摘要
目的设计并合成一系列吡啶并[2,3-b]吡嗪类成纤维细胞生长因子受体(FGFR)抑制剂,同时对其抗胃癌活性进行初步评价。方法以5-溴吡啶-2-胺为起始原料,经9步反应合成了13个未见报道的化合物,并通过MTT法评价其抗胃癌活性。结果与结论目标化合物的结构经NMR和HRMS确证,其中多个化合物对胃癌SNU-16细胞系具有良好的抑制活性,具有进行更深入的构效研究价值,有望成为一种潜在的新增FGFR抑制剂。
In recent clinical research,JNJ-42756493 has been proved to be an effective oral compound to treat the cancer,including gastric carcinoma,caused by FGFR gene changes. In this study,considering JNJ-42756493 as the leading compound for reasonable structure modification,a series of pyrido [2,3-b]pyrazine derivatives as FGFR inhibitors were designed and synthesized based on classical drug design principles,the minimum change principle and bioisosterism. A total of 13 newcompounds were synthesized by 9 steps using 5-bromopyridin-2-amine as the starting material. The target compounds were characterized by NMR,MS and some of them showed good inhibitory activities against SNU-16 cell lines. The IC50 suggested that compounds 10 g and 10 h had a superb anticancer activity at a micromole level. It also indicated that a suitable length of amino chain could contribute to enhance its anti-cancer function. In general,this work is very promising and more work is in progress,including the further design and modification of the potential active structures.
作者
张力
付秋旖
蒋憧
赵毅
郭丽
吴勇
ZHANG Li;FU Qiu-yi;JIANG Chong;ZHAO Yi;GUO Li;WU Yong(West China School of Pharmacy, Sichuan University, Chengdu 610041, China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2018年第2期105-112,共8页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金项目(81573286
81773577
21472130)
关键词
FGFR抑制剂
抗胃癌
吡啶并吡嗪
合成
FGFR inhibitor
anti-gastric cancer
pyrido[2,3-b] pyrazine
synthesis