Transition metal complexes are of increasing interest as photosensitizers in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT). In recent years, Ru (II) polypyridyl complexes have emerged as the most widely studied systems for both PDT and PCT. Their rich photochemical and photophysical properties derive from a variety of excited-state electronic configurations accessible with visible and near-infrared light, and these properties can be exploited for both energy-and electron-transfer processes that can yield highly potent oxygen-dependent and/or oxygen-independent photobiological activity. Selected examples highlight the use of rational design in coordination chemistry to control the lowest-energy triplet excited state configurations for eliciting a particular type of photoreactivity for PDT and/or PCT effects. These principles are also discussed in the context of the development of TLD1433, the first Ru(II)-based photosensitizer for PDT to enter a human clinical trial. The design of TLD1433 arose from a tumor-centered approach, as part of a complete PDT package that included the light component and the protocol for treating nonmuscle invasive bladder cancer. Briefly, this review summarizes *

Reaction of the bridging ligand 3,6-bis-[6'-(1' ',8' '-naphthyrid-2' '-yl)-pyrid-2'-yl]pyridazine (1) with [Ru(DMSO)4Cl2] in aqueous ethanol followed by excess 4-substituted pyridine (4-R-py) in the presence of triethylamine provides a series of three well-organized dinuclear complexes characterized by 1H NMR, MS, and X-ray. Mononuclear analogues are prepared from 4-tert-butyl-2,6-di(1',8'-naphthyrid-2'-yl)pyridine (5) and characterized in a similar fashion. All six complexes show electronic absorption and redox properties consistent with the electron donor/acceptor ability of the axial 4-R-py ligand. When an acetonitrile solution of the catalyst is added to an aqueous Ce(IV)-CF3SO3H solution (pH = 1.0) at 24 degrees C, oxygen evolution is observed for both mono and dinuclear systems. Turnover numbers range from 50 to 3200 with the best results being found when the axial ligand is 4-methylpyridine (mononuclear TN = 580 and dinuclear TN = 3200).

Two series of mononuclear ruthenium(II) complexes involving polypyridine-type ligands have been prepared, and their ability to act as catalysts for water oxidation has been examined. One series is of the type [Ru(tpy)(NN)Cl](PF(6)) (tpy = 2,2'; 6,2''-terpyridine), where NN is one of 12 different bidentate ligands, and the other series includes various combinations of 4-picoline, 2,2'-bipyridine (bpy), and tpy as well as the tetradentate 2,9-dipyrid-2'-yl-1,10-phenanthroline (dpp). The electronic absorption and redox data for these compounds have been measured and reported. The long-wavelength metal-to-ligand charge-transfer absorption and the first oxidation and reduction potentials are found to be consistent with the structure of the complex. Of the 23 complexes, 14 catalyze water oxidation and all of these contain a tpy or dpp. Kinetic measurements indicate a first-order reaction and together with a catalyst recovery experiment argue against the involvement of RuO(2). A tentative mechanism is proposed that involves a seven-coordinate Ru(VI)=O species that is attacked by water to form the critical O-O bond. Density functional theory calculations, which support the proposed mechanism, are performed.

Members of a family of Ru(II)-appended pyrenylethynylene dyads were synthesized, characterized according to their photophysical and photobiological properties, and evaluated for their collective potential as photosensitizers for metal-organic photodynamic therapy. The dyads in this series possess lowest-lying (3)IL-based excited states with lifetimes that can be tuned from 22 to 270 μs in fluid solution and from 44 to 3440 μs in glass at 77 K. To our knowledge, these excited-state lifetimes are the longest reported for Ru(II)-based dyads containing only one organic chromophore and lacking terminal diimine groups. These excited states proved to be extremely sensitive to trace amounts of oxygen, owing to their long lifetimes and very low radiative rates. Herein, we demonstrate that (3)IL states of this nature are potent photodynamic agents, exhibiting the largest photocytotoxicity indices reported to date with nanomolar light cytotoxicities at very short drug-to-light intervals. Importantly, these new agents are robust enough to maintain submicromolar PDT in pigmented metastatic melanoma cells, where the presence of melanin in combination with low oxygen tension is known to compromise PDT. This activity underscores the potential of metal-organic PDT as an alternate treatment strategy for challenging environments such as malignant melanoma.

A detailed characterization of intermediates in water oxidation catalyzed by a mononuclear Ru polypyridyl complex [Ru(II)-OH(2)](2+) (Ru = Ru complex with one 4-t-butyl-2,6-di-(1',8'-naphthyrid-2'-yl)-pyridine ligand and two 4-picoline ligands) has been carried out using electrochemistry, UV-vis and resonance Raman spectroscopy, pulse radiolysis, stopped flow, and electrospray ionization mass spectrometry (ESI-MS) with H(2)(18)O labeling experiments and theoretical calculations. The results reveal a number of intriguing properties of intermediates such as [Ru(IV)═O](2+) and [Ru(IV)-OO](2+). At pH > 2.9, two consecutive proton-coupled one-electron steps take place at the potential of the [Ru(III)-OH](2+)/[Ru(II)-OH(2)](2+) couple, which is equal to or higher than the potential of the [Ru(IV)═O](2+)/[Ru(III)-OH](2+) couple (i.e., the observation of a two-electron oxidation in cyclic voltammetry). At pH 1, the rate constant of the first one-electron oxidation by Ce(IV) is k(1) = 2 × 10(4) M(-1) s(-1). While pH-independent oxidation of [Ru(IV)═O](2+) takes place at 1420 mV vs NHE, bulk electrolysis of [Ru(II)-OH(2)](2+) at 1260 mV vs NHE at pH 1 (0.1 M triflic acid) and 1150 mV at pH 6 (10 mM sodium phosphate) yielded a red colored solution with a Coulomb count corresponding to a net four-electron oxidation. ESI-MS with labeling experiments clearly indicates that this species has an O-O bond. This species required an additional oxidation to liberate an oxygen molecule, and without any additional oxidant it completely decomposed slowly to form [Ru(II)-OOH](+) over 2 weeks. While there remains some conflicting evidence, we have assigned this species as (1)[Ru(IV)-η(2)-OO](2+) based on our electrochemical, spectroscopic, and theoretical observations alongside a previously reported analysis by T. J. Meyer's group (J. Am. Chem. Soc. 2010, 132, 1545-1557).

