Modification and Biological Evaluation of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion

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• 作者：Shilong Zheng ; Qiu Zhong ; Yulan Xi ; Madhusoodanan Mottamal ; Qiang Zhang ; Richard L. Schroeder ; Jayalakshmi Sridhar ; Ling He ; Harris McFerrin ; Guangdi Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6653-6667
• 全文大小：761K
• ISSN：1520-4804

文摘

Fascin has recently emerged as a potential therapeutic target, as its expression in cancer cells is closely associated with tumor progression and metastasis. Following the initial discovery of a series of thiazole derivatives that demonstrated potent antimigration and antiinvasion activities via possible inhibition of fascin function, we report here the design and synthesis of 63 new thiazole derivatives by further structural modifications in search of more potent fascin inhibitors. The 5 series of analogues with longer alkyl chain substitutions on the thiazole nitrogen exhibited greater antimigration activities than those with other structural motifs. The most potent analogue, 5p, inhibited 50% of cell migration at 24 nM. Moreover, the thiazole analogues showed strong antiangiogenesis activity, blocking new blood vessel formation in a chicken embryo membrane assay. Finally, a functional study was conducted to investigate the mechanism of action via interaction with the F-actin bundling protein fascin.