Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA)

O-GlcNAcylation or O-GlcNAc modification is a post-translational modification of several proteins responsible for fundamental cellular processes. Dysregulation of the O-GlcNAc pathway has been linked to the etiology of several diseases such as neurodegenerative and cardiovascular diseases, type 2 di...

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Published in:	Carbohydrate research Vol. 471; pp. 43 - 55
Main Authors:	Igual, Michelle O., Nunes, Paulo S.G., da Costa, Rafael M., Mantoani, Susimaire P., Tostes, Rita C., Carvalho, Ivone
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Ltd 01-01-2019
Subjects:	1,2,3-Triazole Click chemistry O-GlcNAcase O-GlcNAcylation Selective inhibitors O-GlcNAcase O-GlcNAcylation Selective inhibitors Click chemistry 1,2,3-Triazole
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Summary:	O-GlcNAcylation or O-GlcNAc modification is a post-translational modification of several proteins responsible for fundamental cellular processes. Dysregulation of the O-GlcNAc pathway has been linked to the etiology of several diseases such as neurodegenerative and cardiovascular diseases, type 2 diabetes and cancer. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from the modified proteins and several carbohydrate-based OGA inhibitors have been synthesized to understand the role of O-GlcNAc-modified proteins in physiological and pathological conditions. However, many of the inhibitors lack selectivity for OGA over lysosomal hexosaminidases A and B. Aiming the selectively inhibition of OGA, we propose herein the synthesis of twelve novel glucopyranoside derivatives exploring the bioisosteric replacement of the GlcNAc 2-acetamide group by 1,4-disubstituted 1,2,3-triazole ring, bearing a variety of central chains with different shapes. Compounds were readily prepared through "Copper(I) Catalyzed Azide/Alkyne Cycloaddition" (CuAAC) reaction between a sugar azide and different terminal alkynes. Initial Western Blot analyses and further inhibitory assays proved that compounds 6a (IC50 = 0.50 ± 0.02 μM, OGA), 6k (IC50 = 0.52 ± 0.01 μM, OGA) and 6l (IC50 = 0.72 ± 0.02 μM, OGA) were the most potent and selective compounds of the series. Structure-activity relationship analyses and molecular docking simulations demonstrated that the bridge of two-carbon atoms between the C-4 position of the triazole and the phenyl ring (6a), which may be replaced by heteroatoms such as N (6k) or O (6l), is fundamental for accommodation and inhibition within OGA catalytic pocket. [Display omitted] •Twelve novel glucopyranoside C2-derived 1,2,3-triazoles were synthesized.•Three derivatives were qualitatively similar to Thiamet-G in augmenting O-GlcNAc-modified proteins levels.•The most potent inhibitors exhibited low micromolar activity toward OGA and high selectivity for OGA over HexA and B.•The central chain extension between the triazole and the phenol ring plays a critical role for OGA activity.•Glucopyranoside C2-derived 1,2,3-triazoles may be novel promising therapeutic candidates.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-6215 1873-426X
DOI:	10.1016/j.carres.2018.10.007