5-Amino-2-aroylquinolines as Highly Potent Tubulin Polymerization Inhibitors. Part 2. The Impact of Bridging Groups at Position C-2

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• 作者：Hsueh-Yun Lee ; Jang-Yang Chang ; Chih-Ying Nien ; Ching-Chuan Kuo ; Kuang-Hsing Shih ; Chun-Hsein Wu ; Chi-Yen Chang ; Wen-Yang Lai ; Jing-Ping Liou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8517-8525
• 全文大小：361K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

A variety of studies on the modification of combretastatin A-4 triggered our interest in the impact of the linkers between the 3,4,5-trimethoxyphenyl ring and 5-amino-6-methoxyquinoline on biological activity. The replacement of the carbonyl group with bond, amine, ether, sulfide, and sulfone groups was evaluated in this study. The results showed that compounds 14 and 15 containing sulfide and sulfone groups between the 3,4,5-trimethoxyphenyl ring (A-ring) and 5-amino-6-methoxyquinoline exhibited substantial antiproliferative activity against KB, HT29, and MKN45 cells with mean IC₅₀ values of 42 and 12 nM, respectively. 15 inhibited the tubulin polymerization with an IC₅₀ value of 2.0 渭M, similar to that with CA4. The continued work on the C-5 substituents of 3鈥?4鈥?5鈥?trimethoxybenzoyl-6-methoxyquinoline derivatives demonstrated that compound 7 possessing OH at C-5 exhibited excellent antiproliferative activity with mean IC₅₀ values of 3.4 nM and microtubule destabilizing potency with an IC₅₀ of 1.5 渭M, comparable to that of CA4 (IC₅₀ = 1.9 渭M). It also exhibited substantial vascular disrupting effects. Compounds 7 and 15 exhibited significant efficacy against MDR/MRP-related drug-resistant cell lines (KB-vin10, KB-S15, and KB-7D) with mean IC₅₀ values of 6.7 and 2.6 nM, respectively.