RESUMEN
Ruthenium(ii) [Ru(ii)] polypyridyl complexes have been the focus of intense investigations since work began exploring their supramolecular interactions with DNA. In recent years, there have been considerable efforts to translate this solution-based research into a biological environment with the intention of developing new classes of probes, luminescent imaging agents, therapeutics and theranostics. In only 10 years the field has expanded with diverse applications for these complexes as imaging agents and promising candidates for therapeutics. In light of these efforts this review exclusively focuses on the developments of these complexes in biological systems, both in cells and in vivo, and hopes to communicate to readers the diversity of applications within which these complexes have found use, as well as new insights gained along the way and challenges that researchers in this field still face.
Asunto(s)
Complejos de Coordinación/farmacocinética , Piridinas/farmacocinética , Rutenio/farmacocinética , Línea Celular , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Humanos , Estructura Molecular , Piridinas/química , Rutenio/químicaRESUMEN
Metal-based drugs with novel targets and modes of action are increasingly being developed as alternatives to classical platinum(ii) chemotherapeutics. Imaging methods in tumour cells and tissues offer valuable insights into the behaviour of these novel complexes; however, mapping the distribution of metal ions and complexes within cellular environments remains challenging. The advantages and limitations of three modes of imaging: synchrotron radiation-induced X-ray fluorescence, mass spectrometry, and fluorescence microscopy are discussed in this review, with particular emphasis on their use in imaging ruthenium-based drugs.
Asunto(s)
Espectrometría de Masas/métodos , Microscopía Fluorescente/métodos , Preparaciones Farmacéuticas/análisis , Rutenio/farmacocinética , Espectrometría por Rayos X/métodos , Colorantes Fluorescentes/análisis , Colorantes Fluorescentes/química , Humanos , Rayos Láser , Preparaciones Farmacéuticas/química , Rutenio/química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , SincrotronesRESUMEN
Using a new mononuclear "building block," for the first time, a dinuclear RuII (dppn) complex and a heteroleptic system containing both RuII (dppz) and RuII (dppn) moieties are reported. The complexes, including the mixed dppz/dppn system, are 1 O2 sensitizers. However, unlike the homoleptic dppn systems, the mixed dppz/dppn complex also displays a luminescence "switch on" DNA light-switch effect. In both cisplatin sensitive and resistant human ovarian carcinoma lines the dinuclear complexes show enhanced uptake compared to their mononuclear analogue. Thanks to a favorable combination of singlet oxygen generation and cellular uptake properties all three of the new complexes are phototoxic and display potent activity against chemotherapeutically resistant cells.
Asunto(s)
Complejos de Coordinación/farmacología , Sustancias Intercalantes/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Fármacos Fotosensibilizantes/farmacología , Rutenio/farmacología , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , ADN/metabolismo , Femenino , Humanos , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacocinética , Neoplasias Ováricas/metabolismo , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Rutenio/química , Rutenio/farmacocinética , Oxígeno Singlete/metabolismoRESUMEN
OBJECTIVES: The objectives of this study were to: (i) determine the in vitro activities of a series of di-, tri- and tetra-nuclear ruthenium complexes (Rubbn, Rubbn-tri and Rubbn-tetra) against a range of Gram-positive and -negative bacteria and compare the antimicrobial activities with the corresponding toxicities against eukaryotic cells; and (ii) compare MIC values with achievable in vivo serum concentrations for the least toxic ruthenium complex. METHODS: The in vitro activities were determined by MIC assays and time-kill curve experiments, while the toxicities of the ruthenium complexes were determined using the Alamar blue cytotoxicity assay. A preliminary pharmacokinetic study was undertaken to determine the Rubb12 serum concentration in mice as a function of time after administration. RESULTS: Rubb12, Rubb12-tri and Rubb12-tetra are highly active, with MIC values of 1-2 mg/L (0.5-1.5 µM) for a range of Gram-positive strains, but showed variable activities against a panel of Gram-negative bacteria. Time-kill experiments indicated that Rubb12, Rubb12-tri and Rubb12-tetra are bactericidal and kill bacteria within 3-8 h. The di-, tri- and tetra-nuclear complexes were â¼50 times more toxic to Gram-positive bacteria and 25 times more toxic to Gram-negative strains, classified as susceptible, than to liver and kidney cells. Preliminary pharmacokinetic experiments established that serum concentrations higher than MIC values can be obtained for Rubb12 with an administered dose of 32 mg/kg. CONCLUSIONS: The ruthenium complexes, particularly Rubb12, have potential as new antimicrobial agents. The structure of the dinuclear ruthenium complex can be readily further modified in order to increase the selectivity for bacteria over eukaryotic cells.