Copper(ii ) complexes of hybrid hydroxyquinoline-thiosemicarbazone ligands: GSK3β inhibition due to intracellular delivery of copper
| Autor: | James L. Hickey, Jonathan M. White, Aphrodite Caragounis, Anthony R. White, Peter J. Crouch, Paul S. Donnelly, Sithorn Mey |
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| Rok vydání: | 2011 |
| Předmět: |
Thiosemicarbazones
Cell Membrane Permeability Inorganic chemistry Molecular Conformation chemistry.chemical_element Crystallography X-Ray Ligands Electrochemistry Inorganic Chemistry Metal Glycogen Synthase Kinase 3 Coordination Complexes GSK-3 Cell Line Tumor Humans Cognitive decline GSK3B Metal ion homeostasis Glycogen Synthase Kinase 3 beta Chemistry Copper visual_art Hydroxyquinolines visual_art.visual_art_medium Biophysics Spectrophotometry Ultraviolet Oxidation-Reduction Intracellular |
| Zdroj: | Dalton Trans.. 40:1338-1347 |
| ISSN: | 1477-9234 1477-9226 |
| DOI: | 10.1039/c0dt01176b |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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