The photophysical behavior of [(bpy) 2 Ru(L)] 2+ complexes (L ) 4-(1′′-pyrenyl)-2,2′-bipyridine, bpy-pyr; 2-(1′-pyrenyl)-1,10-phenanthroline, phen-pyr; and 2-(2′-naphthyl)-1,10-phenanthroline, phen-nap) was investigated in solutions and frozen matrices. The conformation of the linked pyrene differs in the two complexes: The pyrene moiety is conformationally constrained to be nearly perpendicular to the phenanthroline in the phen-pyr complex while the pyrene in the bpy-pyr complex has much greater flexibility about the C-C bond linking the ligand and the pyrene. The 3 MLCT excited state of the Ru(II) diimine complex and the 3 (π f π*) state of the pyrenyl substituent are nearly isoenergetic; the 3 MLCT state is the lowest energy state in the bpy-pyr complex, and the pyrene 3 (π f π*) state is lower in energy for the phen-pyr complex. The bpy-pyr complex is unique in that the 3 MLCT state has a very long lived luminescence (approximately 50 µs in degassed CH 3 CN). Luminescence decays for both pyrene containing complexes can be fit as double exponentials, indicating that the 3 MLCT and 3 (π f π*) states are not in equilibrium. Analysis of decays obtained at several temperatures reveal that energy transfer is slower than relaxation of the 3 MLCT state but more rapid than decay of the pyrene localized 3 (π f π*) state. The results also suggest that electronic coupling between the two states is weak despite the fact that the two chromophores are separated by a single covalent bond.

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The metal ion complexing properties of the ligand DPP (2,9-di-(pyrid-2-yl)-1,10-phenanthroline) were studied by crystallography, fluorimetry, and UV-visible spectroscopy. Because DPP forms five-membered chelate rings, it will favor complexation with metal ions of an ionic radius close to 1.0 A. Metal ion complexation and accompanying selectivity of DPP is enhanced by the rigidity of the aromatic backbone of the ligand. Cd2+, with an ionic radius of 0.96 A, exhibits a strong CHEF (chelation enhanced fluorescence) effect with 10(-8) M DPP, and Cd2+ concentrations down to 10(-9) M can be detected. Other metal ions that cause a significant CHEF effect with DPP are Ca2+ (10(-3) M) and Na+ (1.0 M), whereas metal ions such as Zn2+, Pb2+, and Hg2+ cause no CHEF effect with DPP. The lack of a CHEF effect for Zn2+ relates to the inability of this small ion to contact all four donor atoms of DPP. The structures of [Cd(DPP)2](ClO4)2 (1), [Pb(DPP)(ClO4)2H2O] (2), and [Hg(DPP)(ClO4)2] (3) are reported. The Cd(II) in 1 is 8-coordinate with the Cd-N bonds to the outer pyridyl groups stretched by steric clashes between the o-hydrogens on these outer pyridyl groups and the central aromatic ring of the second DPP ligand. The 8-coordinate Pb(II) in 2 has two short Pb-N bonds to the two central nitrogens of DPP, with longer bonds to the outer N-donors. The coordination sphere around the Pb(II) is completed by a coordinated water molecule, and two coordinated ClO4(-) ions, with long Pb-O bonds to ClO4(-) oxygens, typical of a sterically active lone pair on Pb(II). The Hg(II) in 3 shows an 8-coordinate structure with the Hg(II) forming short Hg-N bonds to the outer pyridyl groups of DPP, whereas the other Hg-N and Hg-O bonds are rather long. The structures are discussed in terms of the fit of large metal ions to DPP with minimal steric strain. The UV-visible studies of the equilibria involving DPP and metal ions gave formation constants that show that DPP has a higher affinity for metal ions with an ionic radius close to 1.0 A, particularly Cd(II), Gd(III), and Bi(III), and low affinity for small metal ions such as Ni(II) and Zn(II). The complexes of several metal ions, such as Cd(II), Gd(III), and Pb(II), showed an equilibrium involving deprotonation of the complex at remarkably low pH values, which was attributed to deprotonation of coordinated water molecules according to: [M(DPP)(H2O)]n+ <==> [M(DPP)(OH)](n-1)+ + H+. The tendency to deprotonation of these DPP complexes at low pH is discussed in terms of the large hydrophobic surface of the coordinated DPP ligand destabilizing the hydration of coordinated water molecules and the build-up of charge on the metal ion in its DPP complex because of the inability of the coordinated DPP ligand to hydrogen bond with the solvent.