Cytotoxic Ruthenium(II) Complexes Containing a Dangling Pyridine: Selectivity for Diseased Cells Mediated by...

Ruthenium(II) complexes of the type [Ru(bpy)₂(L¹/L²/L³)]PF₆ [where bpy = 2,2'-bipyridine, H(L = N-(pyrid-2-yl)salicylaldimine (1), H(L = N-(6-methylpyrid-2-yl)salicylaldimine (2), and H(L = N-(4,6-dimethylpyrid-2-yl)salicylaldimine (3)] have been isolated. The X-ray structures of 1-3 reveal distorted octahedral coordination geometry with a planar ruthenium phenolate moiety. They exhibit interpair dimeric association in their solid state such as (a) π-π-stacking interactions (1-3) and (b) C-H···π interactions (2). The ¹H NMR spectral data shed light on the characteristics of metal-ligand bonding and chelate ring conformations. The complexes exhibit strong metal-to-ligand charge-transfer transitions in the visible region. The complexes also undergo two successive metal-based oxidative processes corresponding to the Ru^II/Ru^III and Ru^III/Ru^IV couples. Resonance Raman studies strongly suggest that the lowest unoccupied molecular orbital of 1-3 is localized at the bpy ligand. Absorption, emission, and circular dichroic spectral measurements for 1-3 with calf-thymus DNA reveal a groove binding mode of interaction. Interestingly, all of the complexes exhibit pH-dependent DNA damage, and the pH at which the damage is highest corresponds to the pH conditions of the cancer cells. The DNA damage is in the order of 3 > 2 > 1, in which a hydrolytic mechanism dominates. The protein binding properties of the complexes examined by the tryptophan quenching measurements suggest a static mechanism. The positive ΔH and ΔS values indicate that the force acting between the complexes and bovine serum albumin (BSA) is mainly a hydrophobic interaction, and thus BSA may act as a targeted drug-delivery vehicle for ruthenium(II) complexes (K ∼ 10⁵). It is noteworthy that 3 exhibits selectivity with high cytotoxicity against breast cancer cells (EVSA-T and MCF-7), and its potency is comparable to that of cisplatin.