Structural highlights
Publication Abstract from PubMedThe 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 (alpha-cyclosulfate) is a rapidly reacting alpha-glucosidase inhibitor whose 4C1 chair conformation matches that adopted by alpha-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (beta-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. 1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor.,Artola M, Wu L, Ferraz MJ, Kuo CL, Raich L, Breen IZ, Offen WA, Codee JDC, van der Marel GA, Rovira C, Aerts JMFG, Davies GJ, Overkleeft HS ACS Cent Sci. 2017 Jul 26;3(7):784-793. doi: 10.1021/acscentsci.7b00214. Epub, 2017 Jul 13. PMID:28776021[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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