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

Article abstract of DOI:10.1016/S0960-894X(97)00060-7

Novel water-soluble 4β-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-4β-[N-(1 '''-methyl-4'''-nitro-pyrrole-2'''-carbonyl)-4''-aminoanilino]-4 -desoxypodophyllotoxin (10) and its HCl salt (11) were found to exhibit potent cytotoxic activities (average log GI₅₀ = -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/LD₅₀ = 0.04/0.15 and 0.2/0.25 for KB and KB-7d cells, respectively), topoisomerase II inhibitory activity (12.5 μM), and cellular protein DNA complex formation (225%).