12 research outputs found

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

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    [Ru­(bpy)<sub>2</sub>dmdppz]<sup>2+</sup> (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)<sub>2</sub>dppz]<sup>2+</sup> (dppz = dipyridylphenazine). [Ru­(bpy)<sub>2</sub>dmdppz]<sup>2+</sup> 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

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    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

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

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    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

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    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

    Modifying Charge and Hydrophilicity of Simple Ru(II) Polypyridyl Complexes Radically Alters Biological Activities: Old Complexes, Surprising New Tricks

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    Compounds capable of light-triggered cytotoxicity are appealing potential therapeutics, because they can provide spatial and temporal control over cell killing to reduce side effects in cancer therapy. Two simple homoleptic Ru­(II) polypyridyl complexes with almost-identical photophysical properties but radically different physiochemical properties were investigated as agents for photodynamic therapy (PDT). The two complexes were identical, except for the incorporation of six sulfonic acids into the ligands of one complex, resulting in a compound carrying an overall −4 charge. The negatively charged compound exhibited significant light-mediated cytotoxicity, and, importantly, the negative charges resulted in radical alterations of the biological activity, compared to the positively charged analogue, including complete abrogation of toxicity in the dark. The charges also altered the subcellular localization properties, mechanism of action, and even the mechanism of cell death. The incorporation of negative charged ligands provides a simple chemical approach to modify the biological properties of light-activated Ru­(II) cytotoxic agents

    Design of Cytochrome P450 1B1 Inhibitors <i>via</i> a Scaffold-Hopping Approach

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    Cytochrome P450 1B1 (CYP1B1) is a potential drug target in cancer research that is overexpressed in several solid tumors but is present only at low levels in healthy tissues. Its expression is associated with resistance to common chemotherapeutics, while inhibitors restore efficacy to these drugs in model systems. The majority of CYP1B1 inhibitors are derived from a limited number of scaffolds, and few have achieved outstanding selectivity against other human CYPs, which could impede clinical development. This study explores a new chemical space for CYP1B1 inhibitors using a scaffold-hopping approach and establishes 2,4-diarylthiazoles as a promising framework for further development. From a small library, compound 15 emerged as the lead, with picomolar CYP1B1 inhibition, and over 19,000-fold selectivity against its relative, CYP1A1. To investigate the activity of 15, molecular dynamics, optical spectroscopy, point mutations, and traditional structure–activity relationships were employed and revealed key interactions important for the development of CYP1B1 inhibitors

    Photoactive Ru(II) Complexes With Dioxinophenanthroline Ligands Are Potent Cytotoxic Agents

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    Two novel strained ruthenium­(II) polypyridyl complexes containing a 2,3-dihydro-1,4-dioxino­[2,3-<i>f</i>]-1,10-phenanthroline (dop) ligand selectively ejected a methylated ligand when irradiated with >400 nm light. The best compound exhibited a 1880-fold increase in cytotoxicity in human cancer cells upon light-activation and was 19-fold more potent than the well-known chemotherapeutic, cisplatin

    Bacterial Cytological Profiling Reveals the Mechanism of Action of Anticancer Metal Complexes

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    Target identification and mechanistic studies of cytotoxic agents are challenging processes that are both time-consuming and costly. Here we describe an approach to mechanism of action studies for potential anticancer compounds by utilizing the simple prokaryotic system, <i>E. coli,</i> and we demonstrate its utility with the characterization of a ruthenium polypyridyl complex [Ru­(bpy)<sub>2</sub>dmbpy<sup>2+</sup>]. Expression of the photoconvertible fluorescent protein Dendra2 facilitated both high throughput studies and single-cell imaging. This allowed for simultaneous ratiometric analysis of inhibition of protein production and phenotypic investigations. The profile of protein production, filament size and population, and nucleoid morphology revealed important differences between inorganic agents that damage DNA vs more selective inhibitors of transcription and translation. Trace metal analysis demonstrated that DNA is the preferred nucleic acid target of the ruthenium complex, but further studies in human cancer cells revealed altered cell signaling pathways compared to the commonly administrated anticancer agent cisplatin. This study demonstrates <i>E. coli</i> can be used to rapidly distinguish between compounds with disparate mechanisms of action and also for more subtle distinctions within in studies in mammalian cells

    Photoactive Ru(II) Complexes With Dioxinophenanthroline Ligands Are Potent Cytotoxic Agents

    No full text
    Two novel strained ruthenium­(II) polypyridyl complexes containing a 2,3-dihydro-1,4-dioxino­[2,3-<i>f</i>]-1,10-phenanthroline (dop) ligand selectively ejected a methylated ligand when irradiated with >400 nm light. The best compound exhibited a 1880-fold increase in cytotoxicity in human cancer cells upon light-activation and was 19-fold more potent than the well-known chemotherapeutic, cisplatin

    Photoactive Ru(II) Complexes With Dioxinophenanthroline Ligands Are Potent Cytotoxic Agents

    No full text
    Two novel strained ruthenium­(II) polypyridyl complexes containing a 2,3-dihydro-1,4-dioxino­[2,3-<i>f</i>]-1,10-phenanthroline (dop) ligand selectively ejected a methylated ligand when irradiated with >400 nm light. The best compound exhibited a 1880-fold increase in cytotoxicity in human cancer cells upon light-activation and was 19-fold more potent than the well-known chemotherapeutic, cisplatin
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