Catechol‐Based Ligands as Potential Metal Chelators Inhibiting Redox Activity in Alzheimer's Disease

Abstract

The loss of homeostasis of redox metal ions, namely, copper and iron, has been considered to be an important contributing factor in neuronal death observed in the brain of patients affected by Alzheimer's disease (AD). Specific ligands able to regulate the homeostasis of copper and, to a lesser extent, iron ions in the brain have therefore been considered to be potential drugs for the treatment of AD. Herein, the synthesis and metal coordination properties of a series of ligands based on a bis(2,3‐dihydroxyalkylbenzamide) scaffold, which are potentially able to regulate the homeostasis of redox metal ions, are reported. These catechol‐based ligands exhibit high specific affinities for CuII and FeIII, and a lower affinity for ZnII, which indicates that they may interact with redox metal ions without disturbing the structural and dynamic role of zinc chelation in many proteins. These ligands inhibit the reduction of dioxygen induced by CuII–Aβ1–16, and this suggests that they may be able to efficiently reduce the oxidative stress induced by metal‐loaded amyloids in the AD brain.

Preparation of Tetradentate Copper Chelators as Potential Anti‐Alzheimer Agents

“…In all cases, complexes with as toichiometry metal/ligand = 1:1w ere isolated, even where the metal/ligand molar ratio in the crystallizationm ixtures was 1:2. This indicatest hat complexes with stoichiometry metal/ligand = 1:2, previously reported in the case ligandsb ased on an 8-hydroxyquinolines caffold, [28] are unlikely with the TDMQ series.…”

“…For TDMQ4, 5, 8, 9, 10, 11, 12, 13, 16, 20, and 22 (15 μ m in Tris⋅HCl buffer, pH 7.4), 20–40 mol equiv Zn 2+ were required to saturate the ligand, indicating that free and chelated Zn were in equilibrium in the UV/Vis concentration, as the result of a low affinity of Zn II for these ligands. In these cases, the affinity constant of Zn II was calculated from the molar ratio Zn 2+ /L required to achieve half metallation . For instance, the titration of TDMQ5 by Zn 2+ is reported in Figure .…”

“…Direct method (ligands with “low” affinity) : From the titration of TDMQ ligands by Zn 2+ (for the conditions, see the above paragraph “Ligand/metal stoichiometry of TDMQ in the presence of Cu 2+ or Zn 2+ ”), the affinity of TDMQ for Zn II was calculated as reported by Nguyen et al …”

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

“…For this reason, the redox inertness of copper complexes for potential anti-neurodegenerative drugs is often assessed. [38,52] ROS production of Cu complexes of bisHQs was evaluated through kinetics of ascorbate (AA) oxidation, monitored by UV spectroscopy (Figure S20). The studies were also performed in the presence of Zn 2 + to mimic the AD brain conditions, as reported in other studies.…”

“…A major issue is the potential ability of these complexes to generate ROS in the presence of a biological reducing agent. For this reason, the redox inertness of copper complexes for potential anti‐neurodegenerative drugs is often assessed [38,52] …”