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PubMed2000

Effects of NAMI-A and some related ruthenium complexes on cell viability after short exposure of tumor cells.

A series of three ruthenium complexes, i.e. trans-dichlorote-trakisdimethyl-sulfoxide ruthenium(ll) (trans-Ru), imidazolium trans-imidazoletetra-chlororuthenate (ICR) and sodium trans-tetramethylensulfoxideisoquinoline-tetrachlororuthenate (TEQU), were studied in vitro in comparison to NAMI-A, a potent ruthenium-based antimetastasis agent. In vitro challenge of TS/A adenocarcinoma or KB oral carcinoma tumor cells with 10(-4) M concentration for 1 h evidenced the lack of cytotoxicity of NAMI-A, ICR and trans-Ru, the accumulation of cells in the G2/M pre-mitotic cell phase by NAMI-A and the attachment of tumor cells to the plastic substrate was significantly greater for NAMI-A than for ICR. These data stress that in vitro cytotoxicity is not necessary for in vivo activity of ruthenium antitumor complexes: NAMIA, ICR and trans-Ru, are in fact known to be active against murine tumors in the mouse system. Rather, TEQU, the compound free of in vivo activity, was the only one to reduce cell growth of in vitro cultured cells. In conclusion, the data on the effects of NAMI-A on in vitro cultured cells show that the increase of cell adhesion properties and the transient cell cycle arrest in the G2/M phase are much more relevant than the effects on cell properties relevant to cell growth (i.e. on CD44, CD54 or CD71 antigens) for determining in vivo antimetastasis activity.

Adenocarcinoma↗
PubMed2006

DNA binding mode of ruthenium complexes and relationship to tumor cell toxicity.

Transition-metal-based compounds constitute a discrete class of chemotherapeutics, widely used in the clinic as antitumor and antiviral agents. Examples of established antitumor metallodrugs, routinely used in the clinic, are cisplatin [cis-diamminedichloroplatinum(II)] and its analogues carboplatin and oxaliplatin. However, drug resistance and side effects have limited their clinical utility. These limitations have prompted a search for more effective and less toxic metal-based antitumor agents. Some of the efforts have been directed in the design of non-platinum, transition-metal-based antitumor agents and ruthenium complexes have attracted much interest as alternative drugs to cisplatin in cancer chemotherapy. Ruthenium complexes demonstrate similar ligand exchange kinetics to those of platinum(II) antitumor drugs already used in the clinic while displaying only low toxicity. This is in part due to the ability of ruthenium complexes to mimic the binding of iron to molecules of biological significance, exploiting the mechanisms that the body has evolved for transport of iron. In addition, the redox potential between the different accessible oxidation states occupied by ruthenium complexes enables the body to catalyze oxidation and reduction reactions, depending on physiological environment. The biochemical changes that accompany cancer alter physiological environment, enabling ruthenium complexes to be selectively activated in cancer tissues. Due to differing ligand geometry between their complexes, ruthenium compounds bind to DNA affecting its conformation differently than cisplatin and its analogues. In addition, non-nuclear targets, such as the mitochondrion and the cell surface, have also been implicated in the antineoplastic activity of some ruthenium complexes. Thus, ruthenium compounds offer the potential over antitumor platinum(II) complexes currently used in the clinic of reduced toxicity, a novel mechanism of action, the prospect of non-cross-resistance and a different spectrum of activity. In other words, some chemical properties make ruthenium compounds well suited for medicinal applications and as an alternative to platinum antitumor drugs in the treatment of cancer cells resistant to cisplatin. Although the pharmacological target for antitumor ruthenium compounds has not been unequivocally identified, there is a large body of evidence indicating that the cytotoxicity of many ruthenium complexes correlates with their ability to bind DNA although few exceptions have been reported. This review summarizes results demonstrating that several ruthenium compounds that exhibit antitumor effects different from cisplatin or its analogues bind DNA and modify it differently than cisplatin or its analogues.

Animals↗
PubMed2001

Preparation, physicochemical characterization and pharmacological study of novel ruthenium(III) complexes with imidazole and benzimidazole derivatives.

