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.

A new family of neutral ruthenium(II) arene complexes of the type [Ru(η 6 -arene)X(κ 2 -O,N-L)] (η 6 -arene = p-cym, bz; X = Cl − , SCN − ; HL1 = 2-(2′-hydroxyphenyl)benzimidazole, HL2 = 2-(2′hydroxyphenyl)benzothiazole) has been synthesized and characterized. The cytotoxic activity of the Ru(II) complexes was evaluated in several tumor cell lines (A549, HepG2 and SW480) both in the dark and after soft irradiation with UV and blue light. None of the complexes bearing benzimidazole (HL1) as a ligand displayed phototoxicity, whereas the complexes with a benzothiazole ligand (HL2) exhibited photoactivation; the sensitivity observed for UV was higher than for blue light irradiation. The interesting results displayed by HL2 and [Ru(η 6 -p-cym)(NCS)(κ 2 -O,N-L2)], [3a], in terms of photo cytotoxicity prompted us to analyze their interaction with DNA, both in the dark and under irradiation conditions, in an effort to shed some light on their mechanism of action. The results of this study revealed that HL2 interacts with DNA by groove binding, whereas [3a] interacts by a dual mode of binding, an external groove binding, and covalent binding of the metal center to the guanine moiety. Interestingly, both HL2 and [3a] display a clear preference for AT base pairs, and this causes fluorescence enhancement. Additionally, cleavage of the pUC18 plasmid DNA by the complex is observed upon irradiation. The study of the irradiated form demonstrates that the arene ligand is released to yield species such as [Ru(κ 2 -O,N-L2)(κ 1 -S-DMSO) 2 (μ-SCN)] 2 [3c] and [Ru(κ 2 -O,N-L2)(κ 1 -S-DMSO) 3 (SCN)] [3d]. Such photo dissociation occurs even in the absence of oxygen and leads to cytotoxicity enhancement, an effect attributed to the presence of [3d], thus revealing the potential of [3a] as a pro-drug for photoactivated anticancer chemotherapy (PACT).

Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability.

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