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

Milan Bergeron-Brlek; Jake Goodwin-Tindall; Nevena Cekic; Christian Roth; Wesley F. Zandberg; Xiaoyang Shan; Vimal Varghese; Sherry Chan; Gideon J. Davies; David J. Vocadlo; Robert Britton

doi:10.1002/anie.201507985

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

Milan Bergeron-Brlek, Jake Goodwin-Tindall, Nevena Cekic, Christian Roth, Wesley F. Zandberg, Xiaoyang Shan, Vimal Varghese, Sherry Chan, Gideon J. Davies, David J. Vocadlo^*, Robert Britton

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Number of pages	6
Journal	Angewandte Chemie International Edition
Early online date	6 Dec 2015
DOIs	https://doi.org/10.1002/anie.201507985
Publication status	Published - 14 Dec 2015

Bibliographical note

Keywords

Enzymes
Glycosides
Heterocycles
Hydrolases
Inhibitors

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title = "A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA 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.",

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doi = "10.1002/anie.201507985",

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T2 - Generation of Potent Brain-Permeable OGA Inhibitors

AU - Bergeron-Brlek, Milan

AU - Goodwin-Tindall, Jake

AU - Cekic, Nevena

AU - Roth, Christian

AU - Zandberg, Wesley F.

AU - Shan, Xiaoyang

AU - Varghese, Vimal

AU - Chan, Sherry

AU - Davies, Gideon J.

AU - Vocadlo, David J.

AU - Britton, Robert

PY - 2015/12/14

Y1 - 2015/12/14

N2 - 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.

AB - 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.

KW - Enzymes

KW - Glycosides

KW - Heterocycles

KW - Hydrolases

KW - Inhibitors

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U2 - 10.1002/anie.201507985

DO - 10.1002/anie.201507985

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SN - 1433-7851

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

ER -

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

Abstract

Bibliographical note

Keywords

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