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Células Eucariotas/efectos de los fármacos , Compuestos Organometálicos/farmacología , Rutenio/farmacología , Animales , Antibacterianos/farmacocinética , Antibacterianos/toxicidad , Supervivencia Celular/efectos de los fármacos , Colorimetría/métodos , Femenino , Masculino , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/toxicidad , Oxazinas/análisis , Rutenio/farmacocinética , Rutenio/toxicidad , Suero/química , Xantenos/análisisRESUMEN
Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favorable toxicity and clearance properties. Here, we show that the ruthenium(II) complex [Ru(p-cymene)(bis(3,5-dimethylpyrazol-1-yl)methane)Cl]Cl (UNICAM-1) exhibits potent in vivo antitumor effects. When administered as four-dose course, by repeating a single dose (52.4mgkg-1) every three days, UNICAM-1 significantly reduces the growth of A17 triple negative breast cancer cells transplanted into FVB syngeneic mice. Pharmacokinetic studies indicate that UNICAM-1 is rapidly eliminated from kidney, liver and bloodstream thanks to its high hydrosolubility, exerting excellent therapeutic activity with minimal side effects. Immunohistological analysis revealed that the efficacy of UNICAM-1, mainly relies on its capacity to reverse tumor-associated immune suppression by significantly reducing the number of tumor-infiltrating regulatory T cells. Therefore, UNICAM-1 appears very promising for the treatment of TNBC.
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Rutenio/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Femenino , Humanos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones , Compuestos Organometálicos/sangre , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , Rutenio/sangre , Rutenio/farmacocinética , Rutenio/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: This phase I/II study determined the maximal tolerable dose, dose limiting toxicities, antitumor activity, the pharmacokinetics and pharmacodynamics of ruthenium compound NAMI-A in combination with gemcitabine in Non-Small Cell Lung Cancer patients after first line treatment. METHODS: Initial dose escalation of NAMI-A was performed in a 28 day cycle: NAMI-A as a 3 h infusion through a port-a-cath at a starting dose of 300 mg/m(2) at day 1, 8 and 15, in combination with gemcitabine 1,000 mg/m(2) at days 2, 9 and 16. Subsequently, dose escalation of NAMI-A in a 21 day schedule was explored. At the maximal tolerable dose level of this schedule an expansion group was enrolled of which 15 patients were evaluable for response. RESULTS: Due to frequent neutropenic dose interruptions in the third week, the 28 day schedule was amended into a 21 day schedule. The maximal tolerable dose was 300 and 450 mg/m(2) of NAMI-A (21 day schedule). Main adverse events consisted of neutropenia, anemia, elevated liver enzymes, transient creatinine elevation, nausea, vomiting, constipation, diarrhea, fatigue, and renal toxicity. CONCLUSION: NAMI-A administered in combination with gemcitabine is only moderately tolerated and less active in NSCLC patients after first line treatment than gemcitabine alone.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Dimetilsulfóxido/administración & dosificación , Dimetilsulfóxido/efectos adversos , Dimetilsulfóxido/análogos & derivados , Dimetilsulfóxido/farmacocinética , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/efectos adversos , Compuestos Organometálicos/farmacocinética , Rutenio/administración & dosificación , Rutenio/efectos adversos , Rutenio/sangre , Rutenio/farmacocinética , Compuestos de Rutenio , Resultado del Tratamiento , GemcitabinaRESUMEN
Photodynamic therapy utilizes light, a photosensitizer, and molecular oxygen as a treatment modality for a variety of cancers. We have recently combined ruthenium(II) polypyridyl groups with a zinc(II) centered porphyrin as a new photosensitizer for the treatment of melanoma. In-vitro studies have indicated that this photosensitizer is toxic to melanoma cells when irradiated with low energy light; however, it is nontoxic to normal cells under similar conditions. To determine the toxicity and cell viability of this compound in-vivo we present, herein, a study using Drosophila melanogaster. In the absence of light, the new photosensitizer shows no discernible effects to fly larvae at various concentrations of compound and stages of larval development. When the larvae were fed the photosensitizer it was observed, by fluorescence microscopy, that the compound passes through the cell membrane and localizes in the cytosol at lower concentrations and the nucleus at slightly higher concentrations indicating that the compound is not immediately metabolized.
