Glucose-Based Molecular Rotors as Fluorescent Inhibitors and Probes of Glycogen Phosphorylase Function

Glycogen phosphorylase (GP) is an enzyme with a key role in glucose homeostasis. Dysregulation of GP is involved in a number of pathological states such as Type 2 diabetes and cancer, while recent findings connect GP to Alzheimer’s disease and a number of other neurological disorders. The ubiquitous presence of GP has ascended the design and synthesis of GP activity-modulating agents into an exciting field in chemical research. Our team has been working on the synthesis and study of potential GP inhibitors, with the main aim to create new agents against Type 2 diabetes.

Herein, the synthesis and photochemical study of a (β-D-glucopyranosyl)julolidine analogue (GPJ), a fluorescent inhibitor of glycogen phosphorylase with properties of a molecular rotor, are reported. A straightforward synthesis involved the condensation of the corresponding acryloyl chloride with peracetylated β-D-glucopyranosylamine followed by deprotection. Fluorescence measurements in mixtures of ethylene glycol:glycerol solutions of increasing viscosity determined that the fluorescence intensity increases with the viscosity of the medium, indicating that GPJ exhibits the characteristics of a molecular rotor. GPJ does not fluoresce in aqueous buffer solution but, in the presence of increasing amounts of GP, we observed an increase of fluorescence intensity, attributed to the GP:RotA complex. It is expected that this new molecular rotor will find in vitro and in vivo applications as a molecular probe of its interaction with GP, in a cellular environment.