Hour M J, Huang L J, Kuo S C, Xia Y, Bastow K, Nakanishi Y, Hamel E, Lee K H
Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung, Taiwan.
J Med Chem. 2000 Nov 16;43(23):4479-87. doi: 10.1021/jm000151c.
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 cytotoxicity and as inhibitors of tubulin polymerization. In general, a good correlation was found between the two activities. Five of the 6-substituted heterocyclic 2-phenyl-4-quinozolinones (37-51) showed significant cytotoxicity against a panel of human tumor cell lines with EC(50) values in the low micromolar to nanomolar concentration ranges. Compound 38 was the most potent of these compounds, as well as the most potent inhibitor of tubulin polymerization in this series. The activity of 38 was in the same range as those of the antimitotic natural products, 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 P-gp resistant KB-VIN cell lines.
作为我们在2-苯基-4-喹诺酮和2-苯基-4-喹唑啉酮中持续寻找潜在抗癌候选物的一部分，合成了两个系列的6,7,2',3',4',5'-取代的2-苯基-4-喹唑啉酮和6,2',3',4',5'-取代的2,3-二氢-2-苯基-4-喹唑啉酮，并对其细胞毒性和作为微管蛋白聚合抑制剂的活性进行了评估。总体而言，发现这两种活性之间有良好的相关性。6-取代杂环2-苯基-4-喹唑啉酮中的5个（37 - 51）对一组人类肿瘤细胞系显示出显著的细胞毒性，其半数有效浓度（EC50）值在低微摩尔至纳摩尔浓度范围内。化合物38是这些化合物中活性最强的，也是该系列中微管蛋白聚合的最有效抑制剂。38的活性与抗有丝分裂天然产物秋水仙碱、鬼臼毒素和康普瑞他汀A - 4的活性处于同一范围。取代的2-苯基-4-喹唑啉酮和2,3-二氢-2-苯基-4-喹唑啉酮对卵巢癌1A9和P-糖蛋白耐药的KB-VIN细胞系也表现出高度选择性细胞毒性。
