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

Shengqiang Shen; Lili Dong; Wei Chen; Xiangdi Zeng; Huizhe Lu; Qing Yang; Jianjun Zhang

doi:10.1021/acsmedchemlett.8b00406

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

ACS Med Chem Lett. 2018 Nov 15;9(12):1241-1246. doi: 10.1021/acsmedchemlett.8b00406. eCollection 2018 Dec 13.

Authors

Shengqiang Shen¹, Lili Dong¹, Wei Chen², Xiangdi Zeng¹, Huizhe Lu¹, Qing Yang^{2

3}, Jianjun Zhang¹

Affiliations

¹ Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China.
² Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
³ School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116023, China.

Abstract

β-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 β-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 μM against hOGA) with good selectivity (K _i > 100 μM 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.