新型4-苯氧基吡啶类c-Met激酶抑制剂的合成和抗肿瘤活性研究  

Synthesis and Antitumor Activity,Novel 4-Phenoxypyridine Derivatives as Potential c-Met Kinase Inhibitors

作　　者：刘举[1] 高俊峰 荆锐 李春艳 王旭 程蒙 陈烨[1] 丁实 沈继伟 LIU Ju;GAO Jun-feng;JING Rui;LI Chun-yan;WANG Xu;CHENG Meng;CHEN Ye;DING Shi;SHEN Ji-wei(School of Pharmaceutical,Liaoning University,Shenyang 110036,China;Shenyang Xingqi Pharmaceutical Co.,Ltd.,Shenyang 110063,China)

机构地区：[1]辽宁大学药学院,辽宁沈阳110036 [2]沈阳兴齐眼药股份有限公司,辽宁沈阳110063

出　　处：《辽宁大学学报（自然科学版）》2024年第3期258-264,共7页Journal of Liaoning University：Natural Sciences Edition

基　　金：国家自然科学基金青年基金项目(21807055);沈阳市自然科学基金项目(23-503-6-12)。

摘　　要：为了发现新型高活性c-Met激酶抑制剂,以2-氨基-4-氯吡啶为原料,经醚化、酰化、烷基化、还原和酰化等多步反应,制备了6种未见文献报道的4-苯氧基吡啶类化合物,化合物结构经红外光谱、核磁共振氢谱和质谱确证.生物活性测试结果显示,6种化合物对MKN-45、A549、H460和HT-294种肿瘤细胞株具有很好的抗增殖活性,两种化合物对c-Met激酶具有很好的抑制活性.其中化合物7b抑制MKN-45、A549、H460和HT-29细胞株的IC 50值分别为1.89、5.14、0.74、0.60μmol/L.该化合物在1000 nmol/L和200 nmol/L的浓度下对c-Met激酶的抑制率分别为96.2%和82.8%,显示出了优异的抗肿瘤活性.To explore new compounds with high c-Met inhibition activity,six novel 4-phenoxypyridine derivatives were synthesized from 4-chloropyridin-2-amine via etherification,acylation,alkylation,reduction and amidation.The compounds obtained were then identified by infrared spectrum,H nuclear magnetic spectrum and mass spectrum,followed by preliminary evaluations on their antitumor activities.The results indicated that all the six target compounds showed antiproliferative activities against MKN-45,A549,H460 and HT-29.Two compounds showed excellent c-Met inhibition activities.Among them,compound 7b exhibited remarkable antiproliferative activities against MKN-45,A549,H460 and HT-29 cell lines with IC 50 value of 1.89μmol/L,5.14μmol/L,0.74μmol/L and 0.60μmol/L,respectively.The inhibitory activities of 7b in the concentration of 1000 nmol/L and 200 nmol/L against c-Met kinase were 96.2%and 82.8%.These results showed that 7b can serve as a scaffold for further structural optimization and antitumor mechanism studies.

关 键 词：合成 4-苯氧基吡啶 c-Met激酶抑制剂 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]