Complex compounds of ruthenium(III) with 1,2-dimethylimidazole (CAS 1739-84-0), 2-phenylimidazole (CAS 670-96-2) and 2-aminobenzimidazole (CAS 934-32-7) were prepared and were characterised by physicochemical methods. Coordination sites were determined. The complexes were tested for cytotoxic activity using MTT (3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye-reduction assay and the values LD50 were evaluated.

Animals↗
PubMed1999

Molecular interactions of ruthenium complexes in isolated mammalian nuclei and cytotoxicity on V79 cells in culture.

In this paper, the molecular interactions in isolated mammalian nuclei of three ruthenium complexes, which are putative antineoplastic chemotherapeutic agents effective in reducing metastatic tumours in vivo, have been investigated and compared with the well-known antitumour drug CDDP (cis-diamminedichloroplatinum). The compounds studied are: Natrans-RuCl4(DMSO)Imidazole (NAMI), Natrans-RuCl4(DMSO)Oxazole (NAOX) and Natrans-RuCl4(TMSO)- Isoquinoline (TEQU). This study shows that the drugs bind to DNA but induce few, if any, DNA interstrand crosslinks, which are considered as the main biological lesions involved in the cytotoxic activity of several already known antitumour drugs, whilst in the same experimental conditions, CDDP is confirmed to induce them. On the other hand, proteins appear to be an important target in the cell for these drugs, since proteins-DNA crosslinks are shown to be induced by the complexes. Moreover, we investigated Ru complexes for their direct cytotoxicity on V79 cells in culture, showing that two of them (NAMI and NAOX) do not significantly reduce the cloning efficiency of the cells even at concentrations as high as 2-3 mg/ml: only TEQU both reduces cloning efficiency and induces a significant number of mutants in V79 cells in culture.

Animals↗
PubMed2004

Ruthenium-catalyzed functionalization of aryl carbon-oxygen bonds in aromatic ethers with organoboron compounds.

The ruthenium-catalyzed reaction of aryl ethers having a carbonyl group at the ortho position to the ether group with organoboronates (R-B(OCH2CMe2CH2O), R = aryl, alkenyl, and alkyl) resulted in site-selective C-C bond formation. Among the transition metal complexes screened, the RuH2(CO)(PPh3)3 complex showed the highest activity. Several aromatic ketones having methoxy or phenoxy groups at the ortho position can also be used in this coupling reaction. A variety of arylboronates containing electron-donating (NMe2, OMe, methyl, and vinyl) and -withdrawing (F and CF3) groups reacted with methoxy ketones to give the corresponding coupling products in high yields.

Journal Article↗
PubMed1990

Metal complexes of ruthenium: antineoplastic properties and perspectives.

Octahedral ruthenium(III) and ruthenium(II) complexes show antineoplastic properties on a number of experimental tumors. Tetraammine-, pentaammine-, heterocycle-, and dimethylsulfoxide-coordinated ruthenium complexes have shown high affinity for nitrogen donor ligands in vitro and as a result exhibit various degrees of biological activities including antitumor action in vivo. The chemical behavior of ruthenium(III) complexes indicates the possibility of opening a window of selective toxicity, in practice lacking in the chemotherapeutic approach to neoplastic diseases. Ruthenium ions may accumulate in tumor tissues via a mechanism mediated by transferrin transport. Moreover, binding of ruthenium to DNA is several times higher in its reduced ruthenium(II) form and the reduction from ruthenium(III) prodrugs to the more toxic ruthenium(II) compounds is particularly efficient in tumor hypoxic environments. Correspondingly, solid tumors appear to be more susceptible than those of the lymphoproliferative type. In particular, tumors of the colorectal region and lung tumors (primary or metastatic), which are generally associated with a bad prognosis, have given interesting responses in experimental models, indicating these tumors as preferential targets for the development of ruthenium anticancer drugs.

Animals↗
PubMed2002

Photostability profiles of the experimental antimetastatic ruthenium complex NAMI-A.

