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

DOI: 10.1021/acscentsci.7b00214 DOI Help

Authors: Marta Artola (Leiden University) , Liang Wu (University of York) , Maria J. Ferraz (Leiden University) , Chi-lin Kuo (Leiden University) , Lluís Raich (Universitat de Barcelona) , Imogen Z. Breen (University of York) , Wendy A. Offen (University of York) , Jeroen D. C. Codée (Leiden University) , Gijsbert A. Van Der Marel (Leiden University) , Carme Rovira (Universitat de Barcelona; Fundació Catalana de Recerca i Estudis Avançats (ICREA)) , Johannes M. F. G. Aerts (Leiden University) , Gideon J. Davies (University of York) , Herman S. Overkleeft (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Central Science

State: Published (Approved)
Published: July 2017
Diamond Proposal Number(s): 13587

Open Access Open Access

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-epi-cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose 4C1 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.

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
acscentscib.pdf