Inhibition of glcnac-processing glycosidases by c-6-Azido-nag-thiazoline and its derivatives

Abstract

NAG-thiazoline is a strong competitive inhibitor of GH20 β-N-Acetylhexosaminidases 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 GlcNActhiazoline confirmed its decomposition at pH < 6 yielding 2-Acetamido-2-deoxy-1-thio-A/ β- D-glucopyranoses, which presumably dimerize oxidatively into S-S linked dimers; decomposition products of NAG-thiazoline are void of inhibitory activity. © 2014 by the authors; licensee MDPI, Basel, Switzerland.