NAMI-A is a novel ruthenium complex with selective activity against metastases currently in Phase I clinical trials in The Netherlands. The photostability of this new agent in solid state and in solution has been investigated utilizing a stability-indicating reversed-phase high performance liquid chromatographic (HPLC) assay and ultraviolet/visible (UV/VIS) light spectrophotometry. In solid state, NAMI-A proved to be photostable. In solution, however, the compound degraded rapidly, in a pH-independent manner in the pH range of 2-5. At alkaline pH, the degradation rate was higher than at acidic pH. The type of buffer species had little influence. NAMI-A concentration was inversely related to the photostability. Addition of photostabilizers (5% DMSO, 2% benzyl alcohol, 0.001% curcumin) marginally increased the half-life. NAMI-A's photostability in solution was influenced to the greatest extent by addition of an alcohol, with the least polar solvent system (50% propylene glycol) providing the most stable medium. Based on the presented results, it is recommended to store NAMI-A solutions in the dark.

Antineoplastic Agents↗
PubMed2000

Blood concentration and toxicity of the antimetastasis agent NAMI-A following repeated intravenous treatment in mice.

NAMI-A is a new generation antitumour ruthenium-based agent and characterised by strong efficacy against lung metastases of experimental solid tumours in mice. The effects of intravenous administration of 15, 35 and 50 mg/kg/day of NAMI-A for 5 consecutive days on blood concentration and host toxicity were tested on Swiss CD1 male and female mice. The blood concentration of NAMI-A, both after the first injection and at the end of the 5-day treatment fell rapidly and 5 min. after the last injection it was always below 10% of the administered dose. Kinetic parameters, calculated at the end of the 5-day treatment cycle according to a mono-compartment model (fitting with R2=0.9), indicate a t 1/2 of about 18 hr. Toxicity i) was observed only at the highest dose used (50 mg/kg/day), ii) was greater in females than in males, iii) in mice which survived treatment was completely reversed within 3-weeks of the end of the treatment. Haematological examinations, clinical chemistry data and histopathologic studies were consistent in terms of the effect on host lymphoid tissues, consisting in spleen and lymph node depletion and in a general increase of circulating leukocytes. Data on ruthenium organ retention confirm lack of brain penetration and a relatively high lung concentration which might account for the remarkable effect on lung metastases.

Animals↗
PubMed2007

RuCl3/PPh3: an efficient combination for the preparation of chiral 1,3-anti-diols through catalytic hydrogenation.

[reaction: see text] An efficient economical alternative to the commonly used Evans' reagent for the diastereoselective reduction of beta-hydroxy ketones is reported. Thus, ruthenium-mediated hydrogenation of enantioenriched beta-hydroxy ketones using RuCl3 associated to achiral monophosphines allowed the preparation of a series of 1,3-anti-diols in good yields and with a high level of diastereoselectivity. A short screening of ligands pointed out PPh3 as the most effective phosphine, and PCy3 afforded the 1,3-diols with an unexpected moderate syn selectivity.

Catalysis↗
PubMed2004

The hydrolysis of the anti-cancer ruthenium complex NAMI-A affects its DNA binding and antimetastatic activity: an NMR evaluation.

The coordination of the antimetastatic agent NAMI-A, [H(2)im][trans-RuCl(4)(dmso-S)(Him)], (Him=imidazole; dmso=dimethyl sulfoxide), to the DNA model base 9-methyladenine (9-MeAde) was investigated in water. NMR spectroscopy was first applied for the study of the molecular stability and hydrolysis of NAMI-A in aqueous solution over a range of pH (3.0-7.4) and chloride ion concentrations (0-1 M) at 37.0 degrees C. In physiological conditions (phosphate buffer, pH 7.4) NAMI-A disappears from the solution in 15 min due to chloride and dmso hydrolysis, leading to uncharacterised poly-oxo Ru species. Conversely, at lower pH (3.0-6.0) and in water (pH approximately 5.5), only a partial dmso hydrolysis occurs, slowly forming the [trans-RuCl(4)(H(2)O)(Him)](-) complex. This latter species coordinates to 9-MeAde (via the N7 of 9-MeAde), forming the [trans-RuCl(4)(9-MeAde)(Him)](-) complex. NAMI-A and [trans-RuCl(4)(H(2)O)(Him)](-) give comparable intracellular ruthenium concentrations and accumulate in KB cells (human mouth carcinoma) and accumulate these at the G(2)/M phase, while poly-oxo Ru species do not, and their cell uptake is reduced to 50%. On the contrary, G(2)/M arrest and protein content in the murine metastatic cell line metGM, are not influenced by NAMI-A hydrolysis. Hydrolysed NAMI-A species apparently are easier taken up by the metGM cells, showing intracellular ruthenium concentrations one order of magnitude greater than those of intact NAMI-A. Therefore, it is proposed that the selective antimetastatic activity of NAMI-A during in vivo experiments can be attributed to its hydrolysed species.

