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Indexed by:期刊论文

Date of Publication:2018-02-02

Journal:JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

Included Journals:SCIE、PubMed

Volume:33

Issue:1

Page Number:445-452

ISSN No.:1475-6366

Key Words:Thioglycosides; naphthalimide derivatives; beta-N-acetylhexosaminidase; O-GlcNAcase; inhibitors

Abstract:GH20 human beta-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these beta-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (K-i=0.91 mu M against hsHexB; K-i > 100 mu M against hOGA) and compound 15b (K-i = 3.76 mu M against hOGA; K-i = 30.42 mu M against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure-activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific beta-N-acetylhexosaminidase inhibitors.