Jessica K. White

An overview of photosubstitution reactions of Ru(II) imine complexes and their application in photobiology and photodynamic therapy

This article is a short review that presents a short review of photosubstitution reactions of Ru(II) imine complexes and illustrates their use in the development of therapeutic agents. The review begins with an overview of the photophysical behavior and common photoreactions of Ru(II) imine complexes, with select examples from the literature since the 1960s. It is followed by a more detailed picture of the application of knowledge gained over the years in the development of Ru(II) complexes for photobiology and photodynamic therapy.

Selective Release of Aromatic Heterocycles from Ruthenium Tris(2-pyridylmethyl)amine with Visible Light.

Three complexes of the general formula [Ru(TPA)L2](PF6)2 [TPA = tris(2-pyridylmethyl)amine], where L = pyridine (1), nicotinamide (2), and imidazole (3), were prepared and characterized spectroscopically. X-ray crystallographic data were obtained for 1 and 3. Complexes 1-3 show strong absorption in the visible region and selective release of heterocycles upon irradiation with visible light. Time-dependent density functional theory calculations are consistent with the presence of singlet metal-to-ligand charge-transfer bands in the visible region in 1-3. Caged heterocycles 1-3 are highly stable in solution in the dark, including in cell growth media. Cell viability data show no signs of toxicity of 1-3 against PC-3 cells at concentrations up to 100 μM under light and dark conditions, consistent with Ru(TPA) acting as a nontoxic and effective photocaging group for aromatic heterocycles.

Caging the uncageable: using metal complex release for photochemical control over irreversible inhibition

Photochemical control over irreversible inhibition was shown using Ru(ii)-caged inhibitors of cathepsin L. Levels of control were dependent on where the Ru(ii) complex was attached to the organic inhibitor, reaching >10 : 1 with optimal placement. A new strategy for photoreleasing Ru(ii) fragments from inhibitor-enzyme conjugates is also reported.

Effects of Methyl Substitution in Ruthenium Tris(2-pyridylmethyl)amine Photocaging Groups for Nitriles

Four complexes of the general formula [Ru(L)(CH3CN)2](PF6)2, [L = TPA (5), MeTPA (6), Me2TPA (7), and Me3TPA (8)] [TPA = tris[(pyridin-2-yl)methyl]amine, where methyl groups were introduced consecutively onto the 6-position of py donors of TPA, were prepared and characterized by various spectroscopic techniques and mass spectrometry. While 5 and 8 were isolated as single stereoisomers, 6 and 7 were isolated as mixtures of stereoisomers in 2:1 and 1.5:1 ratios, respectively. Steric effects on ground state stability and thermal and photochemical reactivities were studied for all four complexes using (1)H NMR and electronic absorption spectroscopies and computational studies. These studies confirmed that the addition of steric bulk accelerates photochemical and thermal nitrile release.

Imaging Sites of Inhibition of Proteolysis in Pathomimetic Human Breast Cancer Cultures by Light-Activated Ruthenium Compound

The cysteine protease cathepsin B has been causally linked to progression and metastasis of breast cancers. We demonstrate inhibition by a dipeptidyl nitrile inhibitor (compound 1) of cathepsin B activity and also of pericellular degradation of dye-quenched collagen IV by living breast cancer cells. To image, localize and quantify collagen IV degradation in real-time we used 3D pathomimetic breast cancer models designed to mimic the in vivo microenvironment of breast cancers. We further report the synthesis and characterization of a caged version of compound 1, [Ru(bpy)2(1)2](BF4)2 (compound 2), which can be photoactivated with visible light. Upon light activation, compound 2, like compound 1, inhibited cathepsin B activity and pericellular collagen IV degradation by the 3D pathomimetic models of living breast cancer cells, without causing toxicity. We suggest that caged inhibitor 2 is a prototype for cathepsin B inhibitors that can control both the site and timing of inhibition in cancer.

Dual photoreactivity of a new Rh2(II,II) complex for biological applications

A new Rh2(II,II) complex containing one dppn (benzo[i]dipyrido[3,2-a:2,3-c]phenazine) ligand with an extended π-system, cis-H,H-[Rh2(OCCH3NH)2(dppn)(CH3CN)2]2+ (2), was synthesized and characterized. The dppn ligand, which serves as a DNA base pair intercalator, chelates to a single Rh center and is positioned trans to the amidato N atoms of the bridging acetamide ligand. This ligand also possesses a low-lying dppn-centered 3ππ* state that is advantageous for the sensitization of singlet oxygen (1O2), which complex 2 produced with a quantum yield, Φ 1O2460, of 0.22(7) with 460 nm excitation. In addition, one equivalent of CH3CN is released from 2 upon irradiation with visible light, generating cis-H,H-[Rh2(OCCH3NH)2(dppn)(H2O)(CH3CN)]2+ in aqueous media with photoinduced ligand exchange quantum yield, ΦLE450, of 0.0033(1). Thermal denaturation and relative viscosity studies are consistent with a π-stacking interaction of 2 with double-stranded DNA together with covalent binding to the duplex upon irradiation with visible light. Therefore, 2 exhibits dual photoreactivity towards DNA, making it potentially useful for photochemotherapy with enhanced activity relative to compounds able to achieve only one mode of cell death upon irradiation.