新型细胞外信号相关激酶(ERK)小分子抑制剂的设计、合成与抗肿瘤活性研究  

Design,Synthesis and Antitumor Evaluation of Novel Small Molecule Extracellular Regulated Protein Kinase(ERK)Inhibitors

作　　者：朱仲珍 乔雨 张子豪 顾明震 王晋 高志宇 郭文昊 刘明明 李荣[1] Zhu Zhongzhen;Qiao Yu;Zhang Zihao;Gu Mingzhen;Wang Jin;Gao Zhiyu;Guo Wenhao;Liu Mingming;Li Rong(School of Pharmacy,Anhui Medical University,Hefei 230032)

机构地区：[1]安徽医科大学药学院,合肥230032

出　　处：《有机化学》2020年第7期1983-1990,共8页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.81972040)资助项目.

摘　　要：细胞外信号相关激酶(ERK)是恶性肿瘤发生发展中的关键激酶,为了寻找新型结构的ERK抑制剂,采用拼合原理设计合成了两类共12个含有吗啉环的脲类化合物,其结构经1 H NMR、13C NMR和HRMS确证.ERK激酶活力和细胞增殖测试结果表明,大部分目标化合物对人结直肠癌细胞SW480和HCT-116具有中等强度的抑制作用,尤其是1-(4-氟苄基)-3-(5-(4-吗啉代苯基)吡啶-2-基)脲(18f)的IC50分别达到0.36和0.55µmol/L,对正常细胞L02毒性较低(>10µmol/L).同时,18f能抑制ERK的激酶活力(IC50=0.051µmol/L)和磷酸化水平,但不影响总ERK表达和上游丝裂原活化的细胞外信号调节激酶(MEK)的激活.上述结果为新型苄基吡啶基脲类ERK抑制剂的深入研究提供了重要参考信息.Extracellular regulated protein kinase(ERK)is a key kinase in the development of cancer.12 urea compounds containing morpholin rings were designed and synthesized in search of novel ERK inhibitors by using merging strategy.The structures of all compounds were confirmed by 1 H NMR,13C NMR and HRMS.ERK kinase activity and cell proliferation test results indicate that most of the target compounds have moderately inhibitory effects on human colorectal cancer cells SW480 and HCT-116,especially the IC50 of 1-(4-fluorobenzyl)-3-(5-(4-morpholinophenyl)pyridin-2-yl)urea(18f)reaches 0.36 and 0.55µmol/L,respectively,and has low toxicity to normal cells L02(>10µmol/L).At the same time,18f can inhibit ERK kinase activity(IC50=0.051µmol/L)and phosphorylation level,but does not affect total ERK expression and upstream upstream activation of mitogen-activated extracellular signal-regulated kinase(MEK)activation.These research provides important reference for the further study of novel benzylpyridylurea ERK inhibitors.

关 键 词：丝裂原活化蛋白激酶(MAPKs) 细胞外信号相关激酶(ERK) 二芳基脲 合成 抗肿瘤活性 

分 类 号：TQ464.8[化学工程—制药化工]