Antitumor agents.: 181.: Synthesis and biological evaluation of 6,7,2′,3′,4′-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic antitumor agents
Antitumor agents.: 181.: Synthesis and biological evaluation of 6,7,2′,3′,4′-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic antitumor agents
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DOI：
10.1021/jm9707479
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发表时间：
1998-03-26
影响因子：
7.3
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Xia, Y;Yang, ZY;Lee, KH
合成了一系列新的6，7，2 ′，3 ′，4 ′-取代的-1，2，3，4-四氢-2-苯基-4-喹诺酮，并评价了其与微管蛋白的相互作用和对一组人肿瘤细胞系的细胞毒活性，所述肿瘤细胞系包括回盲部癌（HCT-8）、乳腺癌（MCF-7）、肺癌（A-549）、鼻咽表皮样癌（KB）、肾癌（CAKI-1）和黑色素瘤癌（SKMEL-2）。大多数化合物（18、20、22-27）显示出有效的细胞毒性和抗微管蛋白作用。活性最强的化合物（23、26、27）在几乎所有肿瘤细胞系中均表现出较强的细胞毒性作用，ED 50值在纳摩尔或亚纳摩尔范围内。三种活性外消旋体（20，22，25）被分离成对映体，并且通常，光学纯的（-）-异构体（20 a，22 a，25 a）表现出比外消旋体或（+）-异构体更大的生物活性。细胞毒性和抗微管蛋白活性密切相关，最具活性的化合物（23，26，27）具有与秋水仙碱，鬼臼毒素和考布他汀A-4相当的效果。
A novel series of 6,7,2',3',4'-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones were synthesized and evaluated for interactions with tubulin and for cytotoxic 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) showed potent cytotoxic and antitubulin effects. The most active compounds (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 enantiomers, and generally, the optically pure (-)-isomers (20a, 22a, 25a) exhibited greater biological activity than the racemates or (+)-isomers. Cytotoxicity 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.