Anomeric Spironucleosides of β-d-Glucopyranosyl Uracil as Potential Inhibitors of Glycogen Phosphorylase.

Aggeliki Stathi,Michael Mamais,Thanasis Gimisis,Evangelia D Chrysina

doi:10.3390/molecules24122327

Abstract

In the case of type 2 diabetes, inhibitors of glycogen phosphorylase (GP) may prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production by the liver. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry and important biological function (e.g., inhibition of GP). For this study, the Suárez radical methodology was successfully applied to synthesize the first example of a 1,6-dioxa-4-azaspiro[4.5]decane system, not previously constructed via a radical pathway, starting from 6-hydroxymethyl-β-d-glucopyranosyluracil. It was shown that, in the rigid pyranosyl conformation, the required [1,5]-radical translocation was a minor process. The stereochemistry of the spirocycles obtained was unequivocally determined based on the chemical shifts of key sugar protons in the 1H-NMR spectra. The two spirocycles were found to be modest inhibitors of RMGPb.

Highlights

Despite the prevalence of type 2 diabetes worldwide, no sufficient treatment has been identified; a molecular approach based on the three-dimensional structure of enzymes directly involved in glycogen metabolism has received increasing attention
Since glucose is the physiological substrate of Glycogen phosphorylase (GP), it promotes the inactive form of the enzyme acting synergistically with insulin towards reducing the rate of glycogen degradation and shifting the equilibrium towards glycogen synthesis
A major product formed under these conditions, spectral analysis revealed that it was the a major product formed under these conditions, spectral analysis revealed that it was the product of a selective mono-debenzylation and did not contain a formyl group

Summary

Introduction

Despite the prevalence of type 2 diabetes worldwide, no sufficient treatment has been identified; a molecular approach based on the three-dimensional structure of enzymes directly involved in glycogen metabolism has received increasing attention. Glycogen phosphorylase (GP) is an allosteric enzyme with a regulatory role in glycogen breakdown to glucose [1]. GP three-dimensional structure in the T state (GPb) has been exploited as a target for the design of glucose-based compounds that inhibit enzymic action preventing glycogenolyis and acting as regulators of glucose levels in the bloodstream [2,3]. One of the early lead inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb) was pyranosyl spironucleosides [5] (2a,b, Figure 1), the structure of which was inspired from hydantocidin (1), a natural spiro compound with herbicidal and plant growth regulatory activity

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