Modifying charge and hydrophilicity of simple Ru(II) polypyridyl complexes radically alters biological activities: old complexes, surprising new tricks.

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.

Magnetic Resonance Imaging of Macrophage Response to Radiation Therapy.

BACKGROUND: Magnetic resonance imaging (MRI) is a non-invasive imaging modality which, in conjunction with biopsies, provide a qualitative assessment of tumor response to treatment. Intravenous injection of contrast agents such as fluorine (19F) nanoemulsions labels systemic macrophages, which can, then, be tracked in real time with MRI. This method can provide quantifiable insights into the behavior of tumor-associated macrophages (TAMs) in the tumor microenvironment and macrophage recruitment during therapy. METHODS: Female mice received mammary fat pad injections of murine breast or colon cancer cell lines. The mice then received an intravenous 19F nanoemulsion injection, followed by a baseline 19F MRI. For each cancer model, half of the mice then received 8 Gy of localized radiation therapy (RT), while others remained untreated. The mice were monitored for two weeks for tumor growth and 9F signal using MRI. RESULTS: Across both cohorts, the RT-treated groups presented significant tumor growth reduction or arrest, contrary to the untreated groups. Similarly, the fluorine signal in treated groups increased significantly as early as four days post therapy. The fluorine signal change correlated to tumor volumes irrespective of time. CONCLUSION: These results demonstrate the potential of 19F MRI to non-invasively track macrophages during radiation therapy and its prognostic value with regard to tumor growth.

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.

Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines.

8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2-15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.

Chemical precipitation of heavy metals from acid mine drainage.

The 1,3-benzenediamidoethanethiol dianion (BDET, known commercially as MetX) has been developed to selectively and irreversibly bind soft heavy metals from aqueous solution. In the present study BDET was found to remove > 90% of several toxic or problematic metals from AMD samples taken from an abandoned mine in Pikeville, Kentucky. The concentrations of metals such as iron, may be reduced at pH 4.5 from 194 ppm to below 0.009 ppm. The formation of stoichiomietric BDET-metal precipitates in this process was confirmed using X-ray powder diffraction (XRD), proton nuclear magnetic resonance (1H NMR), and infrared spectroscopy (IR).

Soft metal preferences of 1,3-benzenediamidoethanethiol.

Recent studies indicate that the sodium salt of 1,3-benzenediamidoethanethiol (BDET) is both economical and effective in precipitating mercury and other heavy metals from water. Because wastewaters and contaminated natural waters may contain a variety of heavy metals, it is important to determine how different heavy metals may interact with BDET, and whether free metals may displace those that are bound. To explore this possibility, Cd-, Cu-, Pb-, Mn-, Hg- and Zn-BDET were leached separately under a nitrogen purge for up to 240 h in pH 3 aqueous solutions containing 0.100 mmol of all five heavy metals. The leaching studies indicate that dissolved Hg has a strong tendency to displace Cd, Cu, Mn, Pb, and Zn from the BDET structure.

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.

A new type of DNA "light-switch": a dual photochemical sensor and metalating agent for duplex and G-quadruplex DNA.

Ru(bpy)2dppz, a well studied "light-switch" metal complex, transforms into a photochemical "light-switch" and DNA damaging agent by incorporating structural strain. This distorted compound is photoreactive and ejects a ligand upon binding duplex and G-quadruplex DNA, producing a reactive metal center that metalates the DNA.

Light-activated ruthenium complexes photobind DNA and are cytotoxic in the photodynamic therapy window.

Incorporation of biquinoline ligands into Ru(II) polypyridyl complexes produces light-activated systems that eject a ligand and photobind DNA after irradiation with visible and near-IR light. Structural analysis shows that distortion facilitates the photochemistry, and gel shift and cytotoxicity studies prove the compounds act as anti-cancer photodynamic therapy (PDT) agents in the tissue penetrant region.

Advanced mercury removal from gold leachate solutions prior to gold and silver extraction: a field study from an active gold mine in Peru.

Mercury contamination in the Gold-Cyanide Process (GCP) is a serious health and environmental problem. Following the heap leaching of gold and silver ores with NaCN solutions, portions of the mercury-cyano complexes often adhere to the activated carbon (AC) used to extract the gold. During the electrowinning and retorting steps, mercury can be (and often is) emitted to the air as a vapor. This poses a severe health hazard to plant workers and the local environment. Additional concerns relate to the safety of workers when handling the mercury-laden AC. Currently, mercury treatment from the heap leach solution is nonexistent. This is due to the fact that chelating ligands which can effectively work under the adverse pH conditions (as present in the heap leachate solutions) do not exist. In an effort to economically and effectively treat the leachate solution prior to passing over the AC, a dipotassium salt of 1,3-benzenediamidoethanethiol (BDET2-) has been developed to irreversibly bind and precipitate the mercury. The ligand has proven to be highly effective by selectively reducing mercury levels from average initial concentrations of 34.5 ppm (parts per million) to 0.014 ppm within 10 min and to 0.008 ppm within 15 min. X-ray powder diffraction (XRD), proton nuclear magnetic resonance (1H NMR), Raman, and infrared (IR) spectroscopy demonstrate the formation of a mercury-ligand compound, which remains insoluble over pH ranges of 0.0-14.0. Leachate samples from an active gold mine in Peru have been analyzed using cold vapor atomic fluorescence (CVAF) and inductively coupled plasma optical emission spectroscopy (ICP-OES) for metal concentrations before and after treatment with the BDET2- ligand.