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

Abstract

The complex [(η 6 -p-cymene)Ru(OH 2 )(κ 2 -N,N-HL 1 )](OTf) 2 (HL 1 = 2-pyridin-2-yl-1H-benzimidazole), [2c]-(OTf) 2 , undergoes easy deprotonation of the N−H group at physiological pH, producing [(η 6 -p-cymene)Ru(OH 2 )(κ 2 -N,N-L 1 )] + , [2c′] + , prone to dimerization both in solution and in the solid state. X-ray measurements on [2c′]BF 4 have shown that dimer units are formed in the solid state by a combination of π−π stacking contacts between the aromatic rings of [L 1 ] − 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 ↔ D 2 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) [(η 6 -p-cymene)Ru(κ 2 -N,N-L 1 )]/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 [(η 6 -p-cymene)Ru(κ 2 -N,N-L 1 )]/DNA complex is established.

Alteration of steric hindrance modulates glutathione resistance and cytotoxicity of three structurally related RuII-p-cymene complexes

“…The similarity in the DNA binding constants for the 12 h hydrolyzed sample and the fresh solution of complexes may be attributed to the slow hydrolysis, since the timescale of the DNA binding experiment is smaller (1.5 h). The p-cymene complexes of Ru II show similar binding constants with DNA as reported by Garcia et al [47][48][49][50] Aquation is thought to be a major step which may be involved in activation of this type of metal complex. However, extracellular aquation may prevent the internalization of the complexes due to their di-positive charge and higher hydrophilicity.…”

“…The intrinsic pathways lead to greater change in mitochondrial membrane potential. Complex 3 in spite of a poorer IC 50 shows the highest change in MMP followed by complex 1 and the least change in MMP is observed with 2. Hence, the mitochondria mediated intrinsic apoptotic pathway may be least feasible in 2.…”

Editorial of Special Issue Ruthenium Complex: The Expanding Chemistry of the Ruthenium Complexes

“…That interest in the bioactivity profiles of ruthenium complexes has grown rapidly is amply demonstrated by design of new Ru compounds inhibiting enzymes, by the novel multinuclear systems acting as drug delivery vehicles or imaging and theranostics agents and signal transduction elements. A major contribution came as well from the advent of refined bioanalytical, biophysical and spectroscopic techniques used to elucidate the structure and the in vivo functioning of these complexes [79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100]. Some arene-functionalized dinuclear organometallic Ru(II) complexes are capable of crosslinking model peptide and oligonucleotide sequences while cytotoxicities are linked to their more rigid or more flexible conformations [81].…”

DNA-Binding and Anticancer Activity of Binuclear Gold(I) Alkynyl Complexes with a Phenanthrenyl Bridging Ligand

“…Ligands such as the π-delocalized planar polypyridyls (e.g., diphenylphenazine) have afforded moderate-to-strong DNA-intercalating complexes [15,16]. Modified acetylacetonato [17], amine [18,19], arene [20][21][22], and Schiff base [23,24] ligands have also been used in DNA-binding complex construction. In the pursuit of efficient DNA binders, one well-known strategy is to use a polycyclic aromatic fragment in the ligand that has been designed to form π-π interactions with specific units in the DNA [25,26].…”