The binding of C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides to glycogen phosphorylase b: synthesis, biochemical and biological assessment

Eur J Med Chem. 2012 Aug:54:740-9. doi: 10.1016/j.ejmech.2012.06.029. Epub 2012 Jun 22.


C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides have been synthesized and studied as inhibitors of glycogen phosphorylase b (GPb). Kinetic experiments have shown that most of these compounds were low micromolar inhibitors of the enzyme. The best inhibitor was 1-(β-D-glucopyranosyl)-5-ethynyluracil (K(i)=4.7 μM). Crystallographic analysis of these compounds in complex with GPb revealed that inhibitors with a long C5-alkynyl group exploited interactions with β-pocket of the active site and induced significant conformational changes of the 280s loop compared to GPb in complex with compounds with a short C5-alkynyl group. The results highlight the importance in the length of the aliphatic groups used to enhance inhibitory potency for the exploitation of the hydrophobic β-pocket. The best of the inhibitors had also a moderate effect on glycogenolysis in the cellular lever with an IC(50) value of 291.4 μM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / chemistry*
  • Animals
  • Catalytic Domain
  • Chemistry Techniques, Synthetic
  • Glycogen Phosphorylase / chemistry
  • Glycogen Phosphorylase / metabolism*
  • Hep G2 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / metabolism*
  • Molecular Docking Simulation*
  • Protein Binding
  • Pyrimidine Nucleosides / chemical synthesis*
  • Pyrimidine Nucleosides / chemistry
  • Pyrimidine Nucleosides / metabolism*
  • Rabbits


  • Alkynes
  • Hypoglycemic Agents
  • Pyrimidine Nucleosides
  • Glycogen Phosphorylase