Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives

• Main Authors: Jana Krejzová, Petr Šimon, Lubica Kalachova, Natallia Kulik, Pavla Bojarová, Petr Marhol, Helena Pelantová, Josef Cvačka, Rüdiger Ettrich, Kristýna Slámová, Vladimír Křen
• Format: Article
• Language: English
• Published: MDPI AG 2014-03-01
• Series: Molecules
• Subjects: NAG-thiazoline; enzyme inhibition; O-GlcNAcase; click chemistry; azide; β-N-acetylhexosaminidase
• Online Access: http://www.mdpi.com/1420-3049/19/3/3471

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.