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

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.