Asunto(s)
Metaloporfirinas/toxicidad , Fármacos Fotosensibilizantes/toxicidad , Rutenio/toxicidad , Zinc/toxicidad , Animales , Encéfalo/metabolismo , Drosophila melanogaster , Ensayos de Selección de Medicamentos Antitumorales , Larva/efectos de los fármacos , Larva/metabolismo , Metaloporfirinas/farmacocinética , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacocinética , Rutenio/farmacocinética , Zinc/farmacocinéticaRESUMEN
A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η(6)-p-cym)RuCl(PPh3)2](+), allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N'-di-Boc-Nâ³-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 µM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 µM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 µM in DU-145 and IC50 = 11.33 µM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 â« 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 µM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 µM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.
Asunto(s)
Antineoplásicos/química , Neomicina/análogos & derivados , Compuestos Organometálicos/química , Rutenio/química , Aminoglicósidos/química , Aminoglicósidos/farmacocinética , Aminoglicósidos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Transporte Biológico Activo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Células MCF-7 , Masculino , Neomicina/farmacocinética , Neomicina/farmacología , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , ARN Neoplásico/efectos de los fármacos , ARN Neoplásico/metabolismo , Rutenio/farmacocinética , Rutenio/farmacologíaRESUMEN
We report herein a systematic study on interactions of organometallic ruthenium(II) anticancer complex [(η(6)-arene)Ru(en)Cl](+) (arene = p-cymene (1) or biphenyl (2), en = ethylenediamine) with human transferrin (hTf) and the effects of the hTf-ligation on the bioavailability of these complexes with cisplatin as a reference. Incubated with a 5-fold excess of complex 1, 2, or cisplatin, 1 mol of diferric hTf (holo-hTf) attached 0.62 mol of 1, 1.01 mol of 2, or 2.14 mol of cisplatin. Mass spectrometry revealed that both ruthenium complexes coordinated to N-donors His242, His273, His578, and His606, whereas cisplatin bound to O donors Tyr136 and Tyr317 and S-donor Met256 in addition to His273 and His578 on the surface of both apo- and holo-hTf. Moreover, cisplatin could bind to Thr457 within the C-lobe iron binding cleft of apo-hTf. Neither ruthenium nor platinum binding interfered with the recognition of holo-hTf by the transferrin receptor (TfR). The ruthenated/platinated holo-hTf complexes could be internalized via TfR-mediated endocytosis at a similar rate to that of holo-hTf itself. Moreover, the binding to holo-hTf well preserved the bioavailability of the ruthenium complexes, and the hTf-bound 1 and 2 showed a similar cytotoxicity toward the human breast cancer cell line MCF-7 to those of the complexes themselves. However, the conjugation with holo-hTf significantly reduced the cellular uptake of cisplatin and the amount of platinated DNA adducts formed intracellularly, leading to dramatic reduction of cisplatin cytotoxicity toward MCF-7. These findings suggest that hTf can serve as a mediator for the targeting delivery of Ru(arene) anticancer complexes while deactivating cisplatin.
