Antitumor agents .177. Design, syntheses, and biological evaluation of novel etoposide analogs bearing pyrrolecarboxamidino group as DNA topoisomerase II inhibitors

[摘要] Novel water-soluble 4 beta-amino-4'-O-demethylepipodophyllotoxin derivatives (6-12), designed to enhance minor groove binding ability, were synthesized and screened against NCI's in vitro disease-oriented human tumor cells. Among them, 4'-O-demethyl-4 beta-[N-(1 triple prime-methyl-4 triple prime-nitro-pyrrole-2 triple prime-carbonyl)-4 ''-aminoanilino]-4-desoxypodophyllotoxin (10) and its HCl salt (11) were found to exhibit potent cytotoxic activities (average log GI(50) = -6.91, -7.00, and -5.01 for 10, 11, and etoposide, respectively). Compounds 10 and 12 were further tested for their inhibitory activities against DNA topoisomerase II. Compound 10 again exhibited a superior activity profile compared to that of etoposide, displaying increased cytotoxicity against KB and KB-7d cells (ID50/LD(50) = 0.04/0.15 and 0.2/0.25 for KB and KB-7d cells, respectively), topoisomerase II inhibitory activity (12.5 mu M), and cellular protein DNA complex formation (225%). (C) 1997 Elsevier Science Ltd. All rights reserved.

[发布日期] 1997-03-04