Design, synthesis, anti-tumor activity, and molecular modeling of quinazoline and pyrido[2,3-d]pyrimidine derivatives targeting epidermal growth factor receptor
Design, synthesis, anti-tumor activity, and molecular modeling of quinazoline and pyrido[2,3-d]pyrimidine derivatives targeting epidermal growth factor receptor
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DOI：
10.1016/j.ejmech.2016.04.026
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发表时间：
2016-08-08
影响因子：
6.7
通讯作者：
Zhang, Jiajie
中科院分区：
文献类型：
--
作者：
Hou, Ju;Wan, Shanhe;Zhang, Jiajie
设计、合成了三个系列的新型喹唑啉和吡啶并[2，3-d]嘧啶衍生物，并评价了它们抑制EGFR酪氨酸激酶和一组五种人癌细胞系（MCF-7、A549、BT-474、SK-BR-3和MDA-MB-231）的能力。生物活性测定结果表明，其中5个化合物（12 c-12 e和13 c-13 d）对EGFR和SK-BR-3细胞株具有明显的抑制活性。化合物12 c和12 e显示出最强的EGFR抑制活性（IC 50分别为2.97 nM和3.58 nM）和对SK-BR-3细胞的良好的抗增殖作用，IC 50值分别为3.10 μ M和5.87 μ M。分子对接和分子动力学模拟研究证实，化合物12 c和12 e与吉非替尼在EGFR结合口袋中具有相似的结合模式。MM-GBSA结合自由能表明化合物12 c和12 e对EGFR具有与吉非替尼几乎相同的抑制活性，并且货车德瓦尔斯相互作用的主导作用驱动结合过程。(C)2016 Elsevier Masson SAS。All rights reserved.
Three series of novel quinazoline and pyrido[2,3-d]pyrimidine derivatives were designed, synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase and a panel of five human cancer cell lines (MCF-7, A549, BT-474, SK-BR-3, and MDA-MB-231). Bioassay results indicated that five of these prepared compounds (12c-12e and 13c-13d) exhibited remarkably higher inhibitory activities against EGFR and SK-BR-3 cell line. Compounds 12c and 12e displayed the most potent EGFR inhibitory activity (IC50 = 2.97 nM and 3.58 nM, respectively) and good anti-proliferative effect against SK-BR-3 cell with the IC50 values of 3.10 mu M and 5.87 mu M, respectively. Furthermore, molecular docking and molecular dynamics simulation studies verified that compound 12c and 12e shared similar binding pattern with gefitinib in the binding pocket of EGFR. MM-GBSA binding free energy revealed that the compound 12c and 12e have almost the same inhibitory activity against EGFR as gefitinib, and that the dominating effect of van der Waals interactions drives the binding process. (C) 2016 Elsevier Masson SAS. All rights reserved.