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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].

Table 7 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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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... .
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