Identification of a potent activator of Akt phosphorylation from a novel series of phenolic, picolinic, pyridino, and hydroxamic zinc(II) complexes
作者:Savvas N. Georgiades、Lok Hang Mak、Inmaculada Angurell、Evelyn Rosivatz、M. Firouz Mohd Mustapa、Christoulla Polychroni、Rudiger Woscholski、Ramon Vilar
DOI:10.1007/s00775-010-0716-0
日期:2011.2
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
信号通路的小分子调节剂的发现是目前特别活跃的研究领域。我们的目标是开发前所未有的基于金属的 Akt 信号传导激活剂,这些激活剂有可能用作调节 Akt 下游葡萄糖代谢的工具或用作开发抗糖尿病药物的先导结构。在这种情况下,制备了一个高度多样化的 11 种新型锌 (II) 配合物文库,其中含有酚类、吡啶啉、吡啶和异羟肟配体,所有这些都包含对药用有益的特征,并在检测中筛选出磷酸化 Akt 水平用化合物处理后来自 NIH3T3 细胞的裂解物。发现以异羟肟配体为特征的复合物是制备的分子中最突出的 Akt 激活剂,最有效的化合物在亚微摩尔浓度下起作用。进一步表征表明,该化合物诱导 Akt 下游效应子糖原合酶激酶 3beta 的磷酸化,但不作为酪氨酸磷酸酶或 PTEN 的抑制剂。