Ruthenium-based Compounds Research Articles

Differential Cytotoxicity, Cellular Uptake, Apoptosis and Inhibition of BRCA1 Expression of BRCA1-Defective and Sporadic Breast Cancer Cells Induced by an Anticancer Ruthenium(II)-Arene Compound, RAPTA-EA1.

The RAPTA-EA1 complex [ruthenium(II)-arene 1,3,5-triaza-7-phosphaadamantane (pta) complex with an arene-tethered ethacrynic acid ligand] has been reported to overcome drug resistance that developed due to the current use of platinum-based treatments. However, the exact mechanism of action of RAPTA-EA1 remains largely unexplored and unknown. Here we have further studied the effect of RAPTA-EA1 on BRCA1-defective HCC1937 breast cancer cells and compared its effects on BRCA1-competent MCF-7 breast cancer cells. HCC1937 and MCF-7 breast cancer cells were treated with the RAPTA-EA1 complex. The cytotoxicity of ruthenium-induced cells was evaluated by a MTT assay. Cellular uptake of ruthenium was determined by ICP-MS. Cell cycle and apoptosis were assessed using a flow cytometer. Expression of BRCA1 mRNA and its encoded protein was quantitated by a real-time RT-PCR and Western blotting. Differences in cytotoxicity were correlated with the differential accumulations of ruthenium and the induction of apoptosis. The ruthenium complex caused dramatically more damage to the BRCA1 gene in the BRCA1-defective HCC1937 cells than to the BRCA1-competent MCF-7 cells. It decreased the expression of BRCA1 mRNA in the BRCA1-competent cells, while in contrast, its expression increased in the BRCA1-defective cells. However, the expression of the BRCA1 protein was significantly reduced in both types of breast cancer cells. The results presented here have demonstrated a differential cellular response for the BRCA1-defective and BRCA1-competent breast cancer cells to RAPTA-EA1. These findings have provided more insight into the actions and development of the ruthenium-based compounds for use for the treatment of breast cancer.

BRCA1-Associated Triple-Negative Breast Cancer and Potential Treatment for Ruthenium-Based Compounds.

Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2). The clinicopathological characteristics of TNBC include a high grading, a high rate of cell proliferation and a greater degree of chromosomal rearrangement. Patients with triple-negative breast cancer are more likely to be drug resistant and more difficult to treat, and are also frequently BRCA1 mutants. Methylation of the BRCA1 promoter region is associated with a reduction of the BRCA1 mRNA level. TNBC patients with a methylated BRCA1 had a better disease-free survival compared with those with non-methylated BRCA1. From a therapeutic perspective, the expression level of BRCA1 has been a major determinant of the responses to different classes of chemotherapy. BRCA1-dysfunctional tumors are hypersensitive to DNA damaging chemotherapeutic agents like platinum drugs. Although platinum based drugs are currently widely used as conventional chemotherapeutic drugs in breast cancer chemotherapy, their use has several disadvantages. It is therefore of interest to seek out alternative therapeutic metal-based compounds that could overcome the limitations of these platinum based drugs. Ruthenium-based compounds could be the most promising alternative to the platinum drugs. This review highlights the use of BRCA1 as a predictive marker as well as for a potential drug target for anticancer ruthenium compounds.

Interpreting the Paramagnetic NMR Spectra of Potential Ru(III) Metallodrugs: Synergy between Experiment and Relativistic DFT Calculations.

Ruthenium-based compounds are potential candidates for use as anticancer metallodrugs. The central ruthenium atom can be in the oxidation state +2 (e.g., RAPTA, RAED) or +3 (e.g., NAMI, KP). In this study we focus on paramagnetic NAMI analogs of a general structure [4-R-pyH](+)trans-[Ru(III)Cl4(DMSO)(4-R-py)](-), where 4-R-py stands for a 4-substituted pyridine. As paramagnetic systems are generally considered difficult to characterize in detail by NMR spectroscopy, we performed a systematic structural and methodological NMR study of complexes containing variously substituted pyridines. The effect of the paramagnetic nature of these complexes on the (1)H and (13)C NMR chemical shifts was systematically investigated by temperature-dependent NMR experiments and density-functional theory (DFT) calculations. To understand the electronic factors influencing the orbital (δ(orb), temperature-independent) and paramagnetic (δ(para), temperature-dependent) contributions to the total NMR chemical shifts, a relativistic two-component DFT approach was used. The paramagnetic contributions to the (13)C NMR chemical shifts are correlated with the distribution of spin density in the ligand moiety and the (13)C isotropic hyperfine coupling constants, Aiso((13)C), for the individual carbon atoms. To analyze the mechanism of spin distribution in the ligand, the contributions of molecular spin-orbitals (MSOs) to the hyperfine coupling constants and the spatial distribution of the z-component of the spin density in the MSOs calculated at the relativistic four-component DFT level are discussed and rationalized. The significant effects of the substituent and the solvent on δ(para), particularly the contact contribution, are demonstrated. This work should contribute to further understanding of the link between the electronic structure and the NMR chemical shifts in open-shell systems, including the ruthenium-based metallodrugs investigated in this account.

