Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC
Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC
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DOI：
10.1016/j.ejmech.2015.12.033
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发表时间：
2016-02-15
影响因子：
6.7
通讯作者：
Shi, Lei
中科院分区：
文献类型：
--
作者：
Peng, Fan-Wei;Xuan, Ji;Shi, Lei
同时抑制多个靶点的单一药物通过干扰多个途径和潜在的协同作用，可能比单作用药物在癌症中提供更大的治疗益处。在这项工作中，设计并鉴定了一系列带有N-苯基喹唑啉-4-胺和异羟肟酸部分的杂合物作为双重VEGFR-2/HDAC抑制剂。化合物6 fd对HDAC的抑制活性最强，IC 50为2.2 nM，对VEGFR-2的抑制作用最强，IC 50为74 nM。它还显示出对人乳腺癌细胞系MCF-7最有效的抑制活性，IC 50为0.85 μ M。对接模拟结果支持了最初的药效学假说，并提示化合物6 fd在VEGFR-2和HDLP（Histone Deacetylase-Like Protein）的活性结合位点存在共同的相互作用模式，表明化合物6 fd是一种潜在的肿瘤治疗药物，值得进一步研究。(C)2015年Elsevier Masson SAS。All rights reserved.
A single agent that simultaneously inhibits multiple targets may offer greater therapeutic benefits in cancer than single-acting agents through interference with multiple pathways and potential synergistic action. In this work, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties were designed and identified as dual VEGFR-2/HDAC inhibitors. Compound 6fd exhibited the most potent inhibitory activity against HDAC with IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 with IC50 of 74 nM. It also showed the most potent inhibitory activity against a human breast cancer cell line MCF-7 with IC50 of 0.85 mu M. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for cancer therapy deserving further researching. (C) 2015 Elsevier Masson SAS. All rights reserved.