Cisplatin is an anticancer drug used in the treatment of various cancers. However, cisplatin is toxic towards both healthy and tumor cells alike, resulting in several undesirable side effects. Moreover, some of the most aggressive cancers develop resistance to cisplatin. Photodynamic therapy (PDT) uses light to localize activation of otherwise non-toxic compounds in tumor tissue. Current PDT agents achieve toxicity by the photosensitization of highly reactive singlet oxygen through energy transfer from an excited state. However, this need for the presence of molecular oxygen represents a disadvantage since malignant and drug resistant cells are often hypoxic. To address the drawbacks of cisplatin and PDT drugs as antitumor agents, a combined approach has been made with the development of several photoactive Ru(II) complexes that produced with antitumor activity under irradiation. This blend of cisplatin mimetic metal complexes, inorganic photochemistry and photodynamic therapy has led to the discovery of several photo-activated ruthenium complexes referred to as photo-cisplatin analogs.
A series of Ru(II) complexes were synthesized with the deprotonated forms of the ligands 8-hydroxyquinoline (quo−) and 5-NO2-8-hydroxyquinolate (5-NO2-quo−) as analogs to the prototypical complex [Ru(bpy)3]2+ (bpy = 2, 2′-bipyridine) in order to red shift absorption of the new complexes into the optimized PDT window. Electrochemistry, spectroscopy and density functional theory calculations were utilized to investigate the electronic tuning of the occupied t2g-type orbitals of the metal center with variation in the ligation sphere. The maximum of the lowest energy absorption of complexes containing one, two and three 8-quinolate ligands progressively red shifts from 452 nm in [Ru(bpy)3]2+ to 510 nm in [Ru(bpy)2(quo)]+, 515 nm in [Ru(bpy)(quo)2], and 540 nm in [Ru(quo)3]− in water. This bathochromic shift results from the increase in energy of the occupied t2g-type orbital across the series afforded by coordination of each subsequent quo− ligand to the Ru(II) center.
The complex cis-[Ru(phpy)(phen)(CH3CN)2]+ (phpy = 2-phenylpyridine, phen = 1,10–phenantrholine) was investigated as a potential photodynamic therapy (PDT) agent, since the complex exhibits a low energy absorption tail extending into the PDT window (600 – 850 nm) and undergoes photoinduced exchange of the CH3CN ligands with λirr ≥ 630 nm. Selective irradiation into the Ru-phen 1MLCT band (λirr = 500 nm) of cis-[Ru(phpy)(phen)(CH3CN)2]+ results in more efficient photoinduced production of [Ru(phpy)(phen)(CH3CN)Cl] (Φ = 0.25) as compared to that with irradiation into the Ru-phpy 1MLCT peak (λirr = 450 nm; Φ =0.08) in the presence of excess chloride ion in CH2Cl2. The lower quantum yield observed for irradiation into the Ru-phpy– 1MLCT is explained on the basis of orbital mixing of the phpy– ligand with the t2g-type filled set in the metal, giving this state a significant ligand-centered character. Conversely, the higher quantum yield of ligand dissociation for selective irradiation into the Ru-phen 1MLCT state is proposed to be a consequence of a large degree of communication between the 1MLCT and 3LF state(s), where the M–CH3CN s* character of the latter results in efficient ligand dissociation. In addition, a decrease in the mobility of linearized ds-DNA was observed for samples irradiated in the presence of cis-[Ru(phpy)(phen)(CH3CN)2]+ indicative of covalent binding by the transition metal complex, whereas no change in mobility was found for samples kept in the dark. In addition, LC50 values determined for cis-[Ru(phpy)(phen)(CH3CN)2]+ in the dark and under irradiation showed a 3-fold increase in toxicity upon irradiation, indicating the potential of cis-[Ru(phpy)(phen)(CH3CN)2]+ as PDT agent.