3-Glucosylated 5-amino-1,2,4-oxadiazoles: synthesis and evaluation as glycogen phosphorylase inhibitors.

Marion Donnier-Maréchal,Vincent Folliard,Jean-Pierre Praly,David Goyard,Tibor Docsa,Sébastien Vidal,Pal Gergely

doi:10.3762/bjoc.11.56

Abstract

Glycogen phosporylase (GP) is a promising target for the control of glycaemia. The design of inhibitors binding at the catalytic site has been accomplished through various families of glucose-based derivatives such as oxadiazoles. Further elaboration of the oxadiazole aromatic aglycon moiety is now reported with 3-glucosyl-5-amino-1,2,4-oxadiazoles synthesized by condensation of a C-glucosyl amidoxime with N,N’-dialkylcarbodiimides or Vilsmeier salts. The 5-amino group introduced on the oxadiazole scaffold was expected to provide better inhibition of GP through potential additional interactions with the enzyme’s catalytic site; however, no inhibition was observed at 625 µM.

Highlights

Glycogen phosphorylase (GP) is a homodimeric enzyme that is responsible for the depolymerization of glycogen into glucose1-phosphate, which is further converted into glucose delivered into the blood stream [1,2]
The present study reports on the introduction of such amino groups between the oxadiazole and aromatic cores
The target GP inhibitor scaffold was obtained from the condensation of Vilsmeier salts with the C-glucosyl-amidoxime 3 [28] in the presence of a base

Summary

Introduction

Glycogen phosphorylase (GP) is a homodimeric enzyme that is responsible for the depolymerization of glycogen into glucose1-phosphate, which is further converted into glucose delivered into the blood stream [1,2]. The isomeric 1,2,4-triazole E was recently identified as a sub-micromolar GP inhibitor [20,21] and highlights the influence of the aromatic moiety used in these studies. Inhibition could be restored by introducing a nitrogen atom (NH) between the glucosyl and aromatic aglycon (I [26]), while introduction on the other position (J [27]) did not help.

Results

Conclusion