ANTITUMOR AGENTS .155. SYNTHESIS AND BIOLOGICAL EVALUATION OF 3',6,7-SUBSTITUTED 2-PHENYL-4-QUINOLONES AS ANTIMICROTUBULE AGENTS

A series of 3',6,7-substituted 2-phenyl-4-quinolones were designed and synthesized as antimitotic antitumor agents. All compounds showed cyt otoxic effects (log GI(50) less than or equal to -4.0; log drug molar concentration required to cause 50% inhibition) against the growth of a variety of human tumor cell lines, including those derived from soli d tumors such as non-small cell lung, colon, central nervous system, o vary, prostate, and breast cancers, when evaluated in the National Can cer Institute's 60 human tumor cell line in vitro screen. The most pot ent compound (26) demonstrated strong cytotoxic effects with GI(50) va lues in the nanomolar or subnanomolar range in almost all the tumor ce ll lines. Compound 26 was also a potent inhibitor of tubulin polymeriz ation and radiolabeled colchicine binding to tubulin, with activity co mparable to those of the potent antimitotic natural products colchicin e, podophyllotoxin, and combretastatin A-4.