4-氨基嘧啶取代的双芳基脲类化合物的合成及抗肿瘤细胞增殖活性

目的设计并合成含有不同取代苯环结构的双芳基脲类化合物,初步评价其体外抗肿瘤细胞增殖活性。方法以ABT-869为先导化合物,利用生物电子等排原理,将其3-氨基-1H-吲唑结构改造为氨基嘧啶环设计新目标化合物;以对硝基苯乙腈为起始原料,经与N,N-二甲基甲酰胺二甲缩醛(DMF-DMA)缩合、环合、还原、酰化、成脲共5步反应合成目标化合物;以索拉非尼(sorafenib)为阳性对照药,采用MTT法,测试目标化合物对乳腺癌细胞株MDA-MB-231的抗增殖活性。结果与结论合成了18个未见报道的双芳基脲类化合物,其结构经1H-NMR和MS谱确证;6个化合物显示较好的体外活性,其中,化合物5r活性突出,为对照药索拉非尼的1.8倍;并且初步探讨了目标化合物的构效关系。

Synthesis and antiproliferative activity of novel 4-amino pyrimidine-containing diaryl urea derivatives

Based on the leading compound structure of ABT-869, a series of 4-amino pyrimidine-containing diaryl urea derivatives were designed based on the principle of bioisosterism. Starting from 4-nitrophenylacetonitrile and DMF-DMA, the target compounds were synthesized via cyclization,reduction and acylation reactions. Thus, eighteen new compounds 5a-5r were obtained and their structures were confirmed by 1H-NMR and MS. Their in vitro antiproliferative activity against MDA-MB-231 cancer cell lines was evaluated by MTT assay. The pharmacological data indicated that six compounds （5r,Sp ,50 ,Sn ,Sm,Sk） showed antiproliferative potency, and compound 5r displayed promising activity which was 1.8 times better than sorafenib.