Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site

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• 作者：Xiao-Feng Wang ; Fang Guan ; Emika Ohkoshi ; Wanjun Guo ; Lili Wang ; Dong-Qing Zhu ; Sheng-Biao Wang ; Li-Ting Wang ; Ernest Hamel ; Dexuan Yang ; Linna Li ; Keduo Qian ; Susan L. Morris-Natschke ; Shoujun Yuan ; Kuo-Hsiung Lee ; Lan Xie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1390-1402
• 全文大小：548K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a鈥?b>c and 5a鈥?b>m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI₅₀ 1.9鈥?.2 nM), significant potency against tubulin assembly (IC₅₀ 0.77 渭M), and substantial inhibition of colchicine binding (99% at 5 渭M). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.