8-Hydroxyquinoline Schiff-base Compounds as Antioxidants and Modulators of Copper-Mediated Aβ Peptide Aggregation

Resource type
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 pH 7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with CuII, 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 CuII. 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 CuII, 8-H2QH, 8-H2QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of CuII. However, in the presence of ligands and CuII, the results match those for the peptide alone, suggesting that the ligands function by sequestering CuII and limiting oligomer formation in this assay.
Document
Published as
Gomes, L. M. F., Vieira, R. P., Jones, M. R., Wang, M. C. P., Dyrager, C., Souza-Fagundes, E. M., Da Silva, J. G., Storr, T., Beraldo, H. 8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated AB peptide aggregation, J. Inorg. Biochem., 2014, 139, 106-116. DOI: 10.1016/j.jinorgbio.2014.04.011
Publication title
Inorg. Biochem
Document title
8-Hydroxyquinoline Schiff-base Compounds as Antioxidants and Modulators of Copper-Mediated Aβ Peptide Aggregation
Date
2014
First page
106
Last page
116
Publisher DOI
10.1016/j.jinorgbio.2014.04.011
Copyright statement
Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
Language
Member of collection
Attachment Size
JIB_Storr_Beraldo-2014.pdf 1.19 MB