新型组蛋白去乙酰化酶抑制剂的设计、合成及活性评价:含硫锌离子结合基团的发现

摘要

Zinc binding group (ZBG) is the crucial moiety in the chemical structure of any HDAC inhibitor.In the present study,a series of sulphur-containing ZBG were designed and synthesized in the novel HDAC inhibitors to replace the classical ZBGs of SAHA and BML-210,hydroxamic acids and benzamides,respectively.The HDAC inhibitory activity and the structure-activity relationships of these molecules were analyzed.A sulphur-rich group,diethylcarbamo (dithioperoxo) thioate,was finally identified as a novel potent ZBG.Among all the synthesized compounds,4d was much more potent compared with BML-210,and it showed similar inhibitory effect of SAHA against HDAC isoforms 1 and 2.Therefore,it was chosen as a lead compound.%锌离子结合基团是组蛋白去乙酰化酶(HDAC)抑制剂结构中的关键部分.本文中设计了一系列含硫的基团,替换了SAHA中的羟肟酸以及BML-210中的苯甲酰胺等经典的锌离子结合基团,合成了新的HDAC抑制剂.经过对HDAC抑制活性的测试及构效关系分析,最终发现了一类富含硫的基团(二乙胺基二硫代过硫甲酸酯)是新的有效锌离子结合基团.在所有合成的化合物中,4d显著优于BML-210,对HDAC的亚型1,2的抑制活性与SAHA相当,被选为先导化合物.