Photochemical and spectroscopic studies of ruthenium(II) complexes as potential photodynamic therapy agents.

摘要

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 that bind DNA in a manner similar to cisplatin. This new class of compounds is referred to as photo-cisplatin analogs.;A successful PDT agent should possess high molar absorbtivity at long wavelengths where tissue penetration is greatest and there is low absorption by biomolecules. A series of Ru(II) complexes were synthesized with the deprotonated forms of the ligands 8-hydroxyquinoline (quo--) and 5-NO 2-8-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. TD-DFT calculations along with electrochemical analysis reveals that the lowest energy transition has contributions in the HOMO from both the quo-- ligand and the metal, such that the lowest energy transition is not from an orbital that is purely metal-centered in character as in [Ru(bpy)3] 2+.;The photolabile complex cis-[Ru(phpy)(phen)(CH 3CN)2]+ (4, phpy-- = 2-phenylpyridine, phen = 1,10-phenantrholine) was investigated as a potential photodynamic therapy (PDT) agent. A low energy transition assigned as Ru-phen MLCT was observed with a broad tail extending into the PDT window (600--850 nm). Irradiation of 4 with long wavelengths (lambda irr ≥ 630 nm) resulted in photoinduced ligand exchange of the monodentate acetonitrile ligands with quantum yield (phiCl) of 0.25 (lambda irr = 450 nm) for the photosubstitution by chloride in CH2Cl 2 to generate [Ru(phpy)(phen)(CH3CN)Cl]. This value is similar to that previously reported for the photosubstitution by chloride in CH 2Cl2 in cis-[Ru(bpy)2(CH 3CN)2] 2+ (3, bpy= 2, 2'-bipyridine) phi = 0.31 (lambdairr = 430 nm). A dependence of the quantum yield of ligand exchange on the wavelength of irradiation was observed for 4. Selective irradiation into the Ru-phen 1MLCT (lambda irr = 500 nm) of 4 results in more efficient ligand substitution (phi = 0.25) as compared to irradiation into the Ru-phpy 1MLCT peak (lambdairr = 450 nm; phi = 0.08) for chloride in CH 2Cl2. It is generally accepted that ligand dissociation occurs from the M--L (sigma*) antibonding metal centered 3LF state(s). Therefore, a small energy gap between the lowest energy Ru→phen 3MLCT state(s) and 3LF state is proposed. In addition, the lower quantum yield observed for irradiation in to the Ru→phpy 3MLCT is believed to result from the rapid deactivation of the excited species through strong metal-ligand orbital overlap between phpy- and the metal center.