Chemical synthesis, inhibitory activity and molecular mechanism of 1-deoxynojirimycin-chrysin as a potent alpha-glucosidase inhibitor

Hyperglycemia can be efficaciously regulated by inhibiting alpha-glucosidase activity and this is regarded as an effective strategy to treat type 2 diabetes. 1-Deoxynojimycin, an alpha-glucosidase inhibitor, can penetrate cells rapidly to potently inhibit alpha-glucosidase in a competitive manner. However, the application of 1-deoxynojimycin is limited by its poor lipophilicity and low bioavailability. Herein, three 1-deoxynojimycin derivatives 4-6 were designed and synthesized by linking 1-deoxynojimycin and chrysin to ameliorate the limitations of 1-deoxynojimycin. Among them, compound 6, a conjugate of 1-deoxynojimycin and chrysin linked by an undecane chain, could better bind to the alpha-glucosidase catalytic site, thereby exhibiting excellent alpha-glucosidase inhibitory activity (IC50 = 0.51 +/- 0.02 mu M). Kinetics analyses revealed that compound 6 inhibited the activity of alpha-glucosidase in a reversible and mixed competitive manner. Fluorescence quenching and UV-Vis spectra showed that compound 6 changed the conformation of the alpha-glucosidase via complex formation, which triggered a static fluorescence quenching of the enzyme protein.