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

David Goyard (1) , Tibor Docsa (2) , Pál Gergely (2) , Jean-Pierre Praly (1) , Sébastien Vidal (1)

1 CO2GLYCO - Chimie Organique 2-Glycochimie
2 Department of Medicinal Chemistry

Glycogen 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).

Keywords: Click chemistry, Carbohydrate, Triazole, Inhibitor, Glycogen phosphorylase

Domains: Organic chemistry

David Goyard, Tibor Docsa, Pál Gergely, Jean-Pierre Praly, Sébastien Vidal. Synthesis of 4-amidomethyl-1-glucosyl-1,2,3-triazoles and evaluation as glycogen phosphorylase inhibitors. Carbohydrate Research, 2015, 402, pp.245-251. ⟨10.1016/j.carres.2014.10.009⟩. ⟨hal-02123965⟩