Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

J Am Chem Soc. 2017 May 17;139(19):6534-6537. doi: 10.1021/jacs.7b01773. Epub 2017 May 5.


The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine-both covalent retaining β-glucosidase inhibitors-we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4H3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4H3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (Ki = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4H3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclohexanols / chemistry
  • Cyclohexanols / pharmacology*
  • Glycoside Hydrolase Inhibitors / chemistry
  • Glycoside Hydrolase Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Quantum Theory
  • Thermotoga maritima / enzymology
  • alpha-Glucosidases / metabolism*


  • Cyclohexanols
  • Glycoside Hydrolase Inhibitors
  • cyclophellitol
  • alpha-Glucosidases