TGFβR1抑制剂的设计、合成及抗癌活性  

Design,synthesis and anticancer activity of TGFβR1 inhibitors

作　　者：梅嘉伟 唐潇 王勉[2] 韦天宝 王坚毅[1,4] MEI Jia-wei;TANG Xiao;WANG Mian;WEI Tian-bao;WANG Jian-yi(College of Chemistry and Chemical Engineering,Guangxi University,Nanning 530004,China;College of Life Science and Technology,Guangxi University,Nanning 530004,China;Guangxi Weiwei Pharmaceutical CO.,LTD,Nanning 530225,China;Medical College,Guangxi University,Nanning 530004,China)

机构地区：[1]广西大学化学化工学院,广西南宁530004 [2]广西大学生命与科学技术学院,广西南宁530004 [3]广西维威制药有限公司,广西南宁530225 [4]广西大学医学院,广西南宁530004

出　　处：《化学研究与应用》2024年第6期1302-1308,共7页Chemical Research and Application

基　　金：国家自然科学基金项目(21967003,81960649)资助;广西自然科学基金项目(2022GXNSFAA035453)资助。

摘　　要：TCFβ蛋白家族包括转化生长因子、激活素、NODAL、骨形态发生蛋白等等,是组织形态发生的关键调节因子,在胚胎发育、器官发生以及成人组织稳态、炎症过程和创伤愈合中决定细胞早期命运。研究证明,抑制TCFβR1能够有效阻断TGFβ信号通路,显著破坏肿瘤细胞微环境,达到遏制肿瘤细胞发展的目的。为了获得具有抗癌活性的新型TGFβR1抑制剂,在保留传统的邻二芳基唑类结构的基础上,通过增环等策略,建立了新型骨架的目标化合物模型。合成的中间体及目标化合物结构经过了核磁共振氢谱、碳谱、质谱的确证。MTT实验和计算机模拟分子对接表明,目标化合物具有较好的类药性质,其中化合物CD-2具有进一步结构优化与筛选的可能。TGFβprotein family includes transforming growth factor,activin,NODAL,bone morphogenetic protein and so on.It is a key regulator of tssue morphogenesis and determines the early cell fate in embryonic development,organogenesis,as well as adult tissue homeostasis,inflammatory process and wound healing.Studies have shown that inhibition of TGFβR1 can effectively block TGFβsignaling pathway,significantly destroy the tumor cell microenvironment,and achieve the goal of halting the development of tumor cells.In order to obtain novel TGFR1 inhibitors with anticancer activity,the target compound model of the novel skeleton was established by retaining the traditional o-diarylazole structure through strategies such as ring addition.The structures of the syn-thesized intermediates and target compounds were confirmed by'H NMR,I°C NMR and HRMS.MTT assay and computer simulation molecular docking showed that the target compounds had good drug-like properties,and compound CD-2 had the possibility of fur-ther structure optimization and screening.

关 键 词：抗癌 TGFβR1 抑制剂 新型骨架 合成 

分 类 号：O626[理学—有机化学]