Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit tubulin polymerization.
Chen K, Kuo SC, Hsieh MC, Mauger A, Lin CM, Hamel E, Lee KH.
As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed significant cytotoxic effects (log GI50 < -4.0; log molar drug concentration 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 breast cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ring at the 2'- and 3'-positions also generated compounds with potent antitumor activity. Incorporation of an aromatic ring at the 3'- and 4'-positions produced compounds with reduced activity. Interestingly, introduction of a halogen at the 3'-position yielded compounds with different 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, and combretastatin A-4. Active agents also inhibited the binding of [3H]colchicine to tubulin.