Department of Pharmacy, School of Medicine, Qingdao University , Qingdao, Shandong , China .
J Enzyme Inhib Med Chem. 2014 Aug;29(4):582-9. doi: 10.3109/14756366.2013.827678. Epub 2013 Sep 23.
To develop potent histone deacetylase inhibitors as antitumor agents, structural modification was performed. The synthesized molecules were tested by enzymatic inhibition assay and anti-proliferation assay. Several molecules show improved activities in the enzymatic inhibition assay. However, in the MTT assays, all these derived molecules have limited performance compared with SAHA. The IC50 values of molecule ((S)-N-(6-(hydroxyamino)-6-oxohexyl)-4-(3-(2-oxo-1-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethyl)ureido)benzamide, L8) which has the best enzymatic inhibition activity (with an IC50 value of 11.7 nm and 967 nm against Hela nucleus extract and HDAC8, respectively) were calculated compared with SAHA. Molecular docking was performed to predict the binding mode of molecule L8 in the active site of HDAC2 and HDAC8. Hydrophobic interaction, chelate binding, electrostatic attraction and H-bond interaction in combination make contribution to the ligand-receptor interactions.
为了开发有效的组蛋白去乙酰化酶抑制剂作为抗肿瘤药物，我们进行了结构修饰。通过酶抑制试验和抗增殖试验对合成的分子进行了测试。一些分子在酶抑制试验中表现出了更好的活性。然而，在 MTT 试验中，与 SAHA 相比，所有这些衍生分子的性能都受到了限制。具有最佳酶抑制活性（对 Hela 核提取物和 HDAC8 的 IC50 值分别为 11.7nm 和 967nm）的分子((S)-N-(6-(羟基氨基)-6-氧代己基)-4-(3-(2-氧代-1-苯基-2-((3-(三氟甲基)苯基)氨基)乙基)脲基)苯甲酰胺，L8)与 SAHA 相比，其 IC50 值被计算出来。进行了分子对接，以预测分子 L8 在 HDAC2 和 HDAC8 活性位点的结合模式。疏水相互作用、螯合结合、静电吸引和氢键相互作用的结合有助于配体-受体相互作用。
