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

• Published in: Carbohydrate research 2015-01, Vol.402, p.245-251
• Main Authors: Goyard, David, Docsa, Tibor, Gergely, Pál, Praly, Jean-Pierre, Vidal, Sébastien
• Format: Article
• Language: English
• Subjects: Animals; Carbohydrate; Chemical Sciences; Chemistry Techniques, Synthetic; Click chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glycogen phosphorylase; Glycogen Phosphorylase - antagonists & inhibitors; Glycosylation; Hydrophobic and Hydrophilic Interactions; Inhibitor; Organic chemistry; Rabbits; Stereoisomerism; Structure-Activity Relationship; Triazole; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0008-6215; 1873-426X; 0008-6215
• DOI: 10.1016/j.carres.2014.10.009

[Display omitted] •Glycogen phosphorylase is a target enzyme for the regulation of glycemia in the context of type 2 diabetes.•Synthesis of 4-amidomethyl-1-glucosyl-1,2,3-triazoles was achieved from the condensation of glucosyl azide and Boc-protected propargyl amine.•Inhibition of GP was in the high micromolar range for the designed inhibitors.•The Boc-carbamate group could be identified as a potential pharmacophore for the inhibition of GP. 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=620μM) unexpectedly slightly better than the 2-naphthylamido substituted analogue (IC50=650μM).