxypodophyllotoxin: synthesis and evaluation of the antitumour activity. Bioorg. Med. Chem. Lett., 12, 3435-3438.
  189. You, Y. J., Kim, Y., Nam, N. H., Bang, S. C., Ahn, B. Z. (2004) Alkyl and carboxylalkyl esters of 4´-demethyl-4´-deoxypodophyl-lotoxin: synthesis, cytotoxic, and antitumour activity. Eur. J. Med. Chem., 39, 189-193.
  190. You, Y. J., Kim, Y., Nam, N. H., Ahn, B. Z. (2003) Antitumour activity of unsaturated fatty acid esters of 4´-demethyldeoxypodo-phyllotoxin. Bioorg. Med. Chem. Lett., 13, 2629-2632.
  191. Wang, Y. G., Tian, X., Chen, Y. Z. (1988) Progress in spin-labeled antitumour drugs. Acta Pharmaceut. Sin., 23, 792-798.
  192. Chen, Y. Z., Zhang, C.J., Tian, X. (1987) Spin-labeled antitumour derivative of podophyllotoxin. Scientia Sin (series B)., 30, 1070-1079.
  193. Chen, Y. Z., Tian, X., Wang, Y. G. (1989) Spin-labeled antitumour derivative of podophyllotoxin. Life Sci., 45, 2569-2571.
  194. Wang, J. Z., Tian, X., Tsumura, H. (1993) Antitumour activity of a new low immunosuppressive derivative of podophyllotoxin (GP-11) and its mechanisms. Anti-Cancer Drug Des., 8, 193-202
  195. Tian, X., Yan, Z.Q., Li, J. X., Chen, Y. Z. (1995)Anticancer Drugs (V)- Synthesis of etoposide Derivatives. Chem. Res. Chin. Univ., 11, 79-83.
  196. Tian, X., Yang, M.G., Chen, Y. Z. (1996) Anticancer Drugs (VI)-Synthesis and activity of Spin Labeled Derivatives of 4-Amino-4-deoxy-4'- demethylepipodophyllotoxin. Chem. Res. Chin. Univ., 12, 304-308.
  197. Lu, K. K., Wang, Y. G., Chen, Y. Z. (1997) Sythesis of Novel Spin Labeled Analogues of podophyllotoxin glycoside. Synthetic Commun., 27, 1963- 1968.
  198. Tian, X., Wang, Y. G., Yang, M. G., Chen, Y. Z. (1997) Synthesis and antitumour activity of Spin Labeled Derivatives of podophyllotoxin. Life Sci., 60, 511-517.
  199. Wang, Y. G., Pan, J. L., Shi, J. F., Chen, Y. Z. (1997) New Spin Labeled Analogues of podophyllotoxin as potential antitumour agents. Life Sci., 61, 537-542.
  200. Pan, J. L., Wang, Y. G., Shi, J. F., Chen, Y. Z. (1997) Synthesis of New Spin Labeled Derivatives of podophyllotoxin as potential anticancer agents. Chin. Chem. Lett., 8, 207-208.
  201. Tian, X., Zhang, F. M., Li, W. G. (2002) Antitumour and antioxidant activity of spin labeled derivatives of podophyllotoxin (GP-1) and congeners. Life Sci., 70, 2433-2443.
  202. Liu, Y. Q., Tian, X. (2005) Synthesis of Novel Spin Labeled podophyllotoxin derivatives. Chin. J. Org. Chem (S)., 25, 17.
  203. Liu, Y. Q., Tian, X.(2005) Synthesis of Novel Spin Labeled podophyllotoxin derivatives. Synthetic Commun., 27, 1963-1968.
  204. Jin, Y., Chen, S. W., Tian, X. (2006) Synthesis and biological evaluation of new spin-labeled derivatives of podophyllotoxin. Bioorg. Med. Chem., 14, 3062-3068.
