Identification of a potent activator of Akt phosphorylation from a novel series of phenolic, picolinic, pyridino, and hydroxamic zinc(II) complexes.

The discovery of small-molecule modulators of signaling pathways is currently a particularly active area of research. We aimed at developing unprecedented metal-based activators of Akt signaling which can potentially find applications as tools for regulating glucose metabolism downstream of Akt or serve as lead structures for developing antidiabetic drugs. In this context, a highly diverse library of 11 new zinc(II) complexes with phenolic, picolinic, pyridino, and hydroxamic ligands, all containing features beneficial for medicinal purposes, was prepared and screened in an assay that detected levels of phospho-Akt in lysates from NIH3T3 cells after treatment with the compounds. The complexes featuring hydroxamic ligands were found to be the most prominent activators of Akt among the molecules prepared, with the most efficient compound acting at submicromolar concentrations. Further characterization revealed that this compound induces phosphorylation of the Akt downstream effector glycogen synthase kinase 3β, but does not act as an inhibitor of tyrosine phosphatases or PTEN.