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-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 Cu II , 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 Aβ 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 Aβ aggregation using the more neurotoxic Aβ 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.