School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
Dalton Trans. 2011 Feb 14;40(6):1338-47. doi: 10.1039/c0dt01176b. Epub 2010 Dec 21.
Cognitive decline associated with Alzheimer's disease appears to be related to the hyper-phosphorylation of the protein tau as a consequence of increased activity of glycogen synthase kinase 3β (GSK3β), and subsequent formation of neurotoxic neurofibrillary tangles. Abberant metal ion homeostasis, particularly involving copper has been implicitly linked to the pathogenesis of the disease. Increasing intracellular copper concentrations has been found to trigger pathways that result in inhibition of GSK3β. The syntheses and characterisation of tetradentate hybrid hydroxyquinoline-thiosemicarbazone proligands is presented. The ligands form stable complexes with Cu(II) where the copper ion is four coordinate and essentially square planar as characterised by single crystal X-ray crystallography. The reduction of the metal ion to Cu(I) has been studied by electrochemical techniques and occurs at potentials that permit intracellular reduction. The new complexes show class dependent cell membrane permeability in neuronal-like SH-SY5Y cells with subsequent increases in intracellular copper concentrations. The increased intracellular copper results in a dose-dependent inhibition (phosphorylation) of GSK3β.
与阿尔茨海默病相关的认知能力下降似乎与蛋白质 tau 的过度磷酸化有关，这是由于糖原合酶激酶 3β（GSK3β）活性增加，以及随后形成神经毒性神经原纤维缠结所致。异常的金属离子动态平衡，特别是涉及铜，与疾病的发病机制密切相关。已经发现增加细胞内铜浓度会触发导致 GSK3β 抑制的途径。本文介绍了四齿混合羟喹啉-缩氨基硫脲前配体的合成和表征。这些配体与 Cu(II)形成稳定的配合物，其中铜离子是四配位的，基本上是平面正方形，通过单晶 X 射线晶体学进行了表征。通过电化学技术研究了金属离子还原为 Cu(I)的情况，其发生的电位允许细胞内还原。新的配合物在神经元样 SH-SY5Y 细胞中表现出与类别相关的细胞膜通透性，随后细胞内铜浓度增加。增加的细胞内铜导致 GSK3β 的剂量依赖性抑制（磷酸化）。