Asunto(s)
Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Compuestos Organometálicos/metabolismo , Compuestos Organometálicos/farmacocinética , Rutenio/metabolismo , Rutenio/farmacocinética , Transferrina/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Cisplatino/metabolismo , Cisplatino/farmacocinética , Cisplatino/farmacología , Femenino , Humanos , Modelos Moleculares , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Unión Proteica , Receptores de Transferrina/metabolismo , Rutenio/química , Rutenio/farmacologíaRESUMEN
Carbon monoxide has been proved to be an important signal molecule in body. Transition metal carbonyl compounds are solidified form of carbon monoxide. Numerous studies have shown that Ruthenium carbonyl carbon monoxide releasing molecules have a strong pharmacological activity. In this paper, five Ruthenium (II) carbonyl CORMs 1-5 were synthesized and their toxicology, tissue distribution and interaction with blood endogenous substances were investigated. The results showed CORMs' IC50 to fibroblasts are ranged from 212.9 to 2089.2 micromol x L(-1). Their oral LD50 to mouse is between 800 to 1600 mg x kg(-1). After repeated administration, CORMs 1 and CORMs 5 haven't shown an obvious influence to rats' liver and kidney function, but caused the injury to liver and kidney cells. The in vivo distribution result revealed the majority of CORMs were distributed in blood, liver and kidney, only a small part of CORMs distributed in lung, heart and spleen. They could scarcely cross the blood-brain barrier and distribute to brain. The non-CO ligands in structure have an obvious relevance to their in vivo absorption and distribution. Interestingly, CORMs could enhance the fluorescence of bovine serum albumin, and this enhancement was in direct proportion with the concentration of CORMs. Under different conditions, interaction of CORMs with glutathione got different type of products, one is Ruthenium (II) tricarbonyl complexes, and Ruthenium (II) dicarbonyl complexes.
Asunto(s)
Monóxido de Carbono/química , Compuestos Organometálicos/síntesis química , Rutenio/química , Animales , Monóxido de Carbono/farmacocinética , Monóxido de Carbono/toxicidad , Fibroblastos/efectos de los fármacos , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Ratones , Estructura Molecular , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/toxicidad , Ratas , Ratas Wistar , Rutenio/farmacocinética , Rutenio/toxicidad , Distribución TisularRESUMEN
Nitrosyl ruthenium complexes are promising NO donor agents with numerous advantages for the biologic applications of NO. We have characterized the NO release from the nitrosyl ruthenium complex [Ru(NO(2))(bpy)(2)(4-pic)](+) (I) and the reactive oxygen/nitrogen species (ROS/RNS)-mediated NO actions on isolated rat liver mitochondria. The results indicated that oxidation of mitochondrial NADH promotes NO release from (I) in a manner mediated by NO(2) formation (at neutral pH) as in mammalian cells, followed by an oxygen atom transfer mechanism (OAT). The NO released from (I) uncoupled mitochondria at low concentrations/incubation times and inhibited the respiratory chain at high concentrations/incubation times. In the presence of ROS generated by mitochondria NO gave rise to peroxynitrite, which, in turn, inhibited the respiratory chain and oxidized membrane protein-thiols to elicit a Ca(2+)-independent mitochondrial permeability transition; this process was only partially inhibited by cyclosporine-A, almost fully inhibited by the thiol reagent N-ethylmaleimide (NEM) and fully inhibited by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO). These actions correlated with the release of cytochrome c from isolated mitochondria as detected by Western blotting analysis. These events, typically involved in cell necrosis and/or apoptosis denote a potential specific action of (I) and analogs against tumor cells via mitochondria-mediated processes.