Ruthenium (II) complexes containing 2-mercaptothiazolinates as ligands and evaluation of their antimicrobial activity

In this work, two novel ruthenium-based compounds containing mercaptothiazolinate ligands were synthesized. A methanol (MeOH) solution containing [RuCl2(PPh3)3], 2-mercaptothiazoline (Hmctz) or 2-mercaptobenzothiazoline (Hmcbtz) (ligand/Ru=2) and triethylamine (NEt3) was refluxed leading to the formation of neutral complexes with the general formula cis-[Ru(N–S)2(PPh3)2] (N–S=mctz− – complex 1; N–S=mcbtz− – complex 2). We used NMR (1H and 31P{1H}), vibrational spectroscopy (FTIR), and elemental analysis to analyze these two complexes. Cyclic voltammetry revealed that complexes 1 and 2 underwent a reversible one-electron process due to the Ru(III)/Ru(II) pair. Reactivity of the complexes 1 and 2 with dmso leading to the substitution of one PPh3 by dmso was observed (complexes 3 and 4). Complex 1 showed higher antimicrobial activity against Gram (+) and Gram (−) bacteria (Bacillus subtilis and Escherichia coli, respectively). The formation of complex [Ru(mctz)2(dmso)(PPh3)] (3) was faster than complex [Ru(mcbtz)2(dmso)(PPh3)] (4) and this may account for the higher antibacterial activity of complex 1. Single-crystal X-ray diffraction furnished the molecular structures of complex 1 and of the product of its reaction with dmso, [Ru(mctz)2(dmso)(PPh3)] (3).

Cytotoxic effects of the compound cis-tetraammine(oxalato)ruthenium(III) dithionate on K-562 human chronic myelogenous leukemia cells.

Chemotherapy is a common treatment for leukemia. Ruthenium complexes have shown potential utility in chemotherapy and photodynamic therapy. The identification of new chemotherapeutics agents is critical for further progress in the treatment of leukemia. Ruthenium complexes generally have lower toxicities compared to cisplatin attributed to their specific accumulation in cancer tissues. Based on these evidences, in the present work we studied the cytotoxic activity of the ruthenium(III) compound cis-tetraammine(oxalato)ruthenium(III) dithionate - {cis-[Ru(C2O4)(NH3)4]2(S2O6)} against human chronic myelogenous leukemia cells (K-562) tumor cell line. The tested compound induces cell death in a dose and time dependent manner on K-562 cells. It is found that the effect was improved linearly while prolonging the incubation time. Compared to the cell cycle profiles of untreated cells, flow cytometric analysis indicated the sub-G1 arresting effect of ruthenium compound on K-562 cells. In our study, {cis-[Ru(C2O4)(NH3)4]2(S2O6)} shows a significant increase in tailed cells in any of the concentrations tested compared with negative control. Consequently, the concentration of {cis-[Ru(C2O4)(NH3)4]2(S2O6)} might be associated cytotoxicity with direct effect on K-562 cells DNA. Thus, it can be deducted that ruthenium-based compounds present selectivity to enter both tumor and normal cells. Additional studies are needed to determine the molecular mechanisms of the active components and to evaluate the potential in vivo anticancer activity of the cis-tetraammine(oxalato)ruthenium(III) dithionate.

Subcellular localization and transport kinetics of ruthenium organometallic anticancer compounds in living cells: a dose-dependent role for amino acid and iron transporters.

Ruthenium-based compounds are developed for anticancer treatment, but their mode of action including their import mechanism and subcellular localization remains elusive. Here, we used the intrinsic luminescent properties of cytotoxic organoruthenium (Ru(II)) compounds obtained with an anionic cyclometalated 2-phenylpyridine chelate and neutral aromatic chelating ligands (e.g., phenanthrolines) to follow their behavior in living cells. We established that the difference in sensitivity between cancer cells and noncancerous cells toward one of the compounds correlates with its import kinetics and follows a balance between active and passive transport. The active-transport mechanism involves iron and amino-acid transporters, which are transcriptionally regulated by the drug. We also demonstrated a correlation between the accumulation of these compounds in specific compartments (endoplasmic reticulum, nucleus, mitochondria) and the activation of specific cytotoxic mechanisms such as the mitochondrial stress pathway. Our study pinpoints a novel and complex mechanism of accumulation of ruthenium drugs in cancer cells.

Novel electrochemiluminescent materials for sensor applications.

Electrochemiluminescence (ECL) uses redox reactions to generate light at an electrode surface, and is gaining increasing attention for biosensor development due to its high sensitivity and excellent signal-to-noise ratio. ECL studies of monodisperse oligofluorene-truxenes (T4 series) have been reported previously, showing the production of stable radical cations and radical anions, generating blue ECL. The compound in this study differs from the original structures, in that there are 2,1,3-benzothiadazole (BT) units inserted between the first and second fluorene units of the quarterfluorenyl arms. It was therefore anticipated that the incorporation of these highly luminescent and ECL-active compounds into sensor development would lead to significant decreases in detection limits. In this contribution, we report on the impact of incorporating these novel complexes into sensor devices on the ECL efficiency, as well as the ability of these to improve the detection sensitivity and decrease the limit of detection using the reagent-free detection of model analytes. The real world impact of these compounds is elucidated through the comparison with more standard ECL materials such as ruthenium-based compounds. The potential for multiple applications is to be examined within this contribution.

Analysis of the cytotoxic effects of ruthenium-ketoconazole and ruthenium-clotrimazole complexes on cancer cells.

Ruthenium-based compounds have intriguing anti-cancer properties, and some of these novel compounds are currently in clinical trials. To continue the development of new metal-based drug combinations, we coupled ruthenium (Ru) with the azole compounds ketoconazole (KTZ) and clotrimazole (CTZ), which are well-known antifungal agents that also display anticancer properties. We report the activity of a series of 12 Ru-KTZ and Ru-CTZ compounds against three prostate tumor cell lines with different androgen sensitivity, as well as cervical cancer and lymphoblastic lymphoma cell lines. In addition, human cell lines were used to evaluate the toxicity against non-transformed cells and to establish selectivity indexes. Our results indicate that the combination of ruthenium and KTZ/CTZ in a single molecule results in complexes that are more cytotoxic than the individual components alone, displaying in some cases low micromolar CC50 values and high selectivity indexes. Additionally, all compounds are more cytotoxic against prostate cell lines with lower cytotoxicity against non-transformed epidermal cell lines. Some of the compounds were found to primarily induce cell death via apoptosis yet weakly interact with DNA. Our studies also demonstrate that the cytotoxicity induced by our Ru-based compounds is not directly related to their ability to interact with DNA.

Dye Sensitized Solar Cell Using Natural Dyes as Chromophores - Review

The molecular dye is an essential component of the Dye sensitized solar cell (DSSC), and improvements in efficiency over the last 15 years have been achieved by tailoring the optoelectronic properties of the dye. The most successful dyes are based on ruthenium bipyridyl compounds, which are characterized by a large absorption coefficient in the visible part of the solar spectrum, good adsorption properties, excellent stability, and efficient electron injection. However, ruthenium-based compounds are relatively expensive, and organic dyes with similar characteristics and even higher absorption coefficients have recently been reported; solar cells with efficiencies of up to 9% have been reported. Organic dyes with a higher absorption coefficient could translate into thinner nanostructured metal oxide films, which would be advantageous for charge transport both in the metal oxide and in the permeating phase, allowing for the use of higher viscosity materials such as ionic liquids, solid electrolytes or hole conductors. Organic dyes used in the DSSC often bear a resemblance to dyes found in plants, fruits, and other natural products, and several dye-sensitized solar cells with natural dyes have been reported. This paper gives an over-view of the recent works in DSSC using the natural dyes as chromophores.

In VitroEffects of Novel Ruthenium Complexes in Neospora caninum and Toxoplasma gondii Tachyzoites

Upon the screening of 16 antiproliferative compounds against Toxoplasma gondii and Neospora caninum, two hydrolytically stable ruthenium complexes (compounds 16 and 18) exhibited 50% inhibitory concentrations of 18.7 and 41.1 nM (T. gondii) and 6.7 and 11.3 nM (N. caninum). To achieve parasiticidal activity with compound 16, long-term treatment (22 to 27 days at 80 to 160 nM) was required. Transmission electron microscopy demonstrated the rapid impact on and ultrastructural alterations in both parasites. These preliminary findings suggest that the potential of ruthenium-based compounds should thus be further exploited.

New applications of old metal-binding drugs in the treatment of human cancer

Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium-based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept.

Approaching tumour therapy beyond platinum drugs: Status of the art and perspectives of ruthenium drug candidates

The study of metal complexes for the treatment of cancer diseases has resulted in the identification of some unique properties of ruthenium-based compounds. Among these inorganic-based agents, two of them, namely the ruthenium(III) drugs NAMI-A and KP1019 have undertaken with some success the clinical evaluations of phase I and preliminary phase II trials in patients. Here we highlight the strategies that have led to the discovery of metal-based (NAMI-A and KP1019) and of organometallic (RM175, RAPTA-T, RDC11 and DW1/2) ruthenium-based complexes, and we report their main biological/pharmacological characteristics and expectations for further development.

