Synthesis and biological activities of the C-4 esters of 4'-demethylepipodophyllotoxin.
To investigate the structure-activity relationship among podophyllotoxin (POD) derivatives, a number of different esters of the C-4 hydroxyl group of 4'-demethylepipodophyllotoxin (DMEP) and 4'-benzyloxycarbonyl-4'-demethylepipodophyllotoxin have been synthesized. Some of these esters contained the same R groups of aldehydes (e.g. methyl, ethyl, 2-thiophene, phenyl) which, when condensed to either 4'-demethylepipodophyllotoxin-beta-D-glucoside or epipodophyllotoxin-beta-D-glucoside, have yielded compounds with VM26-like activities. The cross-resistance patterns of the DMEP esters towards a set of either POD-resistant (PodR) or VM26-resistant (VpmR) mutants of Chinese hamster ovary (CHO) cells which exhibit highly specific cross-resistance patterns toward POD- or VM26-like compounds have been determined. The PodR mutants were found to exhibit proportionately increased cross resistance toward the various DMEP esters, whereas no increased resistance was observed for the VpmR mutants. The observed cross resistance behavior of the DMEP esters strongly suggests that all of these analogues possess similar biological activity as POD and that none of these act in the same manner as VM26 or VP16-213. Treatment of CHO cells with the various DMEP esters caused a large increase in the mitotic index of cells, which supports the above inference. The POD-like behavior of different DMEP esters indicates that specific attachment of the R group to the C-4 glucoside moiety is required for VM26-like activity. The structure-activity studies on various DMEP esters provide information regarding the role of substituents at the C-4 and C-4' positions on POD-like activity of the compounds.
Gupta
R S
RS
Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
Chenchaiah
P C
PC
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D004351:Drug Resistance; D004952:Esters; D005047:Etoposide / Q000494:pharmacology; D008940:Mitotic Index; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013713:Teniposide / Q000494:pharmacology
D000970:Antineoplastic Agents; D004952:Esters; D005047:Etoposide; D013713:Teniposide; D011034:Podophyllotoxin