ANTITUMOR AGENTS - 181 - SYNTHESIS AND BIOLOGICAL EVALUATION OF BSTITUTED-1,2,3,4-TETRAHYDRO-2-PHENYL-4-QUINOLONES AS A NEW CLASS OF ANTIMITOTIC ANTITUMOR AGENTS

A novel series of bstituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones w ere synthesized and evaluated for interactions with tubulin and for cy totoxic activity against a panel of human tumor cell lines, including ileocecal carcinoma (HCT-8), breast cancer (MCF-7), lung carcinoma (A- 549), epidermoid carcinoma of the nasopharynx (KB), renal cancer (CAKI -1), and melanoma cancer (SKMEL-2). Most compounds (18, 20, 22-27) sho wed potent cytotoxic and antitubulin effects. The most active compound s (23, 26, 27) demonstrated strong cytotoxic effects with ED50 values in the nanomolar or subnanomolar range in almost all tumor cell lines. Three active racemates (20, 22, 25) were separated into the enantiome rs, and generally, the optically pure (-)-isomers (20a, 22a, 25a) exhi bited greater biological activity than the racemates or (+)-isomers. C ytotoxicity and antitubulin activity were closely correlated, with the most active compounds (23, 26, 27) having effects comparable to those of colchicine, podophyllotoxin, and combretastatin A-4.