title: 8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation.
abstract: One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid-β (Aβ) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the Aβ peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of Aβ plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8-H2QH), a thiosemicarbazone (8-H2QT), and a semicarbazone (8-H2QS) derived from 8-hydroxyquinoline. The three compounds are shown to be neutral at pH7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with Cu(II), 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the Aβ1-40 peptide showed that 8-H2QS and 8-H2QH inhibit peptide aggregation in the presence of Cu(II). Native gel electrophoresis/Western blot and TEM images were obtained to give a more detailed picture of the extent and pathways of Aβ aggregation using the more neurotoxic Aβ1-42 in the presence and absence of Cu(II), 8-H2QH, 8-H2QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of Cu(II). However, in the presence of ligands and Cu(II), the results match those for the peptide alone, suggesting that the ligands function by sequestering Cu(II) and limiting oligomer formation in this assay.
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil; Department of Chemistry, Simon Fraser University, V5A-1S6 Burnaby, BC, Canada.
authors.forename: Luiza M F
authors.initials: LM
authors.lastname: Gomes
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil; Department of Chemistry, Simon Fraser University, V5A-1S6 Burnaby, BC, Canada.
authors.forename: Rafael P
authors.initials: RP
authors.lastname: Vieira
authors.affiliation: Department of Chemistry, Simon Fraser University, V5A-1S6 Burnaby, BC, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jones
authors.affiliation: Department of Chemistry, Simon Fraser University, V5A-1S6 Burnaby, BC, Canada.
authors.forename: Michael C P
authors.initials: MC
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Simon Fraser University, V5A-1S6 Burnaby, BC, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Dyrager
authors.affiliation: Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Souza-Fagundes
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Jeferson G
authors.initials: JG
authors.lastname: Da Silva
authors.affiliation: Department of Chemistry, Simon Fraser University, V5A-1S6 Burnaby, BC, Canada. Electronic address: tim_storr@sfu.ca.
authors.forename: Tim
authors.initials: T
authors.lastname: Storr
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil. Electronic address: hberaldo@ufmg.br.
authors.forename: Heloisa
authors.initials: H
authors.lastname: Beraldo
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D016166:Free Radical Scavengers / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D015125:Oxyquinoline / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D066329:Protein Aggregates; D012545:Schiff Bases / Q000737:chemistry; D012664:Semicarbazones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D056831:Coordination Complexes; D016166:Free Radical Scavengers; D066329:Protein Aggregates; D012545:Schiff Bases; D012664:Semicarbazones; D015125:Oxyquinoline; D003300:Copper
keywords: 8-Hydroxyquinoline; Alzheimer's disease; Copper(II) complex