喹唑啉酮类EGFR变构抑制剂的合成与生物活性研究  

Synthesis and biological activity study of quinazolinone EGFR variant inhibitors

作　　者：李蓉蓉 何小玲 龙志武 乐意[1,2] LI Rong-rong;HE Xiao-lin;LONG Zhi-wu;LE Yil(School of Pharmacetutical Sciences,Guizhou University,Guiyang 550025,China;Guizhou Synthetic Drugs of Guizhou Province,Guizhou University,Guiyang 550025,China)

机构地区：[1]贵州大学药学院,贵州贵阳550025 [2]贵州大学贵州省合成药物工程实验室,贵州贵阳550025

出　　处：《化学研究与应用》2024年第11期2497-2505,共9页Chemical Research and Application

基　　金：贵州大学引进人才科研项目(贵大人基合字(2021)73号)资助。

摘　　要：表皮生长因子受体(EGFR)是治疗非小细胞肺癌(NSCLC)的有效药物靶点。然而,由于失去了与Cys797的共价相互作用,EGFR的ATP结合口袋处的三级点突变(C797S)诱导了对第三代EGFR抑制剂的耐药性。EAI045是首个针对T790M和C797S EGFR突变体的变构抑制剂。本文通过分析EAI045结构特点,将苯并异吲哚酮部分替换为喹唑啉酮环,设计了新型喹唑啉酮类EGFR变构抑制剂,并通过1H NMR、13C-NMR和HR-MS进行表征确认其结构。随后,采用MTT法评价了该系列化合物对人非小细胞肺癌细胞NCI-H1975的体外抗肿瘤活性。Epidermal growth factor receptor(EGFR)is an effective drug target for the treatment of non-small cell lung cancer(NSCLC).However,due to the loss of covalent interaction with Cys797,a tertiary point mutation(C797S)at the ATP binding pocket of EGFR induced resistance to third-generation ECFR inhibitors.EAI045 is the first allosteric inhibitor targeting T790M and C797S EGFR mutants.The structural characteristics of EAI045 was analyzed,replacing the benzoindolone with a quinazolone ring,a new quinazolone type EGFR conformational inhibitor was designed,and their structure were conformed through'H NMR,'3C NMR,and HR-MS.Subsequently,the in vitro anti-tumor activity of this series of compounds against human non-small cell lung cancer cell line H-1975 was evaluated using MTT assay.

关 键 词：喹唑啉酮 变构抑制剂 非小细胞肺癌 EGFR 

分 类 号：O626[理学—有机化学]