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A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors

DOI: 10.1002/ange.201507985 DOI Help

Authors: Milan Bergeron-brlek (Simon Fraser University) , Jake Goodwin-tindall (Simon Fraser University) , Nevena Cekic (Simon Fraser University) , Christian Roth (University of York) , Wesley F. Zandberg (Simon Fraser University) , Xiaoyang Shan (Simon Fraser University) , Vimal Varghese (Simon Fraser University) , Sherry Chan , Gideon Davies (University of York) , David J. Vocadlo (Simon Fraser University) , Robert Britton (Simon Fraser University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie , VOL 127 (51) , PAGES 15649 - 15653

State: Published (Approved)
Published: December 2015

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.

Journal Keywords: Enzyme;Glykoside;Heterocyclen;Hydrolasen;Inhibitoren

Subject Areas: Chemistry


Instruments: I04-Macromolecular Crystallography

Added On: 17/02/2016 11:09

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