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.
Keywords: NAG-thiazoline; enzyme inhibition; O-GlcNAcase; click chemistry; azide; β-N-acetylhexosaminidase
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Krejzová, J.; Šimon, P.; Kalachova, L.; Kulik, N.; Bojarová, P.; Marhol, P.; Pelantová, H.; Cvačka, J.; Ettrich, R.; Slámová, K.; Křen, V. Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives. Molecules 2014, 19, 3471-3488.
Krejzová J, Šimon P, Kalachova L, Kulik N, Bojarová P, Marhol P, Pelantová H, Cvačka J, Ettrich R, Slámová K, Křen V. Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives. Molecules. 2014; 19(3):3471-3488.
Krejzová, Jana; Šimon, Petr; Kalachova, Lubica; Kulik, Natallia; Bojarová, Pavla; Marhol, Petr; Pelantová, Helena; Cvačka, Josef; Ettrich, Rüdiger; Slámová, Kristýna; Křen, Vladimír. 2014. "Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives." Molecules 19, no. 3: 3471-3488.