title: Inhibition of GlcNAc-processing glycosidases by C-6-azido-NAG-thiazoline and its derivatives.
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.
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic. hoficek@centrum.cz.
authors.forename: Jana
authors.initials: J
authors.lastname: Krejzová
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic. shimon@seznam.cz.
authors.forename: Petr
authors.initials: P
authors.lastname: Simon
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic. kalachova@biomed.cas.cz.
authors.forename: Lubica
authors.initials: L
authors.lastname: Kalachova
authors.affiliation: 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. kulik@nh.cas.cz.
authors.forename: Natallia
authors.initials: N
authors.lastname: Kulik
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic. fialovap@email.cz.
authors.forename: Pavla
authors.initials: P
authors.lastname: Bojarová
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic. rtepm@seznam.cz.
authors.forename: Petr
authors.initials: P
authors.lastname: Marhol
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic. pelantova@biomed.cas.cz.
authors.forename: Helena
authors.initials: H
authors.lastname: Pelantová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Praha 6, Czech Republic. cvacka@uochb.cas.cz.
authors.forename: Josef
authors.initials: J
authors.lastname: Cvačka
authors.affiliation: 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. ettrich@nh.cas.cz.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Ettrich
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic. slamova.kristyna@gmail.com.
authors.forename: Kristýna
authors.initials: K
authors.lastname: Slámová
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic. kren@biomed.cas.cz.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Křen
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D004355:Drug Stability; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D013844:Thiazoles; D006026:Glycoside Hydrolases; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; C487818:N-acetylglucosamine thiazoline; D000117:Acetylglucosamine