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

Abstract

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).

• Authors: David Goyard, Tibor Docsa, Pál Gergely, Jean-Pierre Praly, Sébastien Vidal
• Journal: Carbohydrate research (Carbohydr Res) Vol. 402 Pg. 245-51 (Jan 30 2015) ISSN: 1873-426X [Electronic] Netherlands
• PMID: 25498027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Triazoles
• Glycogen Phosphorylase

Topics

• Animals
• Chemistry Techniques, Synthetic
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Glycogen Phosphorylase (antagonists & inhibitors)
• Glycosylation
• Hydrophobic and Hydrophilic Interactions
• Rabbits
• Stereoisomerism
• Structure-Activity Relationship
• Triazoles (chemical synthesis, chemistry, pharmacology)