A detailed density functional theory exploration of the photodissociation mechanism of ruthenium complexes for photoactivated chemotherapy

Polypyridyl Ru(ii) complexes have attracted much attention due to their potential as light-activatable anticancer agents in photoactivated chemotherapy (PACT). The action of ruthenium-based PACT compounds relies on the breaking of a coordination bond between the metal center and an organic ligand via a photosubstitution reaction. Here, a detailed computational investigation of the photophysical properties of a novel trisheteroleptic ruthenium complex, [Ru(dpp)(bpy)(mtmp)]2+ (dpp = 4,7-diphenyl-1,10-phenanthroline, bpy = 2,2 '-bipyridine and mtmp = 2-methylthiomethylpyridine), has been carried out by means of DFT and its time-dependent extension. All the aspects of the mechanism by which, upon light irradiation, the mtmp protecting group is released and the corresponding aquated complex, able to bind to DNA inducing cell death, is formed have been explored in detail. All the involved singlet and triplet states have been fully described, providing the calculation of the corresponding energy barriers. The involvement of solvent molecules in photosubstitution and the role played by pyridyl-thioether chelates as caging groups have been elucidated. All the mechanistic aspects of the photodissociation process of a recently synthesized trisheteroleptic Ru(ii) complex as a PACT agent have been computationally explored in depth together with the subsequent water molecule coordination.