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A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain‐Permeable OGA Inhibitors
Author(s) -
BergeronBrlek Milan,
GoodwinTindall Jake,
Cekic Nevena,
Roth Christian,
Zandberg Wesley F.,
Shan Xiaoyang,
Varghese Vimal,
Chan Sherry,
Davies Gideon J.,
Vocadlo David J.,
Britton Robert
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201507985
Subject(s) - epimer , chemistry , pyrrolidine , enzyme , potency , biochemistry , in vitro , stereochemistry , computational biology , biology
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.