Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors

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• 作者：Xiang-Xiang Tao^&dagger ; ; Yong-Tao Duan^&dagger ; ; Long-Wang Chen^&dagger ; ; Dan-Jie Tang ; Meng-Ru Yang ; Peng-Fei Wang ; Chen Xu ; Hai-Liang Zhu ; ^{zhuhl@nju.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pyrazole-nitroimidazole derivatives ; EGFR/HER-2 inhibitors ; Anticancer activity ; Cytotoxicity ; Molecular docking and QSAR
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：26
• 期：2
• 页码：677-683
• 全文大小：1992 K

文摘

A series of novel pyrazole-nitroimidazole derivatives had been arranged and evaluated for their EGFR/HER-2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on four kinds of cancer cell lines (MCF-7, Hela, HepG2, B16-F10). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activity, with the IC₅₀ values ranging from 0.13 μM to 128.06 μM in four tumor cell lines. Among them, compound 5c exhibited remarkable inhibitory activity against EGFR/HER-2 tyrosine kinase with IC₅₀ value of 0.26 μM/0.51 μM, respectively, comparable to the positive control erlotinib (IC₅₀ = 0.41 μM for HER-2 and IC₅₀ = 0.20 μM for EGFR) and lapatinib (IC₅₀ = 0.54 μM for HER-2 and IC₅₀ = 0.28 μM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity of the proposed compounds and activity relationship (SAR) of these pyrazole-nitroimidazole derivatives.