Title:
{Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-($\beta$-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase}
Languages of Item:
English
Abstract:
Dysregulation of glycogen phosphorylase, an enzyme involved in glucose homeostasis, may lead to a number of pathological states such as type 2 diabetes and cancer, making it an important molecular target for the development of new forms of pharmaceutical intervention. Based on our previous work on the design and synthesis of 4-arylamino-1-($\beta$-d-glucopyranosyl)pyrimidin-2-ones, which inhibit the activity of glycogen phosphorylase by binding at its catalytic site, we report herein a general synthesis of 2-substituted-5-($\beta$-d-glucopyranosyl)pyrimidin-4-ones, a related class of metabolically stable, C-glucosyl-based, analogues. The synthetic development consists of a metallated heterocycle, produced from 5-bromo-2-methylthiouracil, in addition to protected d-gluconolactone, followed by organosilane reduction. The methylthio handle allowed derivatization through hydrolysis, ammonolysis and arylamine substitution, and the new compounds were found to be potent ($\mu$M) inhibitors of rabbit muscle glycogen phosphorylase. The results were interpreted with the help of density functional theory calculations and conformational analysis and were compared with previous findings.
Authors:
Konstantinos F. Mavreas
Dionysios D. Neofytos
Evangelia D. Chrysina
Alessandro Venturini
Thanasis Gimisis
Keywords:
5-,cancer,catalytic site inhibitors,dft conformational analysis,glycogen phosphorylase,pyrimidin-4-one synthesis,type 2 diabetes,$\beta$ - d -glucopyranosyl
Main subject category:
Science
Official URL (Publisher):
DOI:
10.3390/molecules25225463
