Artola, Marta, Wu, Liang orcid.org/0000-0003-0294-7065, Ferraz, Maria J. et al. (10 more authors) (2017) 1,6-Cyclophellitol Cyclosulfates:A New Class of Irreversible Glycosidase Inhibitor. ACS Central Science. pp. 784-793. ISSN 2374-7943
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number EUROPEAN COMMISSION 322942 |
Depositing User: | Pure (York) |
Date Deposited: | 07 Sep 2017 16:30 |
Last Modified: | 17 Dec 2024 00:08 |
Published Version: | https://doi.org/10.1021/acscentsci.7b00214 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1021/acscentsci.7b00214 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:121016 |