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Potent non-hydroxamate inhibitors of histone deacetylase-8: Role and scope of an isoindolin-2-yl linker with an α-amino amide as the zinc-binding unit.
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2020-01-09 , DOI: 10.1016/j.bmcl.2019.126926 Simon O R Greenwood 1 , A W Edith Chan 2 , D Flemming Hansen 3 , Charles M Marson 4
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2020-01-09 , DOI: 10.1016/j.bmcl.2019.126926 Simon O R Greenwood 1 , A W Edith Chan 2 , D Flemming Hansen 3 , Charles M Marson 4
Affiliation
A series of potent inhibitors of histone deacetylase-8 (HDAC8) is described that contains an α-amino amide zinc-binding unit and a substituted isoindolinyl capping group. The presence of a 2,4-dichlorophenyl unit located in the acetate-release cavity was shown to confer a gain of approx. 4.3 kJ mol-1 in binding energy compared to a phenyl group, and the isoindoline linker has approx. 5.8 kJ mol-1 greater binding energy than the corresponding tetrahydroisoquinoline ring system. In a series of 5-substituted isoindolin-2-yl inhibitors, a 5-acetylamino derivative was found to be more potent than the 5-unsubstituted lead HDAC8 inhibitor (increase in binding energy of 2.0 kJ mol-1, ascribed to additional binding interactions within the Nε-acetyl-l-lysine binding tunnel in HDAC8, including hydrogen bonding to Asp101. Tolerance of a 5-substituent (capping group) on the isoindoline ring has been demonstrated, and which in some cases confers improved enzyme inhibition, the HDAC8 substrate-binding region providing a platform for additional interactions.
中文翻译:
组蛋白脱乙酰基酶-8的有效非异羟肟酸酯抑制剂:以α-氨基酰胺为锌结合单元的异吲哚啉-2-基接头的作用和范围。
描述了一系列有效的组蛋白脱乙酰基酶-8(HDAC8)抑制剂,其中含有α-氨基酰胺锌结合单元和取代的异吲哚基封端基团。显示位于乙酸盐释放腔中的2,4-二氯苯基单元的存在赋予了约2,4-二氯苯基的增益。与苯基相比,结合能为4.3 kJ mol-1,且异吲哚啉连接基的结合能约为1。比相应的四氢异喹啉环体系大5.8 kJ mol-1的结合能。在一系列5-取代的异吲哚啉-2-基抑制剂中,发现5-乙酰氨基衍生物比5-未取代的铅HDAC8抑制剂更有效(结合能增加2.0 kJ mol-1,归因于其他结合相互作用在HDAC8的Nε-乙酰基-1-赖氨酸结合通道中,包括氢键与Asp101。
更新日期:2020-01-09
中文翻译:
组蛋白脱乙酰基酶-8的有效非异羟肟酸酯抑制剂:以α-氨基酰胺为锌结合单元的异吲哚啉-2-基接头的作用和范围。
描述了一系列有效的组蛋白脱乙酰基酶-8(HDAC8)抑制剂,其中含有α-氨基酰胺锌结合单元和取代的异吲哚基封端基团。显示位于乙酸盐释放腔中的2,4-二氯苯基单元的存在赋予了约2,4-二氯苯基的增益。与苯基相比,结合能为4.3 kJ mol-1,且异吲哚啉连接基的结合能约为1。比相应的四氢异喹啉环体系大5.8 kJ mol-1的结合能。在一系列5-取代的异吲哚啉-2-基抑制剂中,发现5-乙酰氨基衍生物比5-未取代的铅HDAC8抑制剂更有效(结合能增加2.0 kJ mol-1,归因于其他结合相互作用在HDAC8的Nε-乙酰基-1-赖氨酸结合通道中,包括氢键与Asp101。