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

Molecules

Jana Krejzová²  Petr Šimon²  Lubica Kalachova²  Natallia Kulik³  Pavla Bojarová²  Petr Marhol²  Helena Pelantová²  Josef Cvačka¹  R࿍iger Ettrich³  Kristýna Slámová² 

[1] Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Praha 6, Czech Republic; E-Mail:;Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic; E-Mails:;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; E-Mails:

关键词: NAG-thiazoline;    enzyme inhibition;    O-GlcNAcase;    click chemistry;    azide;    β-N-acetylhexosaminidase;   

DOI  :  10.3390/molecules19033471

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.