Convergent Synthesis and Biological Evaluation of 2-Amino-4-(3鈥?4鈥?5鈥?trimethoxyphenyl)-5-aryl Thiazoles as Microtubule Targeting Agents

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• 作者：Romeo Romagnoli ; Pier Giovanni Baraldi ; Andrea Brancale ; Antonio Ricci ; Ernest Hamel ; Roberta Bortolozzi ; Giuseppe Basso ; Giampietro Viola
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 28, 2011
• 年：2011
• 卷：54
• 期：14
• 页码：5144-5153
• 全文大小：1035K
• 年卷期：v.54,no.14(July 28, 2011)
• ISSN：1520-4804

文摘

Combretastatin A-4, a potent tubulin polymerization inhibitor, caused us to synthesize a novel series of 2-amino-4-(3鈥?4鈥?5鈥?trimethoxyphenyl)-5-aryl thiazoles with the goal of evaluating the effects of substituents on the phenyl at the 5-position of the thiazole skeleton on biological activities. An ethoxy group at the para-position produced the most active compound in the series, with IC₅₀ values of 0.03鈥?.9 nM against five of seven cancer cell lines. The most active compounds retained full activity in multidrug resistant cancer cells and acted through the colchicine site of tubulin. Treated cells were arrested in the G2/M phase of the cell cycle, with cell death proceeding through an apoptotic pathway that was only partially caspase-dependent. Preliminary results suggest that, in addition to cell death by apoptosis, cells were also killed via mitotic catastrophe as an alternative cell death mechanism.