Asunto(s)
Complejos de Coordinación/farmacocinética , Mitocondrias Hepáticas/metabolismo , NADP/metabolismo , Donantes de Óxido Nítrico/farmacocinética , Óxido Nítrico/farmacocinética , Rutenio/farmacocinética , Análisis de Varianza , Animales , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Citocromos c/metabolismo , Concentración de Iones de Hidrógeno , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/metabolismo , Oxidación-Reducción , Ratas , Ratas Wistar , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rutenio/química , Rutenio/metabolismo , Compuestos de SulfhidriloRESUMEN
Six different acylthiourea ligands (L1-L6) and their corresponding Ru(II)-p-cymene complexes (P1-P6) were designed to explore the structure-activity relationship of the complexes upon aliphatic chain and aromatic conjugation on the C- and N-terminals, respectively. The compounds were synthesized and adequately characterized using various analytical and spectroscopic techniques. The structures of P2-P6, solved using single crystal X-ray diffraction (XRD), confirmed the neutral monodentate coordination of the S atoms of the acylthiourea ligands to Ru(II) ions. In silico studies showed an increase of lipophilicity for the ligands with an increase in alkyl chain length or aromatic conjugation at the C- or N-terminal, respectively. Subsequently, mitogen-activated protein kinases (MAPK) were predicted as one of the primary targets for the complexes, which showed good binding affinity towards extracellular signal-regulated kinases (ERK1, ERK2 and ERK5), c-Jun N-terminal kinase (JNK) and p38 of the MAPK pathway. Henceforth, the complexes were tested for their anticancer activity in lung carcinoma (A549) and cisplatin-resistant lung carcinoma (cisA549R) cells and human umbilical vein epithelial normal cells (HUVEC). Interestingly, an increase in chain length or aromatic conjugation led to an increase in the activity of the complexes, with P5 (7.73 and 13.04 µM) and P6 (6.52 and 14.45 µM) showing the highest activity in A549 and cisA549R cells, which is better than the positive control, cisplatin (8.72 and 44.28 µM). Remarkably, we report the highest activity yet observed for complexes of the type [(η6-p-cymene)RuIICl2(S-acylthiourea)] in the tested cell lines. Aqueous solution studies showed that complexes P5 and P6 are rapidly hydrolyzed to produce solely aquated species that remained stable for 24 h. Staining assays and flow cytometric analyses of P5 and P6 in A549 cells revealed that the complexes induced apoptosis and arrested the cell cycle predominantly in the S phase. In vivo studies demonstrated the higher toxicity of cisplatin and a comparatively higher survival rate of mice injected with the most active complex P6. Histological analyses revealed that treatment with P6 at high doses of up to 8 mg kg-1 did not cause any palpable damage to the tested organs.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Cimenos , Rutenio , Tioamidas , Tiourea , Células A549 , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Disponibilidad Biológica , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Cimenos/administración & dosificación , Cimenos/química , Cimenos/farmacocinética , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Absorción Intestinal , Ligandos , Masculino , Ratones Endogámicos ICR , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Simulación del Acoplamiento Molecular , Rutenio/administración & dosificación , Rutenio/química , Rutenio/farmacocinética , Tioamidas/administración & dosificación , Tioamidas/química , Tioamidas/farmacocinética , Tiourea/administración & dosificación , Tiourea/química , Tiourea/farmacocinéticaRESUMEN
Guanine-rich DNA sequences can spontaneously fold into four-stranded structures called G-quadruplexes (G4s). G4s have been identified extensively in the promoter regions of several proto-oncogenes, including c-myc, as well as telomeres. G4s have attracted an increasing amount of attention in the field of nanotechnology because of their use as versatile building blocks of DNA-based nanostructures. In this study, we report the self-assembly of c-myc G-quadruplex DNA controlled by a pair of chiral ruthenium(ii) complexes coordinated by 2-(4-phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline (PBEPIP), Λ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Λ-RM0627, bpy = bipyridine) and Δ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Δ-RM0627). Λ-RM0627 could promote the high-order self-assembly of c-myc G-quadruplex DNA into a nanowire structure, whereas Δ-RM0627 could induce DNA condensation into G-quadruplex aggregates. Moreover, in vitro studies on human liver carcinoma HepG2 cells showed that the nanowire of c-myc G-quadruplex DNA promoted by Λ-RM0627 could be localized in the nuclei of cells, whereas the nanoparticle of c-myc G-quadruplex DNA generated by Δ-RM0627 was taken up and localized in the cytoplasm. This study provides examples of the enantioselective self-assembly of G4 DNA molecules controlled by chiral ruthenium(ii) complexes and suggests the potential applications of assembled nanostructures as non-viral DNA vectors for gene therapy.
