Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase.

Konstantinos F Mavreas,Dionysios D Neofytos,Evangelia D Chrysina,Thanasis Gimisis,Alessandro Venturini

doi:10.3390/molecules25225463

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-(β-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-(β-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 (μM) 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.

Highlights

The glycogen phosphorylase (GP) enzyme plays a key role in glucose homeostasis in mammals through the catabolism of glycogen to readily available glucose
Numerous methods for the synthesis of C-glucosyl compounds have been developed over the past decades decades
We propose that the above analysis provides an explanation for the profound 45-fold decrease showed that GLAC’s most stable and populated s-cis/s-trans conformation in solution is the one in Ψ-GLAC’s inhibitory activity towards RMGP when compared with GLAC

Summary

Introduction

The glycogen phosphorylase (GP) enzyme plays a key role in glucose homeostasis in mammals through the catabolism of glycogen to readily available glucose. The discovery of the expression of all isoforms of GP in cancerous tissues [4,5,6,7] is illustrated well in the Human Protein. Apart from providing an energy source, GP expression has been reported to be associated with activation of the pentose phosphate pathway (PPP), decreased levels of reactive oxygen species (ROS) and cell proliferation [9]. These findings have led to a number of works on new possible lines of cancer treatment [10,11,12,13]. There has been renewed interest in elucidating the exact function of the brain isoform of GP expressed in astrocytes [14]

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Conclusion