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 *

A series of strained Ru(II) complexes were studied for potential anticancer activity in hypoxic tissues. The complexes were constructed with methylated ligands that were photolabile and an imidizo[4,5‐f][1,10]phenanthroline ligand that contained an appended aromatic group to potentially allow for contributions of ligand‐centered excited states. A systematic variation of the size and energy of the aromatic group was performed using systems containing 1–4 fused rings, and the photochemical and photobiological behaviors of all complexes were assessed. The structure and nature of the aromatic group had a subtle impact on photochemistry, altering environmental sensitivity, and had a significant impact on cellular cytotoxicity and photobiology. Up to 5‐fold differences in cytotoxicity were observed in the absence of light activation; this rose to 50‐fold differences upon exposure to 453 nm light. Most significantly, one complex retained activity under conditions with 1% O2, which is used to induce hypoxic changes. This system exhibited a photocytotoxicity index (PI) of 15, which is in marked contrast to most other Ru(II) complexes, including those designed for O2‐independent mechanisms of action.

The photophysical and photobiological properties of a new class of cyclometalated ruthenium(II) compounds incorporating π-extended benzo[ h]imidazo[4,5- f]quinoline (IBQ) cyclometalating ligands (C^N) bearing thienyl rings ( n = 1-4, compounds 1-4) were investigated. Their octanol-water partition coefficients (log P) were positive and increased with n. Their absorption and emission energies were red-shifted substantially compared to the analogous Ru(II) diimine (N^N) complexes. They displayed C^N-based intraligand (IL) fluorescence and triplet excited-state absorption that shifted to longer wavelengths with increasing n and N^N-based metal-to-ligand charge transfer (MLCT) phosphorescence that was independent of n. Their photoluminescence lifetimes (τ) ranged from 4-10 ns for IL states and 12-18 ns forMLCT states. Transient absorption lifetimes (τ) were 5-8 μs with 355 nm excitation, ascribed to IL states that became inaccessible for 1-3 with 532 nm excitation (1-3, τ = 16-17 ns); the IL of 4 only was accessible by lower energy excitation, τ = 3.8 μs. Complex 4 was nontoxic (EC > 300 μM) to SK-MEL-28 melanoma cells and CCD1064-Sk normal skin fibroblasts in the dark, while 3 was selectively cytotoxic to melanoma (EC= 5.1 μM) only. Compounds 1 and 2 were selective for melanoma cells in the dark, with submicromolar potencies (EC = 350-500 nM) and selectivity factors (SFs) around 50. The photocytotoxicities of compounds 1-4 toward melanoma cells were similar, but only compounds 3 and 4 displayed significant phototherapeutic indices (PIs; 3, 43; 4, >1100). The larger cytotoxicities for compounds 1 and 2 were attributed to increased cellular uptake and nuclear accumulation, and possibly related to the DNA-aggregating properties of all four compounds as demonstrated by cell-free gel mobility-shift assays. Together, these results demonstrate a new class of thiophene-containing Ru(II) cyclometalated compounds that contain both highly selective chemotherapeutic agents and extremely potent photocytotoxic agents.

A series of cationic dinuclear iridium(III) complexes (Ir1-Ir5) bearing terpyridine-capped fluorenyl bridging ligands and different polypyridyl or cyclometalating terminal tridentate ligands were synthesized, characterized, and evaluated for their photophysical and photobiological activities. The influence of the bridging and terminal ligands on the photophysical properties of the complexes was investigated by UV-vis absorption, emission, and transient absorption spectroscopy and simulated by TDDFT calculations. All of the complexes displayed strong bridging-ligand localized visible π,π* absorption and red- or near-infrared phosphorescence as well as broad triplet excited-state absorption across both visible and NIR wavelengths. These triplet states were assigned as predominantlyπ,π* for Ir1 (τ = 3.1 μs) and Ir4 (τ = 48 μs) and CT (charge transfer) for Ir2, Ir3, and Ir5 (τ = 1.7-2.7 μs). Complexes Ir1-Ir5 acted as in vitro photodynamic therapy (PDT) agents toward human SK-MEL-28 melanoma cells when activated with visible light, with submicromolar photocytotoxicity and phototherapeutic indices ranging from 20 to almost 300. The in vitro PDT effects with visible light did not correlate with singlet oxygen (O) quantum yields or DNA photocleaving capacity probed under cell-free conditions. All of the Ir(III) complexes phosphoresced brightly when associated with compromised cells (with or without light treatment) and exhibited photoactivated cellular uptake, highlighting the theranostic potential of this new class of Ir(III) complex photosensitizers.

Six homo-or heteroleptic tricationic Ir(R 1-tpy)(R 2-tpy) 3+ complexes (Ir1-Ir6, R 1 /R 2 = Ph, 4′-N(CH 3) 2 Ph, pyren-1-yl, or 4′-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}Ph, tpy = 2,2';6',2"terpyridine) were synthesized and tested for photodynamic therapy (PDT) effects. The ground-and excited-state characteristics of these complexes were studied systematically via spectroscopic methods and quantum chemistry calculations. All complexes possessed intraligand charge transfer (1 ILCT) / metal-to-ligand charge transfer (1 MLCT) dominated transition(s) in their low-energy absorption bands, which red-shifted with the increased electron-releasing strength of the R 1 /R 2 substituent. Five of the complexes exhibited ligand-centered 3 π,π*/ 3 ILCT/ 3 MLCT emission. With a stronger electron-releasing R 1 /R 2 substituent, the degree of charge transfer contribution increased, leading to a decrease of the emission quantum yield. When the 4′-N(CH 3) 2 Ph substituent was introduced on both tpy ligands, the emission of Ir3 was completely quenched. Our *