The Chelating Abilities of Tertiary Amines with N-O-Donors Towards Cu(II) Ions and the Catalytic Properties of the Resulting Complexes

Abstract

Oxidative stress, driven by excess reactive oxygen species (ROS), is a key factor in the progression of neurodegenerative diseases like Alzheimer's disease (AD). In this context, copper dysregulation can also contribute to this imbalance, being responsible for enhanced ROS production, so that copper scavenging has been investigated as a possible therapeutic strategy. This study investigates the behavior of two isostructural ligands, featuring an N₃O donor set, that effectively chelate Cu(II) in aqueous solution. Interestingly, their resulting mono- or dinuclear copper complexes feature a coordination environment suitable to foster antioxidant activity. By transforming copper's oxidant potential into antioxidant action, these systems may reduce copper-induced oxidative damage. The work examines the pH-dependent metal-binding behavior of the ligands, the catalytic properties of the resulting complexes under physiological conditions, and their ability to inhibit β-amyloid peptide aggregation.

Keywords: N3O donors; amyloid aggregation; antioxidants; chelators; copper complexes.

Scheme 1

The schematic structures of the HL1 and HL5 ligands at pH 7.4 were obtained with the Avogadro software, Application Version: 1.2.0 [30]. Color code for the atoms: O—red, N—blue, H—white, C—black.

Figure 1

Speciation curves for the ligands HL1 and HL5. Conditions: [ligands] = 0.7 mM in 5% v/v DMSO/H₂O (with HCl/KCl, I = 0.1 M; initial pH = 2.7).

Figure 2

(a) Speciation curves for the in situ-formed complexes ligand/copper (II) 1:1. with ligands HL1 and HL5 (0.7 mM) in 5% v/v DMSO/H₂O (containing HCl and KCl, I = 0.1 M; initial pH = 2.7). (b) The competition diagram for the system HL1:Cu(II):HL5 with molar ratio of 1:1:1.

Scheme 2

The schematic structures of the [Cu(HLx)H₂]³⁺ (a)—the {N_{tertiary amine}, N_Pyr}, (b)—the {2xN_Pyr} binding modes, (c,d)—[Cu(HLx)H]²⁺ and (e)—[Cu(HLx)]⁺ for HL1, taken as example, obtained with the Avogadro software, Application Version: 1.2.0 [30]. Color code for the atoms: O—red, N—blue, H—white, C—black, Cu—orange.

Figure 3

Molecular structures of (a) [Cu(HL1)(CH₃CN)ClO₄]⁺ and (b) [Cu(HL5)(CH₃CN)ClO₄]⁺ cations with selected atomic labels (ellipsoids drawn at the 30% probability level). See Tables S1–S3 in the Supplementary Materials for details.

Figure 4

Cyclic voltammograms of the complex (a) Cu(HL1)(ClO₄)₂ and (b) Cu(HL5)(ClO₄)₂: recorded at scan rates of 50 mV/s, 100 mV/s, 200 mV/s, 400 mV/s, 800 mV/s. Complex = 0.50 mM in 5% v/v CH₃CN/H₂O (10 mM phosphate buffer, 100 mM NaCl, pH 7.8).

Figure 5

Graph “i_p vs. ${\sqrt{v}}_{scan}$” obtained from the cyclic voltammograms of the complexes: (a) Cu(HL1)(ClO₄)₂ and Cu(HL5)(ClO₄)₂; (b) Cu₂L5₂(ClO₄)₂ preformed and mononuclear complex formed in situ. The graphs were recorded at the scan rates of 50, 100, 200, 400, and 800 mV/s.

Figure 6

O₂ production over time, generated from the hydrogen peroxide dismutation, was measured in μmol of O₂ using pressure data and the ideal gas law.

Figure 7

Residual absorbance of morin at the maximum absorption (390 nm) after reaction of the complexes with H₂O₂ for 16 h. [Morin] = 0.16 mM, [Catalyst] = 1.6 μM, [H₂O₂] = 0.01 M, PBS buffer (50 mM), pH 7.8.

Figure 8

Trend over time at maximum absorption of DAP at 418 nm, with (a) Cu(HL1)(ClO₄)₂ (yellow) and Cu(HL5)(ClO₄)₂ (red), (b) Cu₂L1₂(ClO₄)₂ (blue) and Cu₂L5₂(ClO₄)₂ (green). [OPD] = 0.32 mM, [Catalyst] = 0.16 mM, [H₂O₂] = 0.024 M, PBS buffer (50 mM), pH 7.8.

Figure 9

The fluorescence in the sample solutions present in the legend, where P = amyloid peptide. [ThT] = 10 μM; [P] = 10 μM; solutions of complexes, binders at concentration 10 μM, monitoring at 24 h.