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

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  • Marta Artola
  • Liang Wu
  • Maria J. Ferraz
  • Chi Lin Kuo
  • Lluís Raich
  • Imogen Z. Breen
  • Wendy A. Offen
  • Jeroen D.C. Codée
  • Gijsbert A. Van Der Marel
  • Carme Rovira
  • Johannes M.F.G. Aerts
  • Gideon J. Davies
  • Herman S. Overkleeft


Publication details

JournalACS Central Science
DateAccepted/In press - 19 May 2017
DateE-pub ahead of print - 13 Jul 2017
DatePublished (current) - 26 Jul 2017
Issue number7
Number of pages10
Pages (from-to)784-793
Early online date13/07/17
Original languageEnglish


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.

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© 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.

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