Modification of the Thioglycosyl-Naphthalimides as Potent and Selective Human O-GlcNAcase Inhibitors

文献类型： 外文期刊

第一作者： Dong, Lili

作者： Dong, Lili;Zeng, Xiangdi;Lu, Huizhe;Zhang, Jianjun;Chen, Wei;Yang, Qing;Yang, Qing

作者机构：

关键词： Thioglycosides; naphthalimides; human O-GlcNAcase; beta-N-acetylhexosaminidase; inhibitor; docking; MD simulations

期刊名称：ACS MEDICINAL CHEMISTRY LETTERS （ 影响因子：4.345； 五年影响因子：4.273 ）

ISSN： 1948-5875

年卷期： 2018 年 9 卷 12 期

页码：

收录情况： SCI

摘要： beta-N-Acetylhexosaminidases are widely distributed exoglycosidases and have attracted significant attention due to their important roles in the field of pesticide and drug discovery. Remarkably, human O-GlcNAcase (hOGA) and human beta-N-acetylhexosaminidase (HsHex) possess the same catalytic mechanism but play different physiological actions in vivo. In this Letter, we aim to improve the inhibitory potency and selectivity of previously reported thioglycosyl-naphthalimides against hOGA. The rational compound design led to the synthesis of 13r bearing a 4-piperidylnaphthalimide moiety as a highly potent hOGA inhibitor (K-i = 0.6 mu M against hOGA) with good selectivity (K-i > 100 mu M against HsHexB). Furthermore, to investigate the basis for the potency and selectivity of 13r against hOGA, the possible inhibitory mechanisms of selected inhibitors (15b, 13b, and 13r) against hOGA and HsHexB were studied using molecular docking and MD simulations. These 4-substituted naphthalimide thioglycosides may potentially serve as useful tools for the further study of the function of hOGA.

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