title: A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors.
abstract: Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada).
authors.forename: Milan
authors.initials: M
authors.lastname: Bergeron-Brlek
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada).
authors.forename: Jake
authors.initials: J
authors.lastname: Goodwin-Tindall
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada).
authors.forename: Nevena
authors.initials: N
authors.lastname: Cekic
authors.affiliation: Department of Chemistry, University of York, York (UK).
authors.forename: Christian
authors.initials: C
authors.lastname: Roth
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada).
authors.forename: Wesley F
authors.initials: WF
authors.lastname: Zandberg
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada).|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia (Canada).
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Shan
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada).
authors.forename: Vimal
authors.initials: V
authors.lastname: Varghese
authors.affiliation: Department of Chemistry, University of York, York (UK).
authors.forename: Sherry
authors.initials: S
authors.lastname: Chan
authors.affiliation: Department of Chemistry, University of York, York (UK).
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada). dvocadlo@sfu.ca.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia (Canada). dvocadlo@sfu.ca.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vocadlo
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada). rbritton@sfu.ca.
authors.forename: Robert
authors.initials: R
authors.lastname: Britton
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D054812:Cyclitols / Q000737:chemistry / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D013237:Stereoisomerism; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors*
chemical_list: D054812:Cyclitols; D004791:Enzyme Inhibitors; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases
keywords: enzymes; glycosides; heterocycles; hydrolases; inhibitors