Raf激酶抑制剂的设计、合成及抗肿瘤活性

Design,synthesis and bioactivity evaluation of novel Raf kinase inhibitors

目的:设计并合成新型Raf激酶抑制剂并测试其在体外的抗肿瘤活性。方法:根据Raf激酶抑制剂的构效关系和药效团研究成果,设计了一系列双芳基脲类化合物(N-1～N-12);采用MTT法对目标化合物进行4个瘤株(SMMC-7721、A549、BGC-823和HL-60)的体外抑制肿瘤细胞增殖的活性测定;通过FRET法测试对Raf激酶的抑制活性。结果与结论:合成了12个Raf激酶抑制剂,其结构均经IR、1H NMR和MS确证。目标化合物对所测的4种肿瘤细胞均有一定程度的增殖抑制作用;11个目标化合物对Raf激酶有一定程度的抑制作用,其中2个化合物的活性与索拉非尼相当。

Aim： To design and synthesize novel Raf kinase inhibitors and evaluate their bioactivities in vitro. Methods： A series of biphenyl urea compounds were designed and synthesized based on the SAR of Raf kinase inhibitors as well as pharmacophore properties, of which, their in vitro anti-proliferative activities against tumor cell lines SMMC-7721, A549, BGC-823 and HL-60, and inhibitory activities against Raf kinase were inves- tigated by MTT assay and FRET assay, respectively. Results and Conclusion： Twelve Raf kinase inhibitors were synthesized and their structures were confirmed by IR, 1H NMR and MS. The target compounds possessed anti- proliferative activities against four kinds of tumor cell lines tested to at least some degree, and eleven target com- pounds were found to inhibit Raf kinase in vitro to some extent, two of which had comparable or even better activ- ities than sorafenib, a marketed Raf kinase-targeting drug.