title: Design and synthesis of O-GlcNAcase inhibitors via 'click chemistry' and biological evaluations.
abstract: Protein O-GlcNAcylation has been shown to play an important role in a number of biological processes, including regulation of the cell cycle, DNA transcription and translation, signal transduction, and protein degradation. O-GlcNAcase (OGA) is responsible for the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from serine or threonine residues, and thus plays a key role in O-GlcNAc metabolism. Potent OGA inhibitors are useful tools for studying the cellular processes of O-GlcNAc, and may be developed as drugs for the treatment neurodegenerative diseases. In this study, Cu(I)-catalyzed 'Click' cycloaddition reactions between glycosyl azides and alkynes were exploited to generate inhibitory candidates of OGA. Enzymatic kinetic screening revealed that compound 7 was a potent competitive inhibitor of human O-GlcNAcase (K(i)=185.6 μM). Molecular docking simulations of compound 7 into CpOGA (Clostridium perfringens OGA) suggested that strong π-π stacking interaction between the compound and W490 considerably contributed to improving the inhibitory activity.
authors.affiliation: College of Pharmacy, Nankai University, Tianjin 300071, PR China.
authors.forename: Tiehai
authors.initials: T
authors.lastname: Li
authors.forename: Lina
authors.initials: L
authors.lastname: Guo
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jiajia
authors.initials: J
authors.lastname: Wang
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Zhenxing
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Jianping
authors.initials: J
authors.lastname: Lin
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
mesh_terms: D057930:Click Chemistry; D003016:Clostridium perfringens / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase