title: Characterization of new specific copper chelators as potential drugs for the treatment of Alzheimer's disease.
abstract: The non-controlled redox-active metal ions, especially copper, in the brain of patients with Alzheimer disease (AD) should be considered at the origin of the intense oxidative damage in the AD brain. Several bis(8-aminoquinoline) ligands, such as 1 and PA1637, are able to chelate Cu(2+) with high affinity, and are specific chelators of copper with respect to iron and zinc. They are able to efficiently extract Cu(2+) from a metal-loaded amyloid. In addition, these tetradentate ligands are specific for the chelation of Cu(2+) compared with Cu(+). Consequently, the copper ion is easily released from the bis(8-aminoquinoline) ligand under reductive conditions, and can be trapped again by a protein having some affinity for copper such as human serum albumin (HSA) proteins. In addition, the copper is not efficiently released from [Cu(CQ)2] in reductive conditions. The catalytic production of H2O2 by [Cu(2+)-Aβ(1-28)]/ascorbate is inhibited in vitro by the bis(8-aminoquinoline) 1, suggesting that 1 should be able to play a protective role against oxidative damages induced by copper-loaded amyloids.
authors.affiliation: Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, BP 44099, 31077 Toulouse cedex 4 (France).
authors.forename: Michel
authors.initials: M
authors.lastname: Nguyen
authors.forename: Anne
authors.initials: A
authors.lastname: Robert
authors.forename: Alix
authors.initials: A
authors.lastname: Sournia-Saquet
authors.forename: Laure
authors.initials: L
authors.lastname: Vendier
authors.forename: Bernard
authors.initials: B
authors.lastname: Meunier
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000634:Aminoquinolines / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004355:Drug Stability; D055664:Electrochemical Techniques; D004566:Electrodes; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007700:Kinetics; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D056831:Coordination Complexes; D012709:Serum Albumin; D003300:Copper; D006861:Hydrogen Peroxide; C080436:8-aminoquinoline
keywords: amyloid beta-peptides; chelates; copper; ligands; metalation