【摘要】 目的寻找新型组蛋白去乙酰化酶(HDACs)抑制剂,探讨其初步构效关系。方法在前期研究发现活性结构A和B的基础上,参考恩替司他(MS-275)的结构特点,设计合成系列N-(氨基吡啶)苯甲酰胺类新化合物。采用苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸盐(HBTU)为缩合剂,以取代羧酸与2,3-二氨基吡啶或3,4-二氨基吡啶反应生成系列含N-(氨基吡啶)结构的目标化合物;采用CCK-8法进行体外组蛋白去乙酰化酶抑制活性及抗肿瘤细胞增殖活性测试。结果共合成18个未见文献报道的新化合物,其结构经质谱、核磁共振氢谱确认。体外抗肿瘤初步研究表明:所有目标化合物均具有组蛋白去乙酰化酶抑制活性及抗肿瘤细胞增殖活性,Ⅴ-12、Ⅴ-13和Ⅴ-16等化合物体外抑酶活性和抗肿瘤活性与阳性对照药MS-275相当,值得进一步深入研究。结论初步构效关系研究发现,含有活性结构B的化合物具有更好的体外抗肿瘤活性;适当增加化合物酶表面识别区基团(R基团)的空间位阻或在R基团上引入供电子取代基将会增强化合物的抗肿瘤活性。更多还原

【Abstract】 To explore novel histone deacetylases(HDACs) inhibitors with antitumor activity,a series of N-(aminopyridine) benzamide derivatives were synthesized and evaluated for their antitumor activities in vitro against HDACs and five human cancer cell lines.Eighteen target compounds and the promising histone deacetylase inhibitor MS-275 were obtained by optimized procedure with HBTU as the condensation reagent.Meanwhile,their structures were confirmed by MS and 1H-NMR individually.Some compounds showed potent antitumor activities in vitro against HDACs,especially against five human cancer cell lines,such as Hep3B2.1-7 hepatoma cells,Colo320 rectal cancer cells,Jurkat E6-1 T-cell lymphoma,K562 chronic myelogenous leukemia cells,and MDA-MB-435s breast cancer cells.Compounds Ⅴ-12,Ⅴ-13 and Ⅴ-16 are worthy of further investigation.Based on the SAR of these agents and our current understanding of HDACs active site,existence of active site B as the zinc-binding motif in HDACs inhibitors could increase their antitumor activities,and increasing steric hindrance of the surface recognition or introducing electron donating groups could also increase their antitumor activities.These results represent a significant step towards the development of small molecule HDAC inhibitors with favorable pharmaceutical properties.更多还原