| Summary: | 博士 === 中國醫藥學院 === 藥物化學研究所 === 88 === As part of our continuing search for potential anticancer candidates of 2-phenyl-4-quinazolinones and 2-phenyl-4-quinolones, 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 have been synthesized and evaluated for cytotoxicity and inhibition of tubulin polymerization. Through these biological screening, a preliminary structure-activity relationship has been established. On the whole, a good correlation was found between the two activities. Among them, 6-N,N-dimethylamino and 6-heterocyclic 2-phenyl-4-quinazolinones (56-60) showed potent cytotoxicity against a panel of human tumor cell lines with EC50 values in the low micromolar to nanomolar concentration ranges. 2-(3'-Methoxyphenyl)-6-(pyrrolidinyl)-4-quinazolinone (57) was especially the most potent. Moreover, compound 57 was also a potent inhibitor of tubulin polymerization with activity comparable to that of the antimitotic natural products such as colchicine, podophyllotoxin, and combretastatin A-4. Substituted 2-phenyl-4-quinazolinones and 2,3-dihydro-2-phenyl-4-quinazolinones also displayed highly selective cytotoxicity against the ovarian cancer (1A9) and vincristine-resistant epidermoid carcinoma of the nasopharynx (KB-VIN).
On the other hand, a series of 4-alkoxy-2-phenylquinazolines and 4-alkoxy-2-phenylquinolines were synthesized respectively via alkylation of 2-phenyl-4-quinazolinones and 2-phenyl-4-quinolones, and their antiplatelet activities were evaluated. Among them, 4-ethoxy-2-phenylquinazoline (71), 4-methoxy-2-phenylquinoline (92), 4-ethoxy-2-phenylquinoline (93) and 7-fluoro-4-methoxy-2-phenylquinoline (98) showed very potent inhibitory effects on the platelet aggregation induced by arachidonic acid. Their activities were about ten to thirteen times more potent than aspirin.
Compound 57 and 71, which exhibited strong cytotoxicity and antiplatelet activity respectively, were thus selected for further investigation of pharmaceutical mechanism.
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