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

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...

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Autores principales: Krejzová, Jana, Šimon, Petr, Kalachova, Lubica, Kulik, Natallia, Bojarová, Pavla, Marhol, Petr, Pelantová, Helena, Cvačka, Josef, Ettrich, Rüdiger, Slámová, Kristýna, Křen, Vladimír
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271965/
https://www.ncbi.nlm.nih.gov/pubmed/24658571
http://dx.doi.org/10.3390/molecules19033471
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author Krejzová, Jana
Šimon, Petr
Kalachova, Lubica
Kulik, Natallia
Bojarová, Pavla
Marhol, Petr
Pelantová, Helena
Cvačka, Josef
Ettrich, Rüdiger
Slámová, Kristýna
Křen, Vladimír
author_facet Krejzová, Jana
Šimon, Petr
Kalachova, Lubica
Kulik, Natallia
Bojarová, Pavla
Marhol, Petr
Pelantová, Helena
Cvačka, Josef
Ettrich, Rüdiger
Slámová, Kristýna
Křen, Vladimír
author_sort Krejzová, Jana
collection PubMed
description 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.
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spelling pubmed-62719652018-12-20 Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives Krejzová, Jana Šimon, Petr Kalachova, Lubica Kulik, Natallia Bojarová, Pavla Marhol, Petr Pelantová, Helena Cvačka, Josef Ettrich, Rüdiger Slámová, Kristýna Křen, Vladimír Molecules Article 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. MDPI 2014-03-20 /pmc/articles/PMC6271965/ /pubmed/24658571 http://dx.doi.org/10.3390/molecules19033471 Text en © 2014 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Krejzová, Jana
Šimon, Petr
Kalachova, Lubica
Kulik, Natallia
Bojarová, Pavla
Marhol, Petr
Pelantová, Helena
Cvačka, Josef
Ettrich, Rüdiger
Slámová, Kristýna
Křen, Vladimír
Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives
title Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives
title_full Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives
title_fullStr Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives
title_full_unstemmed Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives
title_short Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives
title_sort inhibition of glcnac-processing glycosidases by c-6-azido-nag-thiazoline and its derivatives
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271965/
https://www.ncbi.nlm.nih.gov/pubmed/24658571
http://dx.doi.org/10.3390/molecules19033471
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