Download Mendeley1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor.
Artola, M., Wu, L., Ferraz, M.J., Kuo, C.L., Raich, L., Breen, I.Z., Offen, W.A., Codee, J.D.C., van der Marel, G.A., Rovira, C., Aerts, J.M.F.G., Davies, G.J., Overkleeft, H.S.(2017) ACS Cent Sci 3: 784-793
- PubMed: 28776021
- DOI: https://doi.org/10.1021/acscentsci.7b00214
- Primary Citation of Related Structures:
5NPB, 5NPC, 5NPD, 5NPE, 5NPF, 5O0S - PubMed 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 4 C 1 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.
Organizational Affiliation:
Department of Bio-organic Synthesis and Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
