Cytotoxicity of cyclometallated ruthenium complexes: the role of ligand exchange on the activity

The cyclometallated Ru(II) complexes cis-[Ru(phpy) (phen)(CH₃CN)₂](PF₆) (1; phpy ̅ = deprotonated 2-phenylpyridine, phen = 1,10-phenanthroline) and cis-[Ru(phpy)(bpy)(CH₃CN)₂](PF₆) (2; bpy = 2,2'-bipyridine) were investigated as potential agents for photodynamic therapy. The presence of phpy ̅ in the coordination sphere results in a red-shift of the Ru → phen and Ru → bpy metal-to-ligand charge transfer of 1 and 2, respectively, thus improving the tissue penetration of light while maintaining the efficient photo-induced ligand exchange required for DNA binding. The 14-fold enhancement of OVCAR-5 cell death that occurs upon irradiation with 690 nm light can be attributed to photo-aquation. The role of glutathione (GSH) on the toxicity of the complex was also explored. Complexes 1 and 2 undergo ligand substitution in the presence of GSH in the dark, such that the metal may covalently bind to biomolecules. The combination of photo-induced ligand exchange and GSH-facilitated ligand exchange may explain the observed cytotoxicity.