新型EGFR/IGF-1R双靶点抑制剂的设计、合成与抗肿瘤活性研究  

Design,synthesis and antitumor activity study of 4-(2-aminobenzimidazol)quinazolines as EGFR/IGF-1R dual target inhibitors

作　　者：左赛杰 李菁 马东来 赵京山 王晶 刘彦明 周莉 ZUO Saijie;LI Jing;MA Donglai;ZHAO Jingshan;WANG Jing;LIU Yanming;ZHOU Li(School of Pharmacy,Hebei University of Chinese Medicine,Shijiazhuang 050200,China)

机构地区：[1]河北中医学院药学院,河北石家庄050200

出　　处：《沈阳药科大学学报》2022年第10期1204-1210,共7页Journal of Shenyang Pharmaceutical University

基　　金：河北省高等学校科学技术研究项目(BJ2019060);河北省自然科学基金项目(H2020423163)。

摘　　要：目的发现结构新颖的表皮生长因子受体/胰岛素样生长因子-1受体(epidermal growth factor receptor/insulin-like growth factor 1 receptor,EGFR/IGF-1R)双靶点抑制剂。方法以IGF-1R抑制剂BMS-754807的结构为基础,参照前期合成的EGFR酪氨酸激酶抑制剂ET-1的结构和激酶结合模式,设计、合成一类4位连有2-氨基苯并咪唑片段的喹唑啉类化合物,通过氨基咪唑片段与EGFR和IGF-1R铰链区的关键氨基酸残基形成氢键结合,从而获得新型EGFR/IGF-1R双靶点抑制剂。结果合成了10个4-(苯并咪唑-2-氨基)喹唑啉类化合物,通过^(1)H-NMR和ESI-HRMS表征了目标化合物的结构;激酶活性实验表明目标化合物对EGFR和IGF-1R均具有一定的抑制活性;分子模拟对接结果表明目标化合物结构中的氨基咪唑片段是其产生EGFR/IGF-1R双靶点抑制活性的关键药效团。结论合成的目标化合物为EGFR/IGF-1R双靶点抑制剂,后续通过结构优化有望发现新型抗肿瘤药物。Objective To discover novel epidermal growth factor receptor/insulin-like growth factor 1 receptor(EGFR/IGF-1 R)inhibitors.Methods Based on the structure of IGF-1 R inhibitor BMS-754807 and our previously synthesized EGFR tyrosine kinase inhibitor ET-1,a series of 4-(2-aminobenzimidazol)quinazolines were designed and synthesized.These compounds could be novel EGFR/IGF-1 R dual target inhibitors through hydrogen bonding between imidazole fragment with EGFR and IGF-1 R hinge regions.Results Ten target compounds were synthesized and characterized through ^(1)H-NMR and ESI-HRMS.Their kinase inhibitory activities against EGFR and IGF-1 R were evaluated through luminescent kinase assay.The molecular docking study was also conducted.The in vitro kinase study and docking study showed that amino imidazole fragment was the key pharmacophore of these novel EGFR/IGF-1 R dual target inhibitors.Conclusion The target compounds are EGFR/IGF-1 R dual target inhibitors,which are expected to become novel antitumor agents through further structural optimization.

关 键 词：EGFR酪氨酸激酶抑制剂 IGF-1R抑制剂 4-(苯并咪唑-2-氨基)喹唑啉 双靶点 

分 类 号：R914[医药卫生—药物化学]