N-Aryl-6-methoxy-1,2,3,4-tetrahydroquinolines: A novel class of antitumor agents targeting the colchicine site on tubulin

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• 作者：Xiao-Feng Wang ; Sheng-Biao Wang ; Emika Ohkoshi ; Li-Ting Wang ; Ernest Hamel ; Keduo Qian ; Susan L. Morris-Natschke ; Kuo-Hsiung Lee ; Lan Xie
• 关键词：N-Aryl-6-methoxy-1 ; 2 ; 3 ; 4-tetrahydroquinolines ; Cytotoxicity ; Tubulin polymerization inhibitors ; Colchicine binding site
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：67
• 期：Complete
• 页码：196-207
• 全文大小：1041 K

文摘

Structural optimizations of the prior lead 1a led to the discovery of a series of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinoline derivatives as a novel class of tubulin polymerization inhibitors targeted at the colchicine binding site. The most active compound 6d showed extremely high cytotoxicity against a human tumor cell line panel (A549, KB, KBvin, and DU145) with GI₅₀ values ranging from 1.5 to 1.7?nM, significantly more potent than paclitaxel, especially against the drug-resistant KBvin cell line, in the same assays. Analogs 5f, 6b, 6c, and 6e were also quite potent, with a GI₅₀ range of 0.011-0.19?¦ÌM. In further studies, active compounds 6b-e and 5f significantly inhibited tubulin assembly, with IC₅₀ values of 0.92-1.0?¦ÌM and strongly inhibited colchicine binding to tubulin, with inhibition rates of 75-99 % (at 5?¦ÌM), comparable with or more potent than combretastatin A-4 (IC₅₀ 0.96?¦ÌM). Current studies included design, synthesis, and biological evaluations of 24 new compounds (series 3-6). Related SAR analysis, molecular modeling, and evaluation of essential drug-like properties, i.e. water solubility, log P, and in?vitro metabolic stability, were also performed.