Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose.

Synthetic allosteric activators of human glucokinase are receiving considerable attention as potential diabetes therapeutic agents. Although their mechanism of action is not fully understood, structural studies suggest that activator association requires prior formation of a binary enzyme-glucose complex. Here, we demonstrate that three previously described activators associate with glucokinase in a glucose-independent fashion.

Asymmetric synthesis of 4'-ethoxy-2',3'-didehydro-2',3'-dideoxynucleosides by palladium-catalyzed kinetic discrimination between the corresponding diastereoisomeric lactol acetates.

4'-Substituted nucleoside analogues have been synthesized using palladium-catalyzed asymmetric allylic amination conditions. A kinetic discrimination between the diastereomeric lactol acetates (3) produced the desired aminated products (6a-d) and recovered acetate (alpha-3) in high yields and <97:3 diastereoselectivity. Epimerization of the recovered lactol acetate (alpha-3) produced a 60:40 alpha/beta mixture of (3), which could be resubjected, in principle, to the palladium-catalyzed asymmetric allylic amination conditions.