Asunto(s)
Núcleo Celular/metabolismo , Complejos de Coordinación/metabolismo , Citoplasma/metabolismo , Rutenio/metabolismo , Transporte Biológico , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , ADN/química , ADN/metabolismo , G-Cuádruplex , Células Hep G2 , Humanos , Nanopartículas/química , Nanocables , Fenantrolinas/química , Fenantrolinas/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-myc/química , Proteínas Proto-Oncogénicas c-myc/metabolismo , Rutenio/química , Rutenio/farmacocinética , EstereoisomerismoRESUMEN
A series of ruthenium(II)-arene complexes of several bipyridine and phenanthroline derivatives have been synthesized by employing a green and efficient protocol involving water as a solvent under sonication. The structures of all the complexes were elucidated by the spectroscopic analysis. The geometry of the chlorido and PTA (1,3,5-Triaza-7-phosphaadamantane) complexes were further confirmed by DFT and single crystal XRD. The stability study in various solvents, specifically in the intracellular one was conducted. Most of the compounds exhibited significant potency and selectivity against MCF7 and HeLa cell lines with respect to normal HEK-293 cells compared to cisplatin and RAPTA-C (Ruthenium(II)-arene PTA complex). Complex [(η6-hexamethylbenzene)RuCl(κ2-N,N-4,4'-di-n-nonyl-2,2'-bpy)]Cl (3e) presented best anticancer profiles against all the human cancer cells. Interestingly, few complexes turned up to be highly fluorescent depicted by the quantum yield values. Remarkably, [(η6-p-cymene)RuCl(κ2-N,N-bpy)]Cl (3i) was identified as most significant anticancer theranostic agent interms of potency, selectivity and fluorescence quantum yield. This complex also represented itself as significant cellular imaging agent in live U-87 MG cells which was monitored by confocal microscope. Absorption and emission spectral studies of bypyridine and phenanthroline complex series revealed that the complexes interacted with calf thymus DNA through groove binding as well as intercalative mode. In addition to this, strong binding efficacy of these scaffolds wih BSA (Bovin Serum Albumin) also enhanced their transportation property inside the cells.
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Antineoplásicos , Complejos de Coordinación , Mediciones Luminiscentes , Neoplasias , Fenantrolinas , Piridinas , Rutenio , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , ADN/química , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Fenantrolinas/química , Fenantrolinas/farmacocinética , Fenantrolinas/farmacología , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Rutenio/química , Rutenio/farmacocinética , Rutenio/farmacologíaRESUMEN
Ruthenium complexes are expected to be new opportunities for the development of antitumor agents. Herein, four ruthenium polypyridyl complexes ([Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-1, bpy = 2,2'-bipyridine; CAPIP = (E)-2-(2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ru(phen)2(CA-PIP)](ClO4)2 (Ru(II)-2, phen = 1,10-phenanthroline), [Ru(dmb)2(CAPIP)](ClO4)2 (Ru(II)-3, dmb = 4,4'-dimethyl-2,2'-bipyridine), [Ru(dmb)2(ETPIP)](ClO4)2 (Ru(II)-4, ETPIP = 2-(4-(thiophen-2-ylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phen-anthroline)) have been investigated as mitochondria-targeted antitumor metallodrugs. DNA binding studies indicated that target Ru(II) complexes interacts with CT DNA (calf thymus DNA) by an intercalative mode. Cytotoxicity assay results demonstrate that Ru(II) complexes show high cytotoxicity against A549 cells with low IC50 value of 23.6 ± 2.3, 20.1 ± 1.9, 22.7 ± 1.8 and 18.4 ± 2.3 µM, respectively. Flow cytometry and morphological analysis revealed that these Ru(II) complexes can induce apoptosis in A549 cells. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were also investigated by ImageXpress Micro XLS system. The experimental results indicate that the reactive oxygen species in A549 cells increased significantly and mitochondrial membrane potential decreased obviously. In addition, colocalization studies shown these complexes could get to the cytoplasm through the cell membrane and accumulate in the mitochondria. Furthermore, Ru(II) complexes can effectively induces cell cycle arrest at the S phase in A549 cells. Finally, cell invasion assay and quantitative studies were also performed to investigate the mechanism of this process. All in together, this study suggested that these Ru(II) complexes could induce apoptosis in A549 cells through cell cycle arrest and ROS-mediated mitochondrial dysfunction pathway.
