RESUMO
Flavonoids, a polyphenolic compound family, and the vanadium compounds have interesting biological, pharmacological, and medicinal properties. We report herein the antitumor actions of the complex [VO(chrysin)2EtOH]2 (VOchrys) on the MG-63 human osteosarcoma cell line. Oxovanadium(IV), chrysin and VOchrys caused a concentration-dependent inhibition of cell viability. The complex was the strongest antiproliferative agent (p < 0.05). Cytotoxicity and genotoxicity studies also showed a concentration effect. Reactive oxygen species (ROS) and the alterations in the GSH/GSSG ratio underlie the main mechanisms of action of VOchrys. Additions of ROS scavengers (vitamin C plus vitamin E) or GSH to the viability experiments demonstrated beneficial effects (p < 0.01). Besides, the complex triggered apoptosis, disruption of the mitochondria membrane potential (MMP), increased levels of caspase 3 and DNA fragmentation measured by the sub-G1 peak in cell cycle arrest experiments (p < 0.01). Collectively, VOchrys is a cell death modulator and a promissory complex to be used in cancer treatments.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Flavonoides/química , Compostos Organometálicos/farmacologia , Osteossarcoma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Vanadatos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Osteossarcoma/patologia , Relação Estrutura-AtividadeRESUMO
The interaction of the VO2+ cation with meso-2,3-dimercaptosuccinic acid (DMSA) was investigated by electron absorption spectroscopy in aqueous solution at different pH values. The spectral behavior, complemented with a spectrophotometric titration, shows the generation of a [VO(DMSA)2]2- complex in which the oxocation interacts with two pairs of deprotonated -SH groups of the acid. It was also found that DMSA rapidly reduces VO3- to VO2+, which might be chelated by an excess of the acid. DMSA can also produce the partial reduction of a V2O5 suspension at pH=5.2. The results of this study suggest that DMSA might be a potentially useful detoxification agent for vanadium.
Assuntos
Succímero/metabolismo , Vanádio/metabolismo , Quelantes , Interações Medicamentosas , Inativação Metabólica , Oxirredução , Espectroscopia de Perda de Energia de Elétrons , Vanadatos/metabolismoRESUMO
The interaction of the VO2+ cation with homocysteine was investigated by electron absorption spectroscopy in aqueous solution at different metal-to-ligand ratios. The direct reduction of vanadate(V) solutions with homocysteine was also investigated. The results suggest that the interaction is different from that found in the case of cysteine and occurs through pairs of amino and carboxylate groups of the amino acid. The interaction of VO2+ with homocystine, the oxidation product of homocysteine, was also analyzed. The interest of the results in relation to vanadium metabolism and detoxification is briefly discussed.
Assuntos
Homocisteína/metabolismo , Vanadatos/química , Vanadatos/metabolismo , Aminoácidos/química , Cátions , Cisteína/química , Elétrons , Homocisteína/química , Concentração de Íons de Hidrogênio , Ligantes , Metais/química , Modelos Químicos , Espectrofotometria , OligoelementosRESUMO
The synthesis and spectral and magnetic characterization of VO(2+) complexes with Ibuprofen (2-(4-isobutylphenyl)propionic acid), Naproxen (6-methoxy-alpha-methyl-2-naphthalene acetic acid) and Tolmetin (1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid) were studied. The complexes [VO(Ibu)(2)] x 5CH(3)OH, [VO(Nap)(2)] x 5CH(3)OH and [VO(Tol)(2)] were obtained from methanolic solutions under nitrogen atmosphere. The biological activities of these complexes on the proliferation of two osteoblast-like cells in culture (MC3T3E1 and UMR106) were compared with that of the vanadyl(IV) cation. The complexes exhibited different effects depending on the concentration and the cellular type, while no effect was observed for their parent drugs.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Osteoblastos/efeitos dos fármacos , Vanadatos/síntese química , Vanadatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ibuprofeno/química , Ibuprofeno/farmacologia , Camundongos , Naproxeno/química , Naproxeno/farmacologia , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Ratos , Análise Espectral , Tolmetino/química , Tolmetino/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Vanadatos/químicaRESUMO
A new vanadyl(IV) complex of the disaccharide lactose was obtained in aqueous solution at pH = 13. The sodium salt of the complex, of composition Na4[VO(lactose)2].3H2O, has been characterized by elemental analysis and by ultraviolet-visible, diffuse reflectance, and infrared spectroscopies. Its magnetic susceptibility and thermal behavior were also investigated. The inhibitory effect on alkaline phosphatase activity was tested for this compound as well as for the vanadyl(IV) complexes with maltose, sucrose, glucose, fructose, and galactose. For comparative purposes, the free ligands and the vanadyl(IV) cation were also studied. The free sugars and the sucrose/VO complex exhibited the lowest inhibitory effect. Lactose-VO, maltose-VO, and the free VO2+ cation showed an intermediate inhibition potential, whereas the monosaccharide/VO complexes appeared as the most potent inhibitory agents.
Assuntos
Fosfatase Alcalina/metabolismo , Dissacarídeos/farmacologia , Lactose/química , Monossacarídeos/farmacologia , Vanádio/química , Cátions , Relação Dose-Resposta a Droga , Frutose/metabolismo , Galactose/metabolismo , Glucose/metabolismo , Cinética , Ligantes , Sacarose/metabolismo , Raios UltravioletaRESUMO
Oxovanadium(IV) complexes of the monosaccharides D- and L-arabinose, D-galactose, D-mannose, D-lyxose, D-xylose and the disaccharide maltose were obtained in aqueous solutions at pH 13. Their sodium salts were precipitated with absolute ethanol and characterized by UV-vis spectroscopy (absorption and reflectance), thermo-analytical (TG and DTA) data, magnetic susceptibility measurements and IR-spectroscopy. All the complexes were found to be mononuclear, possessing the VO2+ moiety. The IR spectra were analyzed and discussed in detail allowing one to determine the characteristics of the metal-to-ligand interactions.
Assuntos
Maltose/química , Monossacarídeos/química , Vanadatos/química , Cátions/química , Cátions/metabolismo , Precipitação Química , Concentração de Íons de Hidrogênio , Ligantes , Magnetismo , Maltose/metabolismo , Monossacarídeos/metabolismo , Sais , Sódio/química , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Temperatura , Vanadatos/metabolismo , Água/metabolismoRESUMO
A new VO2+ complex with salicylic acid acetate (Aspirin) of formula C18H18Cl2O12V2 was synthesized and characterized. Its biological effects upon cell proliferation, differentiation and promotion of tyrosine protein phosphorylation have been tested in two lines of osteoblast-like cells in culture.
Assuntos
Aspirina/síntese química , Vanadatos/síntese química , Animais , Aspirina/farmacologia , Western Blotting , Osso e Ossos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Osteoblastos/efeitos dos fármacos , Fosforilação , Fosfotirosina/metabolismo , Espectrofotometria Infravermelho , Vanadatos/farmacologiaRESUMO
The interaction between the VO2+ cation and cystine was investigated by electron absorption spectroscopy in aqueous solutions at different metal-to-ligand ratios. Reduction of NaVO3 solutions with cysteine gave similar spectra. The results suggest that interaction occurs through the carboxylate and amino groups of the ligand. The interest of the results in relation to vanadium metabolism are commented upon.
Assuntos
Cistina/química , Cátions , Oxirredução , Análise Espectral/métodosRESUMO
The interaction of the vanadyl (IV) (VO2+) cation with carnosine (the dipeptide beta-alanyl-histidine) has been investigated by electron absorption spectroscopy at high ligand-to-metal ratios and at different pH values. The results show that in the range 6.0-8.5, the cation interacts with the imidazole group of four different carnosine molecules and points to the presence of an axially coordinated water molecule. These suppositions were confirmed by the behavior of the VO2+/imidazole system, which was investigated under similar experimental conditions, and supported by previous ENDOR (electron-nuclear double resonance) results. The study was complemented with additional measurements using the glycylglycine, glycylglycine/imidazole, and histidine systems as ligands.
Assuntos
Carnosina/química , Glicilglicina/química , Histidina/química , Vanadatos/química , Concentração de Íons de Hidrogênio , Imidazóis , Ligantes , Espectroscopia de Ressonância Magnética , EspectrofotometriaRESUMO
The interaction of VO2+ with cytidine-monophosphate, -diphosphate, and -triphosphate has been investigated at different pH values and metal-to-ligand ratios by differential UV-absorption spectroscopy. It is shown that at pH values between 3 and 5 and for metal-to-ligand ratios up to 0.5, the cytosine ring is involved in coordination. On the other hand, measurements performed at pH = 7 show the absence of this type of interaction. Some comments on the possible structural characteristics of the generated complexes are made on the basis of the known coordination behavior of cytosine. Similar spectroscopic measurements with the systems VO2+/PO(3-)4, VO2+/P2O(4-)7, and VO2+/D-ribose were also performed in order to complement the analysis of the experimental results.
Assuntos
Nucleotídeos de Citosina/química , Citosina/química , Vanádio/química , Espectrofotometria UltravioletaRESUMO
The interaction of the vanadyl (IV) cation with N-acetyl-D-galactosamine, D-galactosamine, and D-glucuronic acid has been investigated by electron absorption spectroscopy at different metal to ligand ratios and pH values. In the case of D-glucuronic acid, a more detailed study was undertaken, using differential IR spectroscopy in solution. The results show that the cation interacts with the two nitrogenated molecules only at higher pH values, generating 2:1 ligand to metal complexes in which coordination occurs through two pairs of deprotonated OH groups of the rings. In the case of D-glucuronic acid, the IR-measurements allowed a wider insight into the structural characteristics of the complexes generated in acidic media. The involvement of the glycosidic oxygen atom in coordination, is suggested at pH = 3.
Assuntos
Acetilgalactosamina/química , Sulfatos de Condroitina/metabolismo , Galactosamina/química , Glucuronatos/química , Vanadatos/metabolismo , Acetilgalactosamina/metabolismo , Cátions Bivalentes , Sulfatos de Condroitina/química , Galactosamina/metabolismo , Glucuronatos/metabolismo , Ácido Glucurônico , Concentração de Íons de Hidrogênio , Ligantes , Espectrofotometria Atômica , Espectrofotometria Infravermelho , Vanadatos/químicaRESUMO
The interaction of VO2+ with the muchopolysaccharide chondroitin sulfate A (CSA) has been investigated by electron absorption spectroscopy and infrared measurements in aqueous solutions at different pH-values and ligand to metal ratios up to 6:1. The generation of a VO(CSA)2 species could be demonstrated. Coordination of the oxocation through the carboxylate group and the glycosidic oxygen of the D-glucuronate moieties is suggested. Infrared spectra of some poorly characterized solid VO/CSA complexes point to the same bonding characteristics. Preliminary results obtained at higher ligand to metal ratios suggest a different coordination behavior.
Assuntos
Sulfatos de Condroitina/química , Vanadatos/química , Configuração de Carboidratos , Sequência de Carboidratos , Dados de Sequência Molecular , Estrutura Molecular , Soluções , Espectrofotometria , Espectrofotometria InfravermelhoRESUMO
Tumor necrosis factor alpha (TNF alpha) has been implicated as one of the major mediators of the gram-negative septic shock syndrome. In our studies, group B streptococci (GBS) induced the production of TNF alpha by human mononuclear cells in a dose- and time-dependent manner. Human mixed mononuclear cell cultures exposed to an encapsulated (657.6 +/- 71.3 pg/ml; n = 30 preparations) or an unencapsulated transposon mutant of type III GBS (755.8 +/- 54.7 pg/ml; n = 9) produced similar amounts of TNF alpha. Isolated monocytes and culture-derived macrophages produced higher amounts of TNF alpha (1565 +/- 211 and 1790 +/- 928 pg/ml respectively) in response to GBS than did mixed mononuclear cell cultures. In response to GBS, mixed mononuclear cells from neonates produced significantly more TNF alpha (729.1 +/- 45 vs 520.3 +/- 47.2 pg/ml; p = 0.004) than did cells from adults. Examination of