Antitumor agents. 1771. Design, syntheses, and biological evaluation of novel etoposide analogs bearing pyrrolecarboxamidino group as DNA topoisomerase II inhibitors

Novel water-soluble 4β-amino-4′-O-demethylepipodophyllotoxin derivatives (6–12), designed to enhance minor groove binding ability, were synthesized and screened against NCIʹs 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%).