title: Copper(II) complexes of hybrid hydroxyquinoline-thiosemicarbazone ligands: GSK3β inhibition due to intracellular delivery of copper.
abstract: 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.
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: James L
authors.initials: JL
authors.lastname: Hickey
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Sithorn
authors.initials: S
authors.lastname: Mey
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Caragounis
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
mesh_terms: D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry*; D008024:Ligands; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet; D013882:Thiosemicarbazones / Q000737:chemistry*
chemical_list: D056831:Coordination Complexes; D006912:Hydroxyquinolines; D008024:Ligands; D013882:Thiosemicarbazones; D003300:Copper; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3