Monomer–Dimer Divergent Behavior toward DNA in a Half-Sandwich Ruthenium(II) Aqua Complex. Antiproliferative Biphasic Activity

The complex [(η6-p-cymene)­Ru­(OH2)­(κ2-N,N-HL1)]­(OTf)2 (HL1 = 2-pyridin-2-yl-1H-benzimidazole), [2c]­(OTf)2, undergoes easy deprotonation
of the N–H group at physiological
pH, producing [(η6-p-cymene)­Ru­(OH2)­(κ2-N,N-L1)]+, [2c′]+, prone to dimerization both in solution and in the
solid state. X-ray measurements on [2c′]­BF4 have shown that dimer units are formed in the
solid state by a combination of π–π stacking contacts
between the aromatic rings of [L1]− and
hydrogen bonding involving the water molecules coordinated to the
metal center and the deprotonated imidazolyl N atom. The T-jump kinetic
curves of the 2D ↔ D2 equilibrium recorded in the
microsecond time scale have allowed us to determine the parameters
of the dimerization process. The dimer content diminishes as the ionic
strength drops. The different kinetic and thermodynamic techniques
have all shown that the monomer reacts with DNA, producing the bifunctional
intercalated (through the benzimidazole ligand)-covalent (Ru/N7G)
[(η6-p-cymene)­Ru­(κ2-N,N-L1)]/DNA complex. The cytotoxic activity of [2c′]+ was evaluated against human lung carcinoma cells
(A549) by the MTT cell viability assay. Interestingly, the percentage
of surviving cells as a function of the [2c′]+ content displayed biphasic behavior, interpreted
as a result of the rise in the dimer content of [2c′]+. As only the monomer can react with DNA,
a reasonable correlation between cytotoxic activity and formation
of the [(η6-p-cymene)­Ru­(κ2-N,N-L1)]/DNA complex is established.