Inhibition of GlcNAc-processing glycosidases by C-6-azido-NAG-thiazoline and its derivatives

Molecules. 2014 Mar 20;19(3):3471-88. doi: 10.3390/molecules19033471.

Abstract

NAG-thiazoline is a strong competitive inhibitor of GH20 β-N-acetyl- hexosaminidases and GH84 β-N-acetylglucosaminidases. Here, we focused on the design, synthesis and inhibition potency of a series of new derivatives of NAG-thiazoline modified at the C-6 position. Dimerization of NAG-thiazoline via C-6 attached triazole linkers prepared by click chemistry was employed to make use of multivalency in the inhibition. Novel compounds were tested as potential inhibitors of β-N-acetylhexosaminidases from Talaromyces flavus, Streptomyces plicatus (both GH20) and β-N-acetylglucosaminidases from Bacteroides thetaiotaomicron and humans (both GH84). From the set of newly prepared NAG-thiazoline derivatives, only C-6-azido-NAG-thiazoline displayed inhibition activity towards these enzymes; C-6 triazole-substituted NAG-thiazolines lacked inhibition activity against the enzymes used. Docking of C-6-azido-NAG-thiazoline into the active site of the tested enzymes was performed. Moreover, a stability study with GlcNAc-thiazoline confirmed its decomposition at pH < 6 yielding 2-acetamido-2-deoxy-1-thio-α/β-D-glucopyranoses, which presumably dimerize oxidatively into S-S linked dimers; decomposition products of NAG-thiazoline are void of inhibitory activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / analogs & derivatives*
  • Acetylglucosamine / chemical synthesis
  • Acetylglucosamine / chemistry
  • Acetylglucosamine / pharmacology
  • Catalytic Domain
  • Drug Stability
  • Glycoside Hydrolases / antagonists & inhibitors*
  • Glycoside Hydrolases / chemistry
  • Glycoside Hydrolases / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*
  • beta-N-Acetylhexosaminidases / antagonists & inhibitors
  • beta-N-Acetylhexosaminidases / chemistry
  • beta-N-Acetylhexosaminidases / metabolism*

Substances

  • Thiazoles
  • Glycoside Hydrolases
  • hexosaminidase C
  • beta-N-Acetylhexosaminidases
  • N-acetylglucosamine thiazoline
  • Acetylglucosamine