PODOPHYLLOTOXIN ANALOGS - EFFECTS ON DNA TOPOISOMERASE-II, TUBULIN POLYMERIZATION, HUMAN-TUMOR KB CELLS, AND THEIR VP-16-RESISTANT VARIANTS
- 1 July 1989
- journal article
- research article
- Vol. 36 (1) , 78-82
Abstract
Several derivatives of podophyllotoxin with modifications at the C-4 position of ring C, in addition to demethylation at the C-4'' position of ring E, were examined for inhibition activity against DNA topoisomerase II and tubullin polymerization, generation of protein-linked DNA break, and cytotoxicity against KB cells and P-16-resistant KB variants. Substitution of podophyllotoxin with group in the .beta. configuration at the C-4 position of ring C resulted in compounds with greater inhibitory activity against. DNA topoisomerase II and lower inhibitory activity aginst tubulin polymerization than those with an .alpha. configuration. These active analogs exhibited the same mechanism of DNA topoisomerase II inhibition as the epipodophyllotoxin derivative VP-16, which causes protein-linked DNA breaks in vitro as well as in cells. Two analogs selectively inhibited DNA topoisomerases II to a greater extent than tubulin polymerization. These analogs were cytotoxic towards KB cells in addition to VP-16-resistant KB cell lines, which indicated limited cross-resistance with VP-16 in VP 16-resistant KB variants.This publication has 4 references indexed in Scilit:
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