A Comparative Study on the Iron and Copper Binding Properties of 8‑Hydroxyquinoline-Derived Mannich Bases Targeting Multidrug-Resistance Cancer Cells

TL;DR

This study compares how 8-hydroxyquinoline derivatives bind to iron and copper, which may help in targeting drug-resistant cancer cells.

Contribution

The study reveals new insights into the metal-binding behavior of MDR-selective 8-hydroxyquinoline Mannich bases.

Findings

Ligands bind Fe(II), Fe(III), and Cu(II) with different stability orders depending on their structure.

Carboxylate-containing ligands prefer Cu(II) over Fe(III) at pH 7.4.

Ligands without carboxylate groups show higher Fe(II) preference and more positive redox potentials.

Abstract

The efficacy of 8-hydroxyquinoline (HQ) Mannich bases
against multidrug-resistant
(MDR) cancer cells is thought to be linked to the complexation with
essential metal ions such as iron and copper. Here, the complex formation
equilibria of five MDR-selective HQs with Fe­(II), Fe­(III), and Cu­(II)
were studied by UV–visible spectrophotometry, complemented
by electron paramagnetic resonance, circular dichroism, and electrospray
ionization mass spectrometry techniques. Cyclic voltammetry and spectroelectrochemistry
were used to map the redox characteristics of the complexes, and their
direct reactivity with glutathione was also monitored. Single-crystal
X-ray diffraction was applied to determine the structures of one of
the selected ligands (HQCl-l-Pro) and its bis-ligand Cu­(II)
complex. The ligands are coordinated to Fe­(II) and Fe­(III) via the
(N,O–) donor set in all cases, leading to the formation
ofmono-, bis-, and tris-ligand complexes. For Cu­(II) complexes of
amino acid conjugates, several species have been identified. In addition
to mono- and bis-ligand complexes, dimeric species are also formed,
supported by density functional theory calculations. At pH 7.4, the
carboxylate-containing ligands bind metal ions in the stability order
of: Fe­(II) < Fe­(III) < Cu­(II). Ligands without carboxylate side
chains (HQCl-pyr and HQCl-pip) and with increased MDR-selectivity
showed a higher preference for Fe­(II) than for Fe­(III), also reflected
in the more positive redox potentials.

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