新型小分子EGFR抑制剂的设计、合成及抗肿瘤活性研究  

Design,synthesis and antitumor activity of novel small molecular EGFR inhibitors

作　　者：吴杰 邹新宇 冯靖 王晓倩 宫平[1] WU Jie;ZOU Xin-yu;FENG Jing;WANG Xiao-qian;GONG Ping(Key Laboratory of Structure-Based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2023年第11期807-819,共13页Chinese Journal of Medicinal Chemistry

摘　　要：目的设计并合成一系列未见文献报道的吡唑并[1,5-a]嘧啶类衍生物,并对其进行抗肿瘤活性研究及分子对接研究。方法依据已上市的第三代小分子EGFR抑制剂AZD9291的构效关系,运用分子杂交策略并结合计算机辅助药物设计,将吡唑并[1,5-a]嘧啶片段引入到目标化合物结构中,并在该骨架上引入氰基以进一步填充蛋白空腔,期望能增强化合物与蛋白的相互作用。以AZD9291为阳性对照,采用MTT法,以人肺癌细胞A549、人乳腺癌细胞MCF-7为测试细胞株,对所合成的目标化合物进行体外抗肿瘤活性测试;利用计算机辅助药物设计方法分析所合成化合物与靶蛋白作用方式。结果与结论共合成了23个目标化合物,其结构均经MS、^(1)H-NMR确证。活性结果表明,化合物A1、A2、A5及A10对肿瘤细胞表现出良好的抑制作用,其中化合物A2对肿瘤细胞A549、MCF-7的IC_(50)值分别为2.07μmol·L^(-1)和2.58μmol·L^(-1)。With compound AZD9291 as the lead compound,twenty-three novel EGFR inhibitors were designed,synthesized and evaluated for antitumor activities to explore the preliminary SARs.The structures of the target compounds were characterized by^(1)H-NMR and MS.The in vitro antitumor activities of these compounds on human non-small cell lung cancer cells(A549),human breast cancer cells(MCF-7)were evaluated by thiazolyl blue(MTT)method.The experimental results showed that compound A2 had the strongest inhibitory activity on A549 cells and MCF-7 cells,with IC_(50)values of 2.07μmol·L^(-1)and 2.58μmol·L^(-1),respectively,which was worthy of further study.

关 键 词：EGFR抑制剂 结构修饰 分子对接 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]