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

Abstract

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.