Design of photoactivatable metallodrugs: Selective and rapid light-induced ligand dissociation from half-sandwich [Ru([9]aneS3)(N–N′)(py)]2+ complexes

The synthesis of the inert Ru(II) half-sandwich coordination compounds, [Ru([9]aneS(3))(bpy)(py)][PF6](2) (1, [9]aneS(3) = 1,4,7-trithiacyclononane, bpy = 2,2'-bipyridine, py = pyridine), [Ru([9] aneS(3))(en)(py)][PF6](2) (2, en = 1,2-diaminoethane), and [Ru([9] aneN(3))(en)(dmso-S)][PF6](2) (3, [9] aneN(3) = 1,4,7-triazacyclo-nonane), is reported along with the X-ray crystal structure of 1. We investigated whether these complexes have photochemical properties which might make them suitable for use as pro-drugs in photochemotherapy. Complexes 1 and 2 underwent rapid (minutes) aquation with dissociation of the pyridine ligand in aqueous solution when irradiated with blue light (lambda = 420 or 467 nm). The photodecomposition of 3 was much slower. All complexes readily formed adducts with 9-ethylguanine (9-EtG) when this model nucleobase was present in the photolysis solution. Similarly, complex 1 formed adducts with the tripeptide glutathione (GSH), but only when photoactivated. HPLC and MS studies of 1 showed that irradiation promoted rapid formation of 1:1 (major) and 1:2 (minor) adducts of the oligonucleotide d(ATACATGCTACATA) with the fragment Ru([9] aneS(3))(bpy)(2+). Density functional theory (DFT) calculations and time-dependent DFT reproduced the major features of the absorption spectra and suggested that the lowest-lying triplet state with (MLCT)-M-3 character, which is readily accessible via intersystem crossing, might be responsible for the observed dissociative behavior of the excited states. These complexes are promising for further study as potential photochemotherapeutic agents.