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Molecules 2014, 19(3), 3471-3488; doi:10.3390/molecules19033471
Article

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

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1 Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic 2 Department of Biochemistry and Microbiology, Institute of Chemical Technology Prague, Technická 5, 16628 Praha 6, Czech Republic 3 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Praha 6, Czech Republic 4 Department of Structure and Function of Proteins, Institute of Nanobiology and Structural Biology of GCRC, Academy of Sciences of the Czech Republic, Zámek 136, 37333 Nové Hrady, Czech Republic 5 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Praha 6, Czech Republic These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 4 February 2014 / Revised: 6 March 2014 / Accepted: 13 March 2014 / Published: 20 March 2014
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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 NAG-thiazoline; enzyme inhibition; O-GlcNAcase; click chemistry; azide; β-N-acetylhexosaminidase
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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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.

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