Antitumor Agents. 234. Design, Synthesis, and Biological Evaluation of Novel 4β-[(4‘ ‘-Benzamido)-Amino]-4‘-<i>O</i>-Demethyl-Epipodophyllotoxin Derivatives

Abstract

A series of 4beta-[(4' '-benzamido)-amino]-4'-O-demethyl-epipodophyllotoxin derivatives (11-23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13-18, 20-22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C(4)-modified new derivatives exhibited superior activity profiles, particularly against drug-resistant cell lines, to those of 1. Preliminary metabolism studies on compounds 16 and 20 revealed that 20 was relatively resistant to metabolism by rat serum and liver enzymes, while 16 was metabolically unstable.