Release Time:2019-03-11  Hits:

Indexed by: Journal Article

Date of Publication: 2018-02-02

Journal: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

Included Journals: PubMed、SCIE

Volume: 33

Issue: 1

Page Number: 445-452

ISSN: 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.