以3,5-二芳基取代吡唑为Cap的新型选择性HDAC6抑制剂:设计、合成及抑酶活性评价

Novel Selective HDAC6 Inhibitors Bearing 3,5-Diaryl-substituted 1 H-Pyrazole as Capmoiety:Design,Synthesis and Evaluation of Enzymatic Activity

为发现新型组蛋白去乙酰化酶抑制剂(Histone deacetylase inhibitors,HDACis),基于现有代表性选择性HDAC6抑制剂的结构特征,采用构象限制型的3,5-二芳基取代吡唑为Cap单元构建目标分子,经Claisen-Schmidt反应、环合、亲核取代、水解、缩合、羟胺解反应合成了9个化合物,并通过氢谱和质谱对其进行结构确证。抑酶活性测试结果显示,化合物4-((3,5-二(4-氯苯基)-1 H-吡唑-1-基)甲基)-N-羟基苯甲酰胺(5a)对HDAC6具有良好的抑制活性(IC_(50)=0.25μmol/L)和一定的亚型选择性。

This study is conducted to discover novel histone deacetylase inhibitors(HDACis).Based on the structural characteristics of the representative histone deacetylase 6(HDAC6)selective inhibitors,nine target compounds that feature conformationally restricted 3,5-diaryl-substituted 1 H-pyrazole as the Capmoiety were designed based on structural characteristics of the representative selective HDAC6is,and synthesized via Claisen-Schmidt reaction,cyclization reaction,substitution reaction,hydroxylaminolysis.Their molecular structures have been confirmed by ^(1)HNMR and MS.The biochemical assay showed that compound 4-((3,5-bis(4-chlorophenyl)-1 H-pyrazol-1-yl)methyl)-N-hydroxybenzamide(5a)exhibited acceptable HDAC6 inhibitory activity(IC_(50)=0.25μmol/L)and moderate selectivity.