DFT Computational Analysis of the Mechanism of Action of Ru(II) Polypyridyl Complexes as Photoactivated Chemotherapy Agents: From Photoinduced Ligand Solvolysis to DNA Binding

Photoactivated chemotherapy (PACT) is a form of target-oriented cancer therapy that exploits light of the proper wavelength to selectively activate the drug. Among the prodrugs used for this purpose, ruthenium-based complexes are particularly interesting, as when irradiated by light, they can release ligands by forming aquo-complexes able to bind DNA in both single and double strand fashions, causing its distortion. Using as model system a Ru(II) polypyridyl complex that has been demonstrated to be a promising photochemotherapeutic agent, all of the key aspects of the photoinduced solvolysis process and subsequent DNA interaction have been scrutinized using density functional theory (DFT) and time-dependent-DFT (TDDFT). Photoexcitation, intersystem crossing, internal conversion, mechanism by which photoinduced ligand release, and subsequent aquation steps occur have been examined. Pathways leading to the formation of both cis and trans biaquated photoproducts have been described, and the formation of the cis form of the biaquated photoproduct being the most favorable one, its reaction with a guanine base has also been reported in order to account for DNA binding.