Antineoplastic Agents↗
PubMed2001

The development of L2X2Ru=CHR olefin metathesis catalysts: an organometallic success story.

In recent years, the olefin metathesis reaction has attracted widespread attention as a versatile carbon-carbon bond-forming method. Many new applications have become possible because of major advances in catalyst design. State-of-the-art ruthenium catalysts are not only highly active but also compatible with most functional groups and easy to use. This Account traces the ideas and discoveries that were instrumental in the development of these catalysts, with particular emphasis on (PCy3)2Cl2Ru=CHPh and its derivatives. The discussion includes an analysis of trends in catalyst activity, a description of catalysts coordinated with N-heterocyclic carbene ligands, and an overview of ongoing work to improve the activity, stability, and selectivity of this family of L2X2Ru=CHR complexes.

Catalysis↗
PubMed1994

Antimetastatic action and toxicity on healthy tissues of Na[trans-RuCl4(DMSO)Im] in the mouse.

The ruthenium-dimethylsulfoxide complex Na(trans-RuCl4(DMSO)Im] was given i.v. to mice bearing MCa mammary carcinoma and its effects on tumor growth and on healthy host tissues were studied by macroscopic examination of primary tumor growth, by survival time, and by histological analysis using light microscopy and SEM. Either by means of vivo-vivo bioassays or by microscopic examination it appeared that the growth of lung tumors was markedly reduced, whereas the growth of the i.m. primary tumor was much less affected. These effects account for the prolongation of survival time and for the cure rate observed. The favourable effect on survival time was also influenced by the lack of significant cytotoxicity for normal tissues such as lung and kidney epithelia, muscle and liver cells, splenocytes and bone marrow. It thus appears that the selective interaction with tumor cells in the lungs cannot simply be attributed to a selectively higher localization of the compound at this site, nor to a modification of the histological structure of primary tumor. These results highlight the pharmacologic properties of this compound for the control of solid tumor metastases, an effect that was shown to be similarly exerted on advanced tumor metastases.

Animals↗
PubMed2004

Encapsulation of cationic ruthenium complexes into a chiral self-assembled cage.

A chiral supramolecular assembly encapsulates the two cationic ruthenium sandwich complexes [CpRu(eta(6)-C(6)H(6))](+) and [CpRu(p-cymene)](+). The host-guest complexes K(11)[CpRu(eta(6)-C(6)H(6)) subset Ga(4)L(6)] (2) and K(11)[CpRu(p-cymene) subset Ga(4)L(6)] (3) were characterized by one- and two-dimensional NMR techniques as well as by electrospray mass spectrometry. Encapsulation of the prochiral complex [CpRu(p-cymene)](+) by the chiral host renders enantiotopic protons diastereotopic as evidenced by (1)H NMR spectroscopy.

Cations↗
PubMedDate not supplied

Tumour cell uptake G2-M accumulation and cytotoxicity of NAMI-A on TS/A adenocarcinoma cells.