Ruthenium(II) Arene Compounds as Versatile Anticancer Agents

Ruthenium-based compounds are an attractive alternative to clinically used platinum drugs due to several features including a wide range of accessible oxidation states, varied synthetic chemistry and typically lower general toxicities. One series of ruthenium(II)-arene-pta, RAPTA (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1] decane) compounds has been found to show particularly high selectivity towards cancer cells in both in vitro and in vivo studies.

Ruthenium-based electrocatalysts for oxygen reduction reaction—a review

A major impediment to the commercialization of fuel cells is the low activity of electrocatalysts for the oxygen reduction reaction that involves multiple electron transfer steps. Platinum is considered the best cathode catalyst toward oxygen reduction to water; however, Pt remains an expensive metal of low abundance, and it is of great importance to find Pt-free metal alternatives. Among various Pt-free catalysts under development, ruthenium-based compounds show significant catalytic activity and selectivity for four-electron reduction of oxygen to water in acidic environments. This article provides a short review on the different classes of Ru-based catalysts focusing on the catalytically active reaction sites and the oxygen reduction mechanism in acidic media. After a brief discussion of the oxygen reduction kinetics on a pure Ru metal, the paper reviews the catalytic properties of the selected Ru compounds, including crystalline Chevrel-phase chalcogenides, nanostructured Ru and Ru–Se clusters, and Ru–N chelate compounds.

Antiangiogenic properties of selected ruthenium(III) complexes that are nitric oxide scavengers.

The nitric oxide synthase (NOS) pathway has been clearly demonstrated to regulate angiogenesis. Increased levels of NO correlate with tumour growth and spreading in different experimental and human cancers. Drugs interfering with the NOS pathway may be useful in angiogenesis-dependent tumours. The aim of this study was to pharmacologically characterise certain ruthenium-based compounds, namely NAMI-A, KP1339, and RuEDTA, as potential NO scavengers to be used as antiangiogenic/antitumour agents. NAMI-A, KP1339 and RuEDTA were able to bind tightly and inactivate free NO in solution. Formation of ruthenium–NO adducts was documented by electronic absorption, FT-IR spectroscopy and 1H-NMR. Pretreatment of rabbit aorta rings with NAMI-A, KP1339 or RuEDTA reduced endothelium-dependent vasorelaxation elicited by acetylcholine. This effect was reversed by 8-Br-cGMP. The key steps of angiogenesis, endothelial cell proliferation and migration stimulated by vascular endothelial growth factor (VEGF) or NO donor drugs, were blocked by NAMI-A, KP1339 and RuEDTA, these compounds being devoid of any cytotoxic activity. When tested in vivo, NAMI-A inhibited angiogenesis induced by VEGF. It is likely that the antitumour properties previously observed for ruthenium-based NO scavengers, such as NAMI-A, are related to their NO-related antiangiogenic properties.

Ruthenium in Medicine: Current Clinical Uses and Future Prospects

There is no doubt about the success of precious metals in the clinic, with, for example, platinum compounds being widely used in the treatment of cancer, silver compounds being useful antimicrobial agents and gold compounds used routinely in the treatment of rheumatoid arthritis. The medicinal properties of the other platinum group metals are now being recognised and of these a ruthenium anticancer agent has recently entered the clinic, showing promising activity on otherwise resistant tumours. Like all metal drugs, the activity of the ruthenium compounds depends on both the oxidation state and the ligands. By manipulating these features ruthenium-centred antimalarial, antibiotic and immunosuppressive drugs have been made. In addition, ruthenium has unique properties which make it particularly useful in drug design. In this review we discuss ruthenium from a clinical stance and outline the medicinal uses of ruthenium-based compounds.

Ruthenium-based compounds and tumour growth control (review).

Heavy metals have often been represented, as an uncertain entity related to renal and other risks of toxicity. In favour of this thought there are several lines of evidence, first of all traffic pollution, other evidence that metals such as arsenite, mercury, cadmium or even iron or radioactive heavy metals, that may be introduced into the body by accident, have been responsible of well known pathologies (for example saturnism with lead) or acute toxicity. Therefore, the biological and medical literature have debated on this subject, mainly from the toxicological point of view, rather than studying possible advantages that might come from compounds based on these metals. Exceptions are represented by studies on the role of metal ions in the biochemistry of enzymes and energy production and, although with less emphasis, on their possible use for correcting metabolic malfunctions. Ruthenium, as a metal, has received an even poorer interest and besides the use in histology, neither ruthenium ions nor ruthenium compounds have a clear place in medicine and biology. Nevertheless, since the middle seventies, many studies have been published, showing in a convincible and repetitive manner, the possible advantages of ruthenium as a base for new competitive drugs. The aim of this review is therefore that of critically examining the past and the actual work on ruthenium compounds with emphasis on their proposed role in cancer therapy.