苯取代异羟肟酸类组蛋白去乙酰化酶抑制剂的合成及体外抗肿瘤活性评价  

Synthesis of benzene substituted hydroxyl acids as histone deacetylase inhibitors and evaluation of antitumor activity in vitro

作　　者：贺殿[1] 马尚贤[1] 郭青欣[1] 牟建平[1] 

机构地区：[1]兰州大学药物化学研究所,兰州730000

出　　处：《中国新药杂志》2014年第12期1438-1442,1446,共6页Chinese Journal of New Drugs

基　　金：国家科技支撑计划课题(2011BAI05B05)

摘　　要：目的:合成一类苯取代的异羟肟酸类组蛋白去乙酰化酶抑制剂,并对这些化合物进行体外活性评价筛选。方法:以硝基苯、对氨基苯甲酸甲酯、苯甲酰氯为原料合成6个化合物。MTT法检测化合物对细胞A549,HeLa,MCF-7的抑制作用。对抑制活性好的化合物做细胞周期分析,Western blot检测组蛋白H3乙酰表达水平,双染法检测化合物诱导细胞凋亡情况。结果:化合物4,18对A549细胞的抑制作用优于阳性对照SAHA(IC50<10μmol·L-1)。通过周期分析,化合物对A549细胞呈现S期阻滞作用。Western blotting蛋白分析结果为化合物16,18对A549细胞乙酰化呈现上调,h6能诱导A549细胞凋亡。结论:苯环取代的异羟肟酸类HDACs抑制剂能有效的抑制HDACs,是一类新型的异羟肟酸类HDAC抑制剂,值得进一步研究。Objective： To synthesize a type of phenyl substituted hydroxamic acids as histone deacetylase inhibitors, and evaluate their in vitro activity and screening active compounds. Methods： Six compounds were synthesized using nitrobenzene, methyl p-aminobenzoate and benzoyl chloride as raw materials. Inhibitory effects of these compounds on A549, HeLa and MCF cells were determined by MTT method. For the active compounds with inhibitory activity, the effects on cell cycle were analyzed. Western blotting was used to detect acetylating expres- sion level of histone H3, and double staining was performed to detect the induction of cell apoptosis by the com- pounds. Results ： Inhibitory effects of compound 4 and 18 on A549 cells were better than the positive control SAHA （IC50〈10μmol·L^-1）. Cell cycle analyses revealed that these two compounds induced S phase retardation on A549 cells. Western blot analyses showed that compound 16 and 18 presented an increasing trend on acetylation of A549 cells, and h6 could induce apoptosis of A549 cells. Conclusion： Phenyl substituted hydroxamie acid HDAC inhibitors can inhibit HDACs effectively, which is a new type of hydroxamie acid HDAC inhibitors and worthy of further study.

关 键 词：组蛋白去乙酰化酶抑制剂 伏立诺他 异羟肟酸类 

分 类 号：R914.5[医药卫生—药物化学] R961[医药卫生—药学]