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

Abstract

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 CuÀ Aβ, metal chelating agents must extract Cu 2 + from Aβ in AD pathological conditions. Bis(8-hydroxyquinoline) ligands can extract Cu 2 + from Aβ and therefore inhibit the Cuinduced Aβ aggregation and the aerobic oxidation of ascorbate. In particular, N-butyl-2,2-imino-bis(8-hydroxyquinoline) can selectively target CuÀ Aβ reactivities in the presence of Zn 2 + 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.

8-Hydroxyquinolines: A Promising Pharmacophore Potentially Developed as Disease-Modifying Agents for Neurodegenerative Diseases: A Review

“…Recently, Oliveri reported a novel bis-8HQ ligand (compound 2) with promising in vitro anti-Aβ activity and good drug-like properties. 13 The study demonstrated that the compound 2 was able to chelate Cu 2+ accumulated in the Aβ plaque (both in the absence and presence of Zn 2+ ) which could address the loss of Cu homeostasis in the AD-mimic condition with the presence of excessive Zn 2+ , which may be due to the higher selectivity of the compound toward Cu 2+ . This indicated that the compound 2 is promising for protection against ROS-induced damages in the Zn-rich AD brain.…”

“…Some multifunctional Cu chelators without anti-Aβ effect were reported (compounds 13-16). 8HQpiperidine compound (13) showed good metal chelating property, antioxidant activity (DPPH IC50 = 544 μM) and inhibitory effects agaisnt both human AChE (% inhibition = 75.8%) and BuChE (IC50 = 11.11 nM). 109 Compound with similar AChE inhibitory effect such as 8HQ-tacrine 14 (AChE inhibitor) hybrid was developed.…”

“…This indicated that the compound 2 is promising for protection against ROS-induced damages in the Zn-rich AD brain. 13 Triazole is an attractive scaffold for discovery of anticancer agents as well as others. 148 Quinoline-triazole compound (MC-AB4, 3) was designed and reported to inhibit both self-and Cu 2+ -induced Aβ aggregation.…”

“…2 Recently, research publications relating to potential therapeutic applications of 8HQ-based compounds and their repurposing potentials for various therapeutic purposes have been continuously reported by our group [3][4][5][6][7][8][9][10] as well as others. [11][12][13] Alzheimer's disease (AD) is one of the most common causes of dementia globally and its prevalence is predicted to be continuously increased. 14 AD is clinically characterized by progressive losses of memory, cognitive functions, and behavioral changes.…”

Advanced nanomaterials for modulating Alzheimer's related amyloid aggregation

“… 8 The process of Aβ aggregation can trigger the production of intra- and extra-cellular reactive oxygen species (ROS), which can lead to oxidation and cellular damage. 9 In addition, neurotoxicity was induced by Aβ oligomers and fibrils through binding to the plasma membrane, resulting in metabolic dysfunction and neuronal cell death. 10 Therefore, the inhibition of Aβ fibrillation, the disintegration of mature Aβ aggregates, and the promotion of the clearance of Aβ to maintain the balance of the metabolism and catabolism of Aβ appear to be quite significant for the prevention and treatment of AD.…”