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Antineoplásicos , Complejos de Coordinación , Neoplasias , Piridinas , Rutenio , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Complejos de Coordinación/farmacología , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Rutenio/química , Rutenio/farmacocinética , Rutenio/farmacologíaRESUMEN
The cellular uptake and localization of a Ru-octaarginine conjugate with and without an appended fluorescein are compared. The inherent luminescence of the Ru(II) dipyridophenazine complex allows observation of its uptake without the addition of a fluorophore. Ru-octaarginine-fluorescein stains the cytosol, nuclei, and nucleoli of HeLa cells under conditions where the Ru-octaarginine conjugate without fluorescein shows only punctate cytoplasmic labeling. At higher concentrations, however, Ru-octaarginine without the fluorescein tag does exhibit cytoplasmic, nuclear, and nucleolar staining. Attaching fluorescein to Ru-octaarginine lowers the threshold concentration required for diffuse cytoplasmic labeling and nuclear entry. Hence, the localization of the fluorophore-bound peptide cannot serve as a proxy for that of the free peptide.
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Núcleo Celular/metabolismo , Fluoresceína/química , Fluoresceína/farmacocinética , Membranas Intracelulares/metabolismo , Oligopéptidos/farmacocinética , Rutenio/farmacocinética , Nucléolo Celular/metabolismo , Citoplasma/metabolismo , Fluoresceína/análisis , Células HeLa , Humanos , Mediciones Luminiscentes , Oligopéptidos/análisis , Oligopéptidos/química , Permeabilidad , Rutenio/análisis , Rutenio/químicaRESUMEN
Rheumatoid arthritis (RA) is a degenerative joint disease caused by autoimmunity; for the effective treatment of RA while avoiding the side effects of conventional drugs, we have proposed a new therapeutic strategy to eliminate the inflammatory response in RA by regulating the immune system that promotes the transformation of M1-type macrophages to M2-type macrophages. Herein, we designed and synthesized a core-shell nanocomposite (QRu-PLGA-RES-DS NPs), which showed an effective therapeutic effect on RA by accurately inducing the polarization of M2 macrophages. In this system, the quadrilateral ruthenium nanoparticles (QRuNPs) with a photothermal effect were utilized as a core and the thermosensitive molecular poly (lactic-co-glycolic acid) (PLGA) modified with the targeted molecule dextran sulfate (DS) was employed as a shell. Then, the nanocarrier QRu-PLGA-DS NPs effectively improved the water solubility and targeting of resveratrol (RES) through self-assembly. Therefore, the QRu-PLGA-RES-DS NPs significantly enhanced the ability of RES to reverse the M1 type macrophages to the M2 type macrophages through an accurate release. In vivo experiments further demonstrated that the QRu-PLGA-RES-DS NPs could effectively accumulate in the lesion area with an exogenous stimulus, and this significantly enhanced the transformation of the M2 type macrophages and decreased the recruitment of the M1 type macrophages. Furthermore, the QRu-PLGA-RES-DS NPs effectively treated RA by eliminating the inflammatory response; in addition, photoacoustic imaging (PA) of the QRu NPs provided image guidance for the distribution and analysis of nanomedicine in inflammatory tissues. Hence, this therapeutic strategy promotes the biological applications of Ru-based nanoparticles in disease treatment.
