© 2015 Elsevier B.V. Dual emission is a reality in many, but not all, ruthenium complex ions, even at room temperature and in fluid solution. It requires significantly different ligands and is more obvious in rigid media such as glasses at low temperature and crystalline powders. However, there are not just two unique lifetimes. Rather, there is a continuum of similar but slightly different lifetimes drawn from a bimodal distribution. In some of the cases that do not show dual emission, there still seems to be a continuum within a unimodal distribution. After reviewing a wide range of data, we describe possible interpretations. Most novel, but in our view most attractive, is a major role for ion pairing. If one admits that ions near charge transfer orbitals should have a stabilizing effect, and if one doubts that there would be any unique configuration for ion pairs, then it would seem that a continuous variation of excited state behavior is mandatory. This mechanism accounts for the fact that highly asymmetric substitutions at the 4-position of the phen ligand that most affects charge transfer always show dual emission and offer the most exaggerated differences between the two emissions. Other possibilities remain, given the data available at this time.

The discovery of new light-triggered prodrugs based on ruthenium (II) complexes is a promising approach for photoactivated chemotherapy (PACT). The light-mediated activation of "strained" Ru(II) polypyridyl complexes resulted in ligand release and produced a ligand-deficient metal center capable of forming covalent adducts with biomolecules such as DNA. Based on the strategy of exploiting structural distortion to activate photochemistry, biologically active small molecules were coordinated to a Ru(II) scaffold to create light-triggered dual-action agents. Thirteen new Ru(II) complexes with pyridyl-pyrazol(in)e ligands were synthesized, and their photochemical reactivity and anticancer properties were investigated. Isomeric bidentate ligands were investigated, where "regular" ligands (where the coordinated nitrogens in the heterocycles are linked by C-C atoms) were compared to "inverse" isomers (where the coordinated nitrogens in the heterocycles are linked by C-N atoms). Coordination of the regular 3-(pyrid-2-yl)-pyrazol(in)es to a Ru(II) bis-dimethylphenanthroline scaffold yielded photoresponsive compounds with promising photochemical and biological properties, in contrast to the inverse 1-(pyrid-2-yl)-pyrazolines. The introduction of a phenyl ring to the 1N-pyrazoline cycle increased the distortion in complexes and improved ligand release upon light irradiation (470 nm) up to 5-fold in aqueous media. Compounds 1-8, containing pyridyl-pyrazol(in)e ligands, were at least 20-80-fold more potent than the parent pyridyl-pyrazol(in)es, and exhibited biological activity in the dark, with half-maximal inhibitory concentration (IC50) values ranging from 0.2 to 7.6 μM in the HL60 cell line, with complete growth inhibition upon light irradiation. The diversification of coligands and introduction of a carboxylic acid into the Ru(II) complex resulted in compounds 9-12, with up to 146-fold improved phototoxicity indices compared with complexes 1-8.

Ruthenium complexes are often investigated as potential replacements for platinum-based chemotherapeutics in hopes of identifying systems with improved tolerability in vivo and reduced susceptibility to cellular resistance mechanisms. Inspired by phenanthriplatin, a non-traditional platinum agent that contains only one labile ligand, monofunctional ruthenium polypyridyl agents have been developed, but until now, few demonstrated promising anticancer activity. Here we introduce a potent new scaffold, based on [Ru(tpy)(dip)Cl]Cl (tpy = 2,2':6',2''-terpyridine and dip = 4,7-diphenyl-1,10-phenanthroline) in pursuit of effective Ru(ii)-based monofunctional agents. Notably, the extension of the terpyridine at the 4' position with an aromatic ring resulted in a molecule that was cytotoxic in several cancer cell lines with sub-micromolar IC₅₀ values, induced ribosome biogenesis stress, and exhibited minimal zebrafish embryo toxicity. This study demonstrates the successful design of a Ru(ii) agent that mimics many of the biological effects and phenotypes seen with phenanthriplatin, despite numerous differences in both the ligands and metal center structure.