Fluorescent-tagged sp2-iminosugars with potent β-glucosidase inhibitory activity

Bioorg Med Chem. 2010 Nov 1;18(21):7439-45. doi: 10.1016/j.bmc.2010.09.003. Epub 2010 Sep 7.

Abstract

New fluorescently-labelled sp(2)-iminosugars based on the 5N,6S-[N'-(4-aminobutyl)iminomethylidene]-6-thionojirimycin skeleton have been synthesized as photoprobes to monitor glycosidase binding. Dansyl, dapoxyl and coumarin fluorophores were appended to the terminal amino group at the N'-substituent by either sulfonamide or amide bridging reaction. All the conjugates behaved as strong (low micromolar to nanomolar) and selective inhibitors of β-glucosidases (almonds and bovine liver) and naringinase, in agreement with the inhibition pattern previously encountered for related iso(thio)urea-type bicyclic sp(2)-iminosugars. The presence of the fluorescent probe allows real-time and continuous monitoring of β-glucosidase inhibition by fluorescence resonance energy transfer (FRET), taking advantage of the intrinsic tryptophan-associated fluorescence of the protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives
  • 1-Deoxynojirimycin / chemistry
  • Animals
  • Cattle
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Fluorescence Resonance Energy Transfer
  • Fluorescent Dyes / chemistry*
  • Imino Sugars / chemistry*
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism
  • beta-Glucosidase / antagonists & inhibitors*
  • beta-Glucosidase / metabolism

Substances

  • Enzyme Inhibitors
  • Fluorescent Dyes
  • Imino Sugars
  • Multienzyme Complexes
  • 1-Deoxynojirimycin
  • naringinase
  • beta-Glucosidase
  • nojirimycin