The ruthenium(III) complex imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate (NAMI-A) was tested on TS/A adenocarcinoma cells to evaluate the relationship between cell uptake, cell cycle arrest and cytotoxicity. The in vitro challenge of TS/A cells with 10(-4) M NAMI-A for 15 minutes to 4 hours showed a partial reduction of cell growth only after 4 hour exposure. In the same experimental conditions NAMI-A caused the increase of cells in G2-M cell cycle phase directly proportional on the length of treatment, and the ruthenium uptake by tumour cells, measured by flameless atomic absorption spectroscopy, that increases up to 2 hours of treatment and then reaches a plateau. The arrest of cell cycle in the pre-mitotic G2-M phase was transient and completely reversed by 48 hours after treatment. This study showed that the effect of NAMI-A on the cell cycle of TS/A cells is not strictly related to NAMI-A uptake as is the effect on tumour cell proliferation.

Adenocarcinoma↗
PubMed2001

Characterization and differentiation of ruthenium(II) complexes with 1,4,7-trithiacyclononane and nitrogen heterocycles by electrospray mass spectrometry.

Electrospray ionization mass spectrometry (ESIMS) was used to characterize a series of new ruthenium(II) complexes with several nitrogen heterocycles and a common ligand: the crown thioether 1,4,7-trithiacyclononane, [9]aneS(3). ESIMS allows the easy identification of the [Ru(II)Cl([9]aneS(3))Y]X complexes, where Y is a bidentate nitrogen heterocycle and X is Cl(-) or PF(6)(-), through the formation of two diagnostic ions by fragmentation of the common ligand [9]aneS(3). Structures for these ions and mechanisms for their gas-phase formation are proposed based on data from product ion spectra.

Ethers, Cyclic↗
PubMedDate not supplied

Increase of tumour infiltrating lymphocytes in mice treated with antimetastatic doses of NAMI-A.

NAMI-A is a novel antitumour agent, based on ruthenium, which has proved effectiveness against lung metastases of solid mouse tumours. The study focuses on the effects of NAMI-A on leukocyte infiltration into the primary tumour of MCa mammary carcinoma, implanted subcutaneously (s.c.) or intramuscularly (i.m.) into CBA mice. NAMI-A, given with a cycle of daily treatments for six consecutive days on advanced tumours at 35 mg/kg/day, markedly reduces lung metastasis independently of the tumour type (Lewis lung carcinoma, MCa mammary carcinoma or TS/A adenocarcinoma) being treated and of the site of tumour implantation (s.c. or i.m.). The analysis of leukocyte infiltration of the primary tumour, performed on a single cell suspension of cells isolated from a Ficoll gradient on which a raw suspension of primary tumour cells was layered, showed NAMI-A to significantly increase tumour infiltrating lymphocytes. These lymphocytes are almost all CD3+ cells with a significant increase of the CD8+ over the CD4+ subpopulation that reduces the helper/suppressor ratio from 2.8 to 2.1. These data indicated the absence of toxicity of NAMI-A for tumour infiltrating lymphocytes and suggested that this compound might even synergize in combined treatments with cancer immunotherapy.

Adenocarcinoma↗
PubMed2006

Synthesis and reactivity of the ruthenium(II) dithiocarbonate complex [Ru(kappa2-S2C=O)(dppm)2] (dppm = bis(diphenylphosphino)methane).

Reaction of cis-[RuCl2(dppm)2] (dppm = bis(diphenylphosphino)methane) with CS2 and NaOH yields the first ruthenium dithiocarbonate complex, [Ru(kappa2-S2C=O)(dppm)2]. Protonation with tetrafluoroboric acid affords the xanthate complex [Ru(kappa2-S2COH)(dppm)2]BF4 in a reversible manner, suggesting that this may be an intermediate in dithiocarbonate formation. [Ru(kappa2-S2C=O)(dppm)2] reacts with methyl iodide or [Me3O]BF4 to give [Ru(kappa2-S2COMe)(dppm)2]+, also obtained from the reaction of cis-[RuCl2dppm)2] with CS2 and NaOMe. Two modifications of [Ru(kappa2-S(2)C=O)(dppm)2] were examined crystallographically and the structure of [Ru(kappa2-S2COMe)(dppm)2]BF4 and a new modification of cis-[RuCl2(dppm)2] are also reported.

Crystallography, X-Ray↗