Solution structure, oxidative DNA damage, biological activity and molecular docking of ternary copper(II)...

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.