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

Peer reviewed: 
Yes, item is peer reviewed.
Scholarly level: 
Faculty/Staff
Final version published as: 

Bergeron-Brlek, M., Goodwin-Tindall, J., Cekic, N., Roth, C., Zandberg, W. F., Shan, X., Varghese, V., Chan, S., Davies, G. J., Vocadlo, D. J., & Britton, R. (2015). A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors. Angewandte Chemie International Edition, 54(51), 15429–15433. https://doi.org/10.1002/anie.201507985

Date created: 
2015-11-06
Identifier: 
DOI: 10.1002/anie.201507985
Keywords: 
Enzymes
Glycosides
Heterocycles
Hydrolases
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.

Language: 
English
Document type: 
Article
Rights: 
Rights remain with the authors.
File(s): 
Sponsor(s): 
Natural Sciences and Engineering Research Council of Canada (NSERC)
Canadian Institutes of Health Research (CIHR)
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