巯基乙酰胺作为强效、选择性且具有脑渗透性的组蛋白去乙酰化酶6抑制剂的设计与合成
Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors.
作者信息
Lv Wei, Zhang Guangming, Barinka Cyril, Eubanks James H, Kozikowski Alan P
机构信息
Department of Medicinal Chemistry and Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada.
出版信息
ACS Med Chem Lett. 2017 Apr 7;8(5):510-515. doi: 10.1021/acsmedchemlett.7b00012. eCollection 2017 May 11.
Abstract
A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue and quinoline analogue displayed potent HDAC6 inhibitory activity (IC, 11 and 2.8 nM) and excellent selectivity against HDAC1. Both and together with their ester prodrug and disulfide prodrugs and were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs and also released a stable concentration of and upon microsomal incubation. Administration of and was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.
摘要
我们制备了一系列非异羟肟酸类HDAC6抑制剂，旨在开发出强效且具有选择性的化合物，用于治疗中枢神经系统（CNS）疾病，从而避免通常与异羟肟酸类相关的基因毒性。在设计的巯基乙酰胺的帽基中引入卤素，以提高其脑内通透性。吲哚类似物和喹啉类似物表现出强效的HDAC6抑制活性（IC，分别为11和2.8 nM），并且对HDAC1具有优异的选择性。发现和及其酯前药以及二硫键前药和在HEK细胞中均能有效促进微管蛋白乙酰化。二硫键前药和在微粒体孵育时也能释放稳定浓度的和。发现给予和会引发小鼠皮层中微管蛋白乙酰化增加。这些结果表明，有必要对这些化合物进行进一步探索，以用于治疗中枢神经系统疾病。
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本文引用的文献
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