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

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

1,2,†email, 1,3,†email, 1email, 4email, 1email, 1email, 1email, 5email, 4email, 1,* email and 1email
Received: 4 February 2014; in revised form: 6 March 2014 / Accepted: 13 March 2014 / Published: 20 March 2014
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.
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
PDF Full-text Download PDF Full-Text [1057 KB, uploaded 18 June 2014 20:36 CEST]

Export to BibTeX |

MDPI and ACS Style

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.

AMA Style

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.

Chicago/Turabian Style

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.

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert