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A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain‐Permeable OGA Inhibitors |
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| Authors: | Milan Bergeron‐Brlek Dr. Jake Goodwin‐Tindall Nevena Cekic Dr. Christian Roth Dr. Wesley F. Zandberg Dr. Xiaoyang Shan Dr. Vimal Varghese Sherry Chan Prof. Gideon J. Davies Prof. David J. Vocadlo Prof. Robert Britton |
| Affiliation: | 1. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia (Canada);2. Department of Chemistry, University of York, York (UK);3. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia (Canada) |
| 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. |
| Keywords: | enzymes glycosides heterocycles hydrolases inhibitors |