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目的:设计并合成含苯乙酰胺基的新型异羟肟酸类组蛋白去乙酰化酶(HDACs)抑制剂,并对这些化合物进行体外活性筛选。方法:以硝基苯、对氨基苯甲酸、苯乙酸为初始原料,合成6个目标化合物。MTT法检测化合物对细胞A549,He La,MCF-7和EC109的抑制活性,并通过HDACs抑制实验进一步验证化合物活性。对抑制活性好的化合物进一步用双染法检测化合物诱导细胞凋亡情况,Western blot检测组蛋白H3乙酰表达水平。结果:l4,l6对A549细胞的抑制作用优于阳性对照SAHA(IC50<10μmol·L-1),酶抑制实验与MTT实验结果基本一致。Western blot蛋白分析结果为l4,l6对A549细胞乙酰化呈现上调。结论:含苯乙酰胺基的异羟肟酸类HDACs抑制剂能有效抑制HDACs活性,是一类新型的异羟肟酸类HDACs抑制剂,为进一步研究提供理论依据。
OBJECTIVE: To design and synthesize novel hydroxamic acid histone deacetylases (HDACs) inhibitors with phenylacetamide groups and to screen these compounds in vitro. Methods: Six target compounds were synthesized with nitrobenzene, p-aminobenzoic acid and phenylacetic acid as starting materials. Compounds were tested for their inhibitory activity on A549, He La, MCF-7 and EC109 cells by MTT assay and the compounds were further tested by HDACs inhibition assay. The compound with good inhibitory activity was further detected by double staining and the protein expression of histone H3 was detected by Western blot. Results: The inhibitory effect of l4 and l6 on A549 cells was better than that of the positive control SAHA (IC50 <10μmol·L-1). The results of enzyme inhibition assay and MTT assay were basically consistent. Western blot analysis of protein results l4, l6 A549 cells showed an increase in acetylation. CONCLUSION: Hydroxamic acid-containing HDACs containing phenylacetamido can effectively inhibit the activity of HDACs. It is a new type of hydroxamate-based HDACs inhibitors, providing a theoretical basis for further study.