4ej2

Publication Abstract from PubMed

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-(beta-d-glucopyranosyl)-5-ethynyluracil (K(i)=4.7muM). Crystallographic analysis of these compounds in complex with GPb revealed that inhibitors with a long C5-alkynyl group exploited interactions with beta-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 beta-pocket. The best of the inhibitors had also a moderate effect on glycogenolysis in the cellular lever with an IC(50) value of 291.4muM.

The binding of C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides to glycogen phosphorylase b: Synthesis, biochemical and biological assessment.,Kantsadi AL, Manta S, Psarra AM, Dimopoulou A, Kiritsis C, Parmenopoulou V, Skamnaki VT, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D Eur J Med Chem. 2012 Jun 22. PMID:22770609^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.