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

Author(s)

Igual, Michelle O. ^[1] ; Nunes, Paulo S. G. ^[1] ; da Costa, Rafael M. ^[2] ; Mantoani, Susimaire P. ^[1] ; Tostes, Rita C. ^[2] ; Carvalho, Ivone ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Ave Cafe S-N, BR-14040930 Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto - Brazil

• Document type: Review article
• Source: Carbohydrate Research; v. 471, p. 43-55, JAN 1 2019.
• Web of Science Citations: 2

Abstract

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 mu M, OGA), 6k (IC50=0.52 +/- 0.01 mu M, OGA) and 6l (IC50=0.72 +/- 0.02 mu M, 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. (AU)

• FAPESP's process: 16/04003-2 - Design, synthesis and biological evaluation of novel selective inhibitors of the hydrolase O-GlcNAcase (OGA)
• Grantee: Michelle Ogava Igual
• Support Opportunities: Scholarships in Brazil - Master