Cytotoxic Ruthenium(II) Complexes Containing a Dangling Pyridine: Selectivity for Diseased Cells Mediated by pH-Dependent DNA Binding

Ruthenium(II) complexes of the type [Ru(bpy) 2 (L 1 /L 2 /L 3 )]PF 6 [where bpy = 2,2′-bipyridine, H(L 1 ) = N -(pyrid-2-yl)salicylaldimine ( 1 ), H(L 2 ) = N -(6-methylpyrid-2-yl)salicylaldimine ( 2 ), and H(L 3 ) = 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 1 H 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 Δ H and Δ S 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 ∼ 10 5 ). 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.