3t3i

Publication Abstract from PubMed

C5 halogen substituted glucopyranosyl nucleosides (1-(beta-D-glucopyranosyl)-5-X-uracil; X=Cl, Br, I) have been discovered as some of the most potent active site inhibitors of glycogen phosphorylase (GP), with respective K(i) values of 1.02, 3.27, and 1.94 muM. The ability of the halogen atom to form intermolecular electrostatic interactions through the sigma-hole phenomenon rather than through steric effects alone forms the structural basis of their improved inhibitory potential relative to the unsubstituted 1-(beta-D-glucopyranosyl)uracil (K(i) =12.39 muM), as revealed by X-ray crystallography and modeling calculations exploiting quantum mechanics methods. Good agreement was obtained between kinetics results and relative binding affinities calculated by QM/MM-PBSA methodology for various substitutions at C5. Ex vivo experiments demonstrated that the most potent derivative (X=Cl) toward purified GP has no cytotoxicity and moderate inhibitory potency at the cellular level. In accordance, ADMET property predictions were performed, and suggest decreased polar surface areas as a potential means of improving activity in the cell.

The sigma-Hole Phenomenon of Halogen Atoms Forms the Structural Basis of the Strong Inhibitory Potency of C5 Halogen Substituted Glucopyranosyl Nucleosides towards Glycogen Phosphorylase b.,Kantsadi AL, Hayes JM, Manta S, Skamnaki VT, Kiritsis C, Psarra AM, Koutsogiannis Z, Dimopoulou A, Theofanous S, Nikoleousakos N, Zoumpoulakis P, Kontou M, Papadopoulos G, Zographos SE, Komiotis D, Leonidas DD ChemMedChem. 2012 Jan 20. doi: 10.1002/cmdc.201100533. PMID:22267166^[1]

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