Light-Activated Compounds

The presently-disclosed subject matter includes light-activated ruthenium compounds. In some embodiments the compounds release one or more ligands when exposed to light, and in specific embodiments the light includes a wavelength of about 500 nm to about 1000 nm. The present compounds can also comprise an overall charge, wherein the overall charge can be a positive overall charge or a negative overall charge. Further still, embodiments include methods of treating cancer in a subject by administering a compound and then exposing a site of the subject to light

Redox Couples of Inducible Nitric Oxide Synthase

We report direct electrochemistry of the iNOS heme domain in a DDAB film on the surface of a basal plane graphite electrode. Cyclic voltammetry reveals Fe^(III/II) and Fe^(II/I) couples at −191 and −1049 mV (vs Ag/AgCl). Imidazole and carbon monoxide in solution shift the Fe^(III/II) potential by +20 and +62 mV, while the addition of dioxygen results in large catalytic waves at the onset of Fe^(III) reduction. Voltammetry at higher scan rates (with pH variations) reveals that the Fe^(III/II) cathodic peak can be resolved into two components, which are attributable to Fe^(III/II) couples of five- and six-coordinate hemes. Digital simulation of our experimental data implicates water dissociation from the heme as a gating mechanism for ET in iNOS

Photodimerizable ditopic ligand.

International audience[reaction: see text] The synthesis, photophysical properties, and structural characterization of a photodimerizable ditopic ligand are described. Upon irradiation at 366 nm, ligand 1 dimerizes to the head-to-tail tetra-bpy ligand 2. This thermally stable photodimer can be dissociated back to 1 using higher energy irradiation (254 nm)

Mechanistic Study on the Photochemical “Light Switch” Behavior of [Ru(bpy)₂dmdppz]²⁺

[Ru­(bpy)₂dmdppz]²⁺ (bpy = 2,2′-bipyridine and dmdppz = 3,6-dimethyl dipyridylphenazine), a strained Ru­(II) polypyridyl complex, is a derivative of the well-known luminescent “light switch”, [Ru­(bpy)₂dppz]²⁺ (dppz = dipyridylphenazine). [Ru­(bpy)₂dmdppz]²⁺ is of interest because it acts as a photochemical sensor and metalating agent for DNA. Here we report a detailed study to elucidate the mechanism of ligand substitution by investigating the photochemical reaction in a variety of solvents and by determining the effects of different incoming ligands, the incoming ligand concentration, and the temperature dependence. Results from these studies indicate that the mechanism of substitution is associative or interchange associative, in contrast with the dissociative mechanism of other photolabile Ru­(II) polypyridyl complexes

Combining a Ru(II) “Building Block” and Rapid Screening Approach to Identify DNA Structure-Selective “Light Switch” Compounds

A chemically reactive Ru­(II) “building block”, able to undergo condensation reactions with substituted diamines, was utilized to create a small library of luminescent “light switch” dipyrido-[3,2-<i>a</i>:2′,3′-<i>c</i>] phenazine (dppz) complexes. The impact of substituent identity, position, and the number of substituents on the light switch effect was investigated. An unbiased, parallel screening approach was used to evaluate the selectivity of the compounds for a variety of different biomolecules, including protein, nucleosides, single stranded DNA, duplex DNA, triplex DNA, and G-quadruplex DNA. Combining these two approaches allowed for the identification of hit molecules that showed different selectivities for biologically relevant DNA structures, particularly triplex and quadruplex DNA

Photochemical and Photobiological Properties of Pyridyl-pyrazol(in)e-Based Ruthenium(II) Complexes with Sub-micromolar Cytotoxicity for Phototherapy

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

Coordination of Hydroxyquinolines to a Ruthenium Bis-dimethyl-phenanthroline Scaffold Radically Improves Potency for Potential as Antineoplastic Agents

A series of ruthenium coordination complexes containing hydroxyquinoline ligands were synthesized that exhibited radically improved potencies up to 86-fold greater than clioquinol, a known cytotoxic compound. The complexes were also >100-fold more potent than clioquinol in a tumor spheroid model, with values similar to currently used chemotherapeutics for the treatment of solid tumors. Cytotoxicity occurs through rapid processes that induce apoptosis but appear to be mediated by cell-cycle independent mechanisms. The ruthenium complexes do not inhibit the proteasome at concentrations relevant for cell death, and contrary to previous reports, clioquinol and other hydroxyquinoline compounds do not act as direct proteasome inhibitors to induce cell death

Strained Ruthenium Complexes Are Potent Light-Activated Anticancer Agents

Strained ruthenium (Ru) complexes have been synthesized and characterized as novel agents for photodynamic therapy (PDT). The complexes are inert until triggered by visible light, which induces ligand loss and covalent modification of DNA. An increase in cytotoxicity of 2 orders of magnitude is observed with light activation in cancer cells, and the compounds display potencies superior to cisplatin against 3D tumor spheroids. The use of intramolecular strain may be applied as a general paradigm to develop light-activated ruthenium complexes for PDT applications