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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 class of benzene-substituted hydroxamic acid histone deacetylase inhibitors, and to evaluate the activity of these compounds in vitro. Methods: Six compounds were synthesized from nitrobenzene, methyl p-aminobenzoate and benzoyl chloride. The inhibitory effect of compounds on A549, HeLa and MCF-7 cells was detected by MTT assay. Cell cycle analysis was performed on compounds with good inhibitory activity. The expression of histone H3 was detected by Western blot and the apoptosis induced by compound was detected by double staining. Results: The inhibitory effect of compound 4,18 on A549 cells was better than the positive control SAHA (IC50 <10μmol·L-1). Through cycle analysis, the compounds showed S-phase arrest on A549 cells. The result of Western blotting analysis showed that the acetylation of compound 16,18 on A549 cells was up-regulated, h6 could induce the apoptosis of A549 cells. CONCLUSION: Hydroxamic acid-substituted HDACs substituted with benzene ring can effectively inhibit HDACs. It is a new class of hydroxamic acid HDAC inhibitors and deserves further study.