Synthesis of 4-amidomethyl-1-glucosyl-1,2,3-triazoles and evaluation as glycogen phosphorylase inhibitors.

International audienceGlycogen phosphorylase (GP) appears as a key enzyme for the control of hyperglycemia in the context of type 2 diabetes. In order to gain additional data for structure-activity studies of the inhibition of this enzyme, a series of eight GP inhibitor candidates were prepared from peracetylglucopyranosyl azide 1 by click-chemistry. The need for a N-Boc-protected propargylamine was identified in the CuAAC with azide 1 under Meldal's conditions, while Sharpless' conditions were better adapted to the CuAAC of azide 1 with propargyl bromide. Cycloaddition of Boc-propargylamine with azide 1 afforded the N-Boc precursor of a 4-aminomethyl-1-glucosyl-1,2,3-triazole which gave access to a series of eight amide and sulfonamide derivatives. After deacetylation, enzymatic studies revealed poor to moderate inhibitions toward this enzyme. The N-Boc-protected amine was the best inhibitor (IC50=620 μM) unexpectedly slightly better than the 2-naphthylamido substituted analogue (IC50=650 μM)

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

International audienceVarious 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

Anomeric Spiro-Annulated Glycopyranosides: An Overview of Synthetic Methodologies and Biological Applications

International audienceOrganic chemistry developed a series of synthetic strategies toward spiro-annulated carbohydrates as potential pharmaceutical drugs or developed new organic synthetic methodologies. The present chapter gives a general overview of the spiro-annulation of carbohydrates at the anomeric position. The main synthetic strategies can be summarized in five paths. Intramolecular cyclizations can be performed through two short tethers with their reactive ends generating th