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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

1,2,†
, 1,3,†
, 1
, 4
, 1
, 1
, 1
, 5
, 4
, 1,*  and 1
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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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