期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 139, 期 -, 页码 106-116出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2014.04.011
关键词
8-Hydroxyquinoline; Copper(II) complex; Alzheimer's disease
资金
- NSERC Discovery Grant
- Michael Smith Career Investigator Award
- Ciencia sem Fronteiras (CNPq), Brazil
- CAPES, Brazil [245405/2012-7]
- Alzheimer Society of Canada
- International postdoctoral grant from the Swedish Research Council [Dnr:350-2012-239]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil)
- INCT-INOFAR [Proc. CNPq 573.364/2008-6]
- Fapemig
One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid-beta (A beta) 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 A beta peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of A beta plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8-H(2)QH), a thiosemicarbazone (8-H(2)QT), and a semicarbazone (8-H(2)QS) derived from 8-hydroxyquinoline. The three compounds are shown to be neutral at pH 7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with Cull, 8-H(2)QT in a 1:1 metal:ligand ratio, and 8-H(2)QH and 8-H(2)QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the A beta(1-40) peptide showed that 8-H(2)QS and 8-H(2)QH 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 A beta aggregation using the more neurotoxic A beta(1-42) in the presence and absence of Cu-II, 8-H(2)QH, 8-H(2)QS 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. (C) 2014 Elsevier Inc. All rights reserved.
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