Synthesis of 1,2,3-triazoles from xylosyl and 5-thioxylosyl azides: evaluation of the xylose scaffold for the design of potential glycogen phosphorylase inhibitors

Various acetylenic derivatives and acetylated β-d-xylopyranosyl azide or the 5-thio-β-d-xylopyranosyl analogue were coupled by Cu(I)-catalyzed azide alkyne 1,3-dipolar cycloaddition (CuAAC) to afford a series of 1-xylosyl-4-substituted 1,2,3-triazoles. Controlled oxidation of the endocyclic sulfur atom of the 5-thioxylose moiety led to the corresponding sulfoxides and sulfones. Deacetylation afforded 19 hydroxylated xylose and 5-thioxylose derivatives, found to be only sparingly water-soluble. Compared to glucose-based analogues, they appeared to be much weaker inhibitors of glycogen phosphorylase, as the absence of a hydroxymethyl group weakens their binding at the enzyme active site. However, such new xylose derivatives might be useful glycomimetics.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of three families of xylose-, and thioxylose-based triazoles by CuAAC cycloaddition. ► Oxidation of 5-thioxylose derivatives to sulfoxides and sulfones. ► Kinetic studies with 19 O-unprotected molecules showing no or poor inhibition of glycogene phosphorylase (GP). ► Discussion about the choice of the xylose scaffold (advantages and limitations) for GP inhibition.