吡啶并[2,3-b]吡嗪类FGFR抑制剂的设计、合成及抗胃癌活性研究

Design,synthesis and anti-gastric activity of pyrido[2,3-b] pyrazine derivatives as FGFR inhibitors

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.