  205. Derry, W. B., Pamidi, C. C., Gupta, R. S. (1993) Synthesis and biological activity of novel thymidine derivatives of podophyllotoxin and 4´- demethylepipodophyllotoxin. Anti-Cancer Drug Des., 8, 203-221.
  206. Ji, Z., Wang, H. K., Bastow, K. F., Zhu, X.K., Cho, S. J., Cheng,Y. C., Lee, K. H. (1997) Antitumour Agents 177. Design, Synthesis and Biological Evaluation of Novel Etoposide analogues bearing pyrrolecarboxyamidino group as DNA topoisomerase II inhibitors. Bioorg. Med. Chem.lett., 7, 607- 612.
  207. Chen, S. W., Tian, X., Tu, Y. Q. (2004) Synthesis and cytotoxic activity of novel derivatives of 4´-demethylepipodophyllotoxin. Bioorg. Med. Chem. Lett., 14, 5063-5066.
  208. Liu, Y. Q., Yang, H., Tian, X. (2006) Design, synthesis and biological evaluation of novel etoposide analogue as cytotoxic agents. Chin. J. Chem., 24, 785-790.
  209. Zhang, F. M., Tian, X. (2002) Synthesis and anticancer activity of novel derivatives of 4´-demethylepipodophyllotoxin. Acta Chim. Sin., 60, 720-724.
  210. Bastow, K. F., Wang, H. K., Cheng, Y. C., Lee, K. H. (1997) Antitumour Agents-CLXXIII. Synthesis and Evaluation of Camptothecin-4β-amino-4'-O- demethyl epipodophyllotoxin conju-gates as Inhibitors of Mammalian DNA Topoisomerases and as Cytotoxic Agents. Bioorg. Med. Chem., 5, 1481- 1488.
  211. Shi, Q., Wang, H. K., Bastow, K.F., Tachibana, Y., Chen, K., Lee, F. K., Lee, K. H. (2001) Antitumour Agents 210. Synthesis and Evaluation of Taxoid-Epipodophyllotoxin conjugates as novel Cytotoxic Agents. Bioorg. Med. Chem., 9, 2999-3004.
  212. Jensen, L.R., Hansen, H. F., Wessel, I., Nitiss, J. L., Schmidt, G., Jensen, P. B., Sehested, M., Jensen, L. H. (2001) Linker length in podophyllotoxin-acridine conjugates determines potency in vivo and in vitro as well as specificity against MDR cell lines. Anti-Cancer Drug Des., 16, 305-315.
  213. Kamal, A., Laxman, E., Khanna, G. B. R., Reddy, P. S. M. M. Rehana, T., Arifuddin, M., Neelima, K., Kondapi, A. K., Dastidar, S. G. (2004) Design, synthesis, biological evaluation and QSAR studies of novel bisepipodophyllotoxins as cytotoxic agents. Bioorg. Med. Chem., 12, 4197- 4209 .
  214. Danieli, B., Giardini, A., Lesma, G., Passarella, D., Peretto, B., Sacchetti, A., Silvani, A., Pratesi, G., Zunino, F. (2006) Thiocol-chicine-Podophyllotoxin Conjugates: Dynamic Libraries Based on Disulfide Exchange Reaction. J. Org. Chem., 71, 2848-2853.
  215. Greenwald, R. B., Conover, C. D., Pendri, A., Choe, Y. H., Martinez, A., Wu, D., Guan, S.Y., Yao, Z. L., Shum, K. L. (1999) Drug delivery of anticancer agents: water soluble 4-poly (ethylene glycol) derivatives of the lignan, podophyllotoxin. J. Control. Rel., 61, 281-294.
  216. Xiao, Z., Xiao, Y. D., Feng, J., Golbraikh, A., Tropsha, A., Lee, K. H. (2002) Antitumour Agents. 213. Modeling of Epipodophyllo-toxin Derivatives Using Variable Selection k Nearest Neighbor QSAR Method. J. Med. Chem., 45, 2294-2309.

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