Bis(8-hydroxyquinoline) Ligands: Exploring their Potential as Selective Copper-Binding Agents for Alzheimer's Disease

Amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress are pathological features of Alzheimer's disease (AD). Aβ and metal ions form metal-Aβ complex species that influence the aggregation of Aβ and, in particular, redox metal ions such as Cu lead to the production of reactive oxygen species (ROS). To target metal coordination to Aβ and the reactivities of Cu−Aβ, metal chelating agents must extract Cu2+ from Aβ in AD pathological conditions. Bis(8-hydroxyquinoline) ligands can extract Cu2+ from Aβ and therefore inhibit the Cu-induced Aβ aggregation and the aerobic oxidation of ascorbate. In particular, N-butyl-2,2-imino-bis(8-hydroxyquinoline) can selectively target Cu−Aβ reactivities in the presence of Zn2+ such as in AD brain patients. The ligands can release Cu in intracellular environments in the presence of a large excess of glutathione, contributing to restore Cu homeostasis.