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Hipertermia Inducida , Macrófagos/metabolismo , Nanocompuestos , Fototerapia , Resveratrol , Fiebre Reumática/terapia , Animales , Células Endoteliales de la Vena Umbilical Humana , Humanos , Macrófagos/patología , Ratones , Nanocompuestos/química , Nanocompuestos/uso terapéutico , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Ácido Poliglicólico/farmacología , Células RAW 264.7 , Resveratrol/farmacocinética , Resveratrol/farmacología , Fiebre Reumática/metabolismo , Fiebre Reumática/patología , Rutenio/química , Rutenio/farmacocinética , Rutenio/farmacologíaRESUMEN
New [Ru(L1)(dcbpy)(NCS)2] complex was synthesized in a one-pot reaction starting from [RuCl2(p-cymene)]2, where the ligands (dcbpy=4,4'-dicarboxy-2,2'-bipyridine, L1=dipyrido[3,2-a:2',3'-c]phenazine-11-ylcarbonyl)-sodium) are introduced sequentially. The resulting complex was characterized by IR, NMR, and elemental analysis. The complex was labeled with I-131. Biodistribution study of the complex was carried out using 131I-labeled [Ru(L1)(dcbpy)(NCS)2] complex. The biodistribution study performed with albino Wistar male rats has shown that the complex has high uptake in the lung, small intestine, fat, and spleen.
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Radioisótopos de Yodo/farmacocinética , Compuestos Organometálicos/farmacocinética , Radiofármacos/farmacocinética , Rutenio/farmacocinética , Animales , Masculino , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Fotoquímica , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/química , Ratas , Ratas Wistar , Solubilidad , Distribución Tisular , AguaRESUMEN
Utilizing the size-dependent adsorption properties of ruthenium carbonyl clusters (Ru-carbon monoxide (CO)) onto graphene oxide (GO), a facile CO-release platform for in situ vasodilation as a treatment for stroke-related vascular diseases is developed. The rate and amount of formation of the CO-release-active RuII (CO)2 species can be modulated by a simple mixing procedure at room temperature. The subsequent thermally induced oxidation of RuII (CO)2 to RuO2 on the GO surface results in the release of CO. Further modulation of thermal and CO-release properties can be achieved via a hybridization of medium- and high-nuclearity of Ru-CO clusters that produces a RuO2 /RuII (CO)2 /6 Ru-CO-GO composite, where 6 Ru-CO-GO provides a photothermally activated reservoir of RuII (CO)2 species and the combined infrared absorption properties of GO and RuO2 provides photothermal response for in situ CO-release. The RuO2 /RuII (CO)2 /6 Ru-CO-GO composite does not produce any cytotoxicity and the efficacy of the composite is further demonstrated in a cortical photothrombotic ischemia rat model.
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Complejos de Coordinación , Grafito , Hipertermia Inducida , Fototerapia , Rutenio , Accidente Cerebrovascular/terapia , Animales , Línea Celular , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Complejos de Coordinación/farmacología , Grafito/química , Grafito/farmacocinética , Grafito/farmacología , Humanos , Ratas , Rutenio/química , Rutenio/farmacocinética , Rutenio/farmacología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patologíaRESUMEN
Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to study the spatial distribution of two metallodrugs with anticancer activities in vivo, namely the organoruthenium plecstatin-1 (1) and its isosteric osmium analogue (2), in liver, kidneys, muscles and tumours of treated mice bearing a CT-26 tumour after single-dose i.p. administration. To the best of our knowledge, this is the first time that the spatial distribution of an osmium drug candidate has been investigated using LA-ICP-MS in tissues. Independent measurements of the average ruthenium and osmium concentration via microwave digestion and ICP-MS in organs and tumours were in good agreement with the LA-ICP-MS results. Matrix-matched standards (MMS) ranging from 1 to 30 µg g-1 were prepared to quantify the spatial distributions of the metals and the average metal content of the MMS samples was additionally quantified by ICP-MS after microwave digestion. The recoveries for osmium and ruthenium in the MMS were 105% and 101% on average, respectively, validating the sample preparation procedure of the MMS. Preparation of MMS was carried out under an argon atmosphere to prevent oxidation of osmium-species to the volatile OsO4. The highest metal concentrations were found in the liver, followed by kidney, lung and tumour tissues, while muscles displayed only very low quantities of the respective metal. Both metallodrugs accumulated in the cortex of the kidneys more strongly compared to the medulla. Interestingly, osmium from 2 was largely located at the periphery and tissue edges, whereas ruthenium from 1 was observed to penetrate deeper into the organs and tumours.