Solution structure, oxidative DNA damage, biological activity and molecular docking of ternary copper(II) L−argininato complexes

Abstract

Continuing our search for metal drugs with markedly higher toxicity to cancer cells than to normal cells, we evaluated the effect of 2,2′-bipyridine (bpy) as a co-ligand in the compounds [Cu(μ−O,O’−NO₃)(L−Arg)(bpy)]NO₃}_n (1) and [CuCl(L−Arg)(bpy)]Cl·3H₂O (2) (L−Arg = L−arginine), on DNA interaction, cytotoxic and antiproliferative activity, compared to the effects induced by other co-ligands i.e. 1,10-phenanthroline (phen) and SCN⁻ ions, in similar Cu(II) compounds we have studied previously. Potentiometric, X-band EPR and UV–Vis experiments were first used to structurally characterise the complexes formed in solutions 1 and 2 and in model Cu(II)/bpy/L−Arg systems. Gel electrophoresis in the presence of H₂O₂ was used to identify DNA damage by 1 and 2. In addition, cyclic voltammetry of both compounds was performed to confirm the existence of Cu(II)/Cu(I) redox pairs involved in the free radical mechanism of this DNA damage. The DNA binding constants of 1 and 2 were determined spectrophotometrically. The selectivity of the cytotoxic and antiproliferative activity of compounds 1 and 2 was tested in vitro against human lung adenocarcinoma (A549), liver cancer (HepG2) and normal cells in comparison with those previously observed by us for compounds consisting of phen and SCN⁻ ligands. Molecular docking calculations were performed for [Cu(L−Arg)(bpy)]²⁺ species (arraised in solutions of 1 and 2) interacting with B-DNA (aureolin), metalloproteinase (S. aureus) and penicillin-binding protein (E. coli) to determine the nature of the complex-receptor interaction, potential binding modes and energies.