The combination of 4-anilinoquinazoline and cinnamic acid: A novel mode of binding to the epidermal growth factor receptor tyrosine kinase
The combination of 4-anilinoquinazoline and cinnamic acid: A novel mode of binding to the epidermal growth factor receptor tyrosine kinase
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4-苯胺基喹唑啉和肉桂酸的组合：与表皮生长因子受体酪氨酸激酶结合的新模式
DOI：
10.1016/j.bmc.2011.06.044
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发表时间：
2011-08-15
影响因子：
3.5
通讯作者：
Zhu, Hai-Liang
中科院分区：
文献类型：
--
作者：
Li, Dong-Dong;Lv, Peng-Cheng;Zhu, Hai-Liang
以喹唑啉为骨架，肉桂酸为侧链，设计了一种新型的肉桂酸喹唑啉酰胺衍生物（20-42），并对其生物活性进行了细胞毒性实验和EGFR抑制实验。化合物42表现出最有效的抑制活性（对EGFR的IC 50 = 0.94 μ M），其可在进一步研究中优化为潜在的EGFR抑制剂。进行对接模拟以将化合物42定位到EGFR活性位点中以确定可能的结合模型。对42活性部位结合构象的分析表明，化合物42与Lys 822通过氢键作用稳定，这与其他衍生物不同。在进一步的研究中，合成了化合物43和44，并对其生物活性进行了评价，结果与预期一致。化合物43作为一种潜在的抗癌剂已显示出显著的EGFR（IC 50 = 0.12 μ M）和肿瘤生长抑制活性。皇冠版权所有（C）2011由爱思唯尔有限公司出版。保留所有权利。
A novel type of cinnamic acid quinazoline amide derivatives (20-42), which designed the combination between quinazoline as the backbone and various substituted cinnamic acid as the side chain, have been synthesized and their biological activities were evaluated within cytotoxicity assay firstly and then potent EGFR inhibitory activity. Compound 42 demonstrated the most potent inhibitory activity (IC50 = 0.94 mu M for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. Docking simulation was performed to position compound 42 into the EGFR active site to determine the probable binding model. Analysis of the binding conformation of 42 in active site displayed compound 42 was stabilized by hydrogen bonding interactions with Lys822, which was different from other derivatives. In the further study, Compounds 43 and 44 had been synthesized and their biological activities were also evaluated, which were the same as that we expected. Compound 43 has demonstrated significant EGFR (IC50 = 0.12 mu M) and tumor growth inhibitory activity as a potential anticancer agent. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved.