苯甲酰胺类组蛋白去乙酰化酶抑制剂的合成及抗肿瘤细胞增殖活性

Synthesis and antitumor activities of benzamide derivatives as novel histone deacetylase inhibitors

目的针对组蛋白去乙酰化酶(HDAC)的结构特点,设计合成一系列化合物并进行体外抗肿瘤活性评价,为进一步优化设计提供指导。方法以2-羟基-4-硝基苯甲醛为原料,经环合、还原、与芳醛衍生物反应、水解后,在N,N-碳酰二咪唑存在下经缩合反应合成目标化合物。结果与结论共合成了11个新苯甲酰胺类衍生物,化合物的结构经质谱、核磁共振氢谱确证;体外抗肿瘤活性评价结果表明,其中4个化合物(4b、4c、4d、4h)对肿瘤细胞具有显著的增殖抑制活性,化合物4h的活性最好,它对HL60、MCF-7、A549肿瘤细胞的IC50值分别为2.81、>50、4.79μmol.L-1。

It is known that HDAC is studied as an important target in the area of tumor inhibition.As a result,it is necessary to find a kind of small molecule HDAC inhibitor.Based on the good antitumor activities of MS-275 and CI-994,eleven novel benzamide derivatives were designed and synthesized.Ethyl 6-aminobenzofuran-2-carboxylate was prepared from 2-hydroxy-4-nitro-benzaldehyde by two steps including cyclization and reduction,and it was converted to the target compounds through reductive amination,hydrolysis and condensation in the presence of CDI.Moreover,the structures of the these compounds were confirmed by 1H-NMR and MS.Their antitumor activities were detected in vitro in three kinds of human tumor cells（HL60,MCF-7,and A549）.These values（the IC50 value of 4b in HL60 was 11.71 μmol · L-1,the IC50 va-lue of 4c in HL60 was 6.90 μmol · L-1,the IC50 value of 4d in MCF-7 was 5.78 μmol · L-1,the IC50 values of 4h in HL60 and A549 were 2.81 μmol · L-1 and 4.79 μmol · L-1） demonstrated that some compounds（4b,4c,4d and 4h） displayed certain antitumor activities.Among them,compound 4h was the best.