含缩氨基脲结构的4-苯氧基喹啉类c-Met激酶抑制剂的合成与抗肿瘤活性  

Synthesis and Anticancer Activity of 4-Phenoxyquinoline Derivatives Bearing Semicarbazone Moiety as c-Met Inhibitors

作　　者：吴霜 林思雨 李楠 林艺涵 丁实 陈烨[1,2,3] 刘举 沈继伟[1,2,3] WU Shuang;LIN Siyu;LI Nan;LIN Yihan;DING Shi;CHEN Ye;LIU Ju;SHEN Jiwei(College of Pharmacy;API Engineering Technology Research Center of Liaoning Province;Shenyang Key Laboratory of Small Molecule Targeted Drug Research and Development,Liaoning University,Shenyang 110036,China)

机构地区：[1]辽宁大学药学院 [2]辽宁省医药原料药制备工程技术研究中心 [3]沈阳市小分子靶向药物研发重点实验室,沈阳110036

出　　处：《高等学校化学学报》2025年第4期35-44,共10页Chemical Journal of Chinese Universities

基　　金：沈阳市自然科学基金重点实验室专项(批准号:23-503-6-12);辽宁省属本科高校基本科研业务费专项(批准号:LJKLJ202419);辽宁省教育厅基本科研项目(批准号:LJKFZ20220177)资助。

摘　　要：基于4-苯氧基喹啉类Type II型小分子c-Met激酶抑制剂的结构特点,设计并合成了13个含缩氨基脲结构的4-苯氧基喹啉类化合物.采用迁移率改变法(MTS)测试了目标化合物对c-Met激酶的抑制活性.采用噻唑蓝(MTT)法测试了目标化合物对A549,PC-3,AGS和MKN45细胞的体外抗增殖活性.体外抗肿瘤活性实验结果表明,大部分化合物对c-Met激酶和4种肿瘤细胞株均具有较好的抑制活性.其中化合物6f和6k具有优秀的抑制c-Met激酶活性[c-Met的半数抑制浓度(IC_(50))分别为14.50和15.68 nmol/L].化合物6f对A549,PC-3,AGS和MKN45细胞的IC_(50)值分别为0.93,7.81,12.88和2.58μmol/L;化合物6k对A549,PC-3,AGS和MKN45细胞的IC_(50)值分别为0.67,6.60,3.04和0.88μmol/L.抗肿瘤作用机制研究结果表明,化合物6k可诱导MKN45和A549细胞发生细胞凋亡,并能够抑制2种肿瘤细胞的迁移能力.Thirteen novel 4-phenoxyquinoline derivatives bearing semicarbazone moiety were successfully designed and synthesized based on the structural characteristics of 4-phenoxyquinoline small molecule type II c-Met kinase inhibitors.The in vitro inhibitory activities of all the target compounds against c-Met kinase were evaluated using mobility shift assay.The in vitro antiproliferative activities of the target compounds against A549,PC-3,AGS and MKN45 cells were evaluated using MTT-based assay.Most of the target compounds showed excellent inhibitory activities against c-Met kinase and all the tested cancer cell lines.Among them,compounds 6f(c-Met:IC_(50)=14.50 nmol/L)and 6 k(c-Met:IC_(50)=15.68 nmol/L)exhibited excellent inhibition activity of against c-Met kinase.The IC_(50)values of 6 f for A 549,PC-3,AGS and MKN-45 cells were 0.93,7.81,12.88,and 2.58μmol/L,respectively.The IC_(50)values of 6 k for A 549,PC-3,AGS and MKN 45 cells were 0.67,6.60,3.04,and 0.88μmol/L,respectively.Further studies on the anti-tumor mechanism indicated that compound 6 k induced MKN 45 and A 549 cells apoptosis,and inhibited the migration ability of MKN 45 and A 549 cells.

关 键 词：药物分子设计 c-Met抑制剂 4-苯氧基喹啉 缩氨基脲 抗肿瘤活性 

分 类 号：O626.3[理学—有机化学] R914.5[理学—化学]