ANTITUMOR AGENTS .178. SYNTHESIS AND BIOLOGICAL EVALUATION OF SUBSTITUTED 2-ARYL-1,8-NAPHTHYRIDIN-4(1H)-ONES AS ANTITUMOR AGENTS THAT INHIBIT TUBULIN POLYMERIZATION

As part of our continuing search for potential anticancer drug candida tes:in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesiz ed two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones a nd 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed signif icant cytotoxic effects (log GI(50) < -4.0; log molar drug concentrati on required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breas t cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ri ng at the 2'- and 3'-positions also generated compounds with potent an titumor activity. Incorporation of an aromatic ring at the 3'- and 4'- positions produced compounds with reduced activity. Interestingly, int roduction of a halogen at the 3'-position yielded compounds with diffe rent selectivity. for the tumor cell lines tested. All 3'-halogenated compounds (29-36) and compounds 38 and 42-44 were potent inhibitors of tubulin polymerization with activities nearly comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, a nd combretastatin A-4. Active agents also inhibited the binding of [H- 3]colchicine to tubulin.