Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors
Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors
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发现苯并咪唑衍生物作为新型多靶点 EGFR、VEGFR-2 和 PDGFR 激酶抑制剂
DOI：
10.1016/j.bmc.2011.06.022
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发表时间：
2011-08-01
影响因子：
3.5
通讯作者：
Jiang, Yuyang
中科院分区：
文献类型：
--
作者：
Li, Yunqi;Tan, Chunyan;Jiang, Yuyang
多靶点EGFR、VEGFR-2和PDGFR抑制剂是非常有用的抗癌药物，具有更好的治疗效果。在这项工作中，我们利用支持向量机（SVM）和分子对接两种虚拟筛选方法，鉴定了一系列新的苯并咪唑衍生物，2-芳基苯并咪唑化合物，作为多靶点EGFR， VEGFR-2和PDGFR抑制剂。合成了2-芳基苯并咪唑类化合物，并对其对肿瘤细胞系HepG-2和特异性激酶的生物学活性进行了评价。其中，化合物5a和5e对HepG-2细胞具有较高的细胞毒性，IC50值接近2 μ m。进一步的激酶实验研究表明，化合物5a具有较好的EGFR抑制活性，VEGFR-2和PDGFR抑制活性中等，而化合物5e具有中等的EGFR抑制活性，VEGFR-2和PDGFR抑制活性稍弱。分子对接分析表明，化合物5a与EGFR和PDGFR的相互作用比化合物5e更紧密。我们的研究发现了一系列新的苯并咪唑衍生物作为多靶点EGFR， VEGFR-2和PDGFR激酶抑制剂。(C) 2011 Elsevier Ltd.版权所有。
Multi-target EGFR, VEGFR-2 and PDGFR inhibitors are highly useful anticancer agents with improved therapeutic efficacies. In this work, we used two virtual screening methods, support vector machines (SVM) and molecular docking, to identify a novel series of benzimidazole derivatives, 2-aryl benzimidazole compounds, as multi-target EGFR, VEGFR-2 and PDGFR inhibitors. 2-Aryl benzimidazole compounds were synthesized and their biological activities against a tumor cell line HepG-2 and specific kinases were evaluated. Among these compounds, compounds 5a and 5e exhibited high cytotoxicity against HepG-2 cells with IC50 values at similar to 2 mu M. Further kinase assay study showed that compound 5a have good EGFR inhibitory activity and moderate VEGFR-2 and PDGFR inhibitory activities, while 5e have moderate EGFR inhibitory activity and slightly weaker VEGFR-2 and PDGFR inhibitory activities. Molecular docking analysis suggested that compound 5a more tightly interacts with EGFR and PDGFR than compound 5e. Our study discovered a novel series of benzimidazole derivatives as multi-target EGFR, VEGFR-2 and PDGFR kinases inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.