Bioorganic & Medicinal Chemistry Letters 2012-08-15

Design, synthesis and biological evaluation of novel acrylamide analogues as inhibitors of BCR-ABL kinase.

Shuxin Li, Zhenglin Yao, Yanjin Zhao, Wei Chen, Huijia Wang, Xianzhao Kuang, Wenhu Zhan, Shan Yao, Shanyou Yu, Wenxiang Hu

文献索引：Bioorg. Med. Chem. Lett. 22(16) , 5279-82, (2012)

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摘要

A series of acrylamide analogues were designed and synthesized from Imatinib and Nilotinib as novel BCR-ABL inhibitors by application of the principle of nonclassical electronic isostere. All new compounds were evaluated for their inhibitory effects on the activity of BCR-ABL kinase and the proliferation of K562 leukemia cancer cells in vitro. The acrylamide analogues in which the substituent in C ring was trifluoromethyl group were identified as highly potent BCR-ABL kinase inhibitors. Compound 13f exhibited an IC(50) value as low as 20.6 nM in ABL kinase inhibition and an IC(50) value of 32.3 nM for antiproliferative activity, about 10.5-fold and 12-fold lower than those of Imatinib respectively. These results suggest that compound 13f is a promising candidate as a novel BCR-ABL kinase inhibitor for further development.Copyright © 2012 Elsevier Ltd. All rights reserved.