6-alkylamino- and 2,3-dihydro-3 '-methoxy-2-phenyl-4-quinazolinones and related compounds: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization

As part of our continuing search for potential anticancer candidates among 2-phenyl-4-quinolones and 2-phenyl-4-quinazolinones, two series of 6,7,2',3 ',4',5'-substituted 2-phenyl-4-quinazolinones and 6,2',3',4',5'-substituted 2,3-dihydro-2-phenyl-4-quinazolinones were synthesized and evaluated for c ytotoxicity and as inhibitors of tubulin polymerization. In general, a good correlation was found between the two activities. Five of the 6-substitute d heterocyclic 2-phenyl-4-quinozolinones (37-51) showed significant cytotox icity against a panel of human tumor cell lines with EC50 values in the low micromolar to nanomolar concentration ranges. Compound 38 was the most pot ent of these compounds, as well as the most potent inhibitor of tubulin pol ymerization in this series. The activity of 38 was in the same range as tho se of the antimitotic natural products, colchicine, podophyllotoxin, and co mbretastatin A-4. Substituted 2-phenyl-4-quinazolinones and 2,3-dihydro-2-p henyl-4-quinazolinones also displayed highly selective cytotoxicity against the ovarian cancer 1A9 and P-gp resistant KB-VIN cell lines.