DFT Computational\nAnalysis of the Mechanism of Action\nof Ru(II) Polypyridyl Complexes as Photoactivated Chemotherapy Agents:\nFrom Photoinduced Ligand Solvolysis to DNA Binding

Photoactivated chemotherapy (PACT) is a form of target-oriented\ncancer therapy that exploits light of the proper wavelength to selectively\nactivate the drug. Among the prodrugs used for this purpose, ruthenium-based\ncomplexes are particularly interesting, as when irradiated by light,\nthey can release ligands by forming aquo-complexes able to bind DNA\nin both single and double strand fashions, causing its distortion.\nUsing as model system a Ru(II) polypyridyl complex that has been demonstrated\nto be a promising photochemotherapeutic agent, all of the key aspects\nof the photoinduced solvolysis process and subsequent DNA interaction\nhave been scrutinized using density functional theory (DFT) and time-dependent-DFT\n(TDDFT). Photoexcitation, intersystem crossing, internal conversion,\nmechanism by which photoinduced ligand release, and subsequent aquation\nsteps occur have been examined. Pathways leading to the formation\nof both <i>cis</i> and <i>trans</i> biaquated\nphotoproducts have been described, and the formation of the <i>cis</i> form of the biaquated photoproduct being the most favorable\none, its reaction with a guanine base has also been reported in order\nto account for DNA binding.