Identification of a potent activator of Akt phosphorylation from a novel series of phenolic,picolinic, pyridino,and hydroxamic zinc(II) complexes |
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Authors: | Savvas N Georgiades Lok Hang Mak Inmaculada Angurell Evelyn Rosivatz M Firouz Mohd Mustapa Christoulla Polychroni Rudiger Woscholski Ramon Vilar |
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Institution: | (1) Department of Chemistry, Imperial College London, Exhibition Road, London, SW7 2AZ, UK;(2) Division of Cell and Molecular Biology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK; |
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Abstract: | 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. |
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