A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain‐Permeable OGA Inhibitors. (6th November 2015)

• Record Type: Journal Article
• Authors: Bergeron‐Brlek, Milan; Goodwin‐Tindall, Jake; Cekic, Nevena; Roth, Christian; Zandberg, Wesley F.; Shan, Xiaoyang; Varghese, Vimal; Chan, Sherry; Davies, Gideon J.; Vocadlo, David J.; Britton, Robert
• Is Part Of: Angewandte Chemie. Volume 127:Number 51(2015)
• Page Start: 15649
• Page End: 15653
• Publication Date: 2015-11-06
• Subjects: Enzyme -- Glykoside -- Heterocyclen -- Hydrolasen -- Inhibitoren; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201507985
• Languages: English
• ISSNs: 0044-8249

Abstract

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.