1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor

Overview

Journal ACS Cent Sci

Specialty Chemistry

Date 2017 Aug 5

PMID 28776021

Citations 28

Authors

Marta Artola

Liang Wu

Maria J Ferraz

Chi-Lin Kuo

Lluis Raich

Imogen Z Breen

Wendy A Offen

Jeroen D C Codee

Gijsbert A van der Marel

Carme Rovira

Johannes M F G Aerts

Gideon J Davies

Herman S Overkleeft

Affiliations

Soon will be listed here.

Abstract

The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6--cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose C chair conformation matches that adopted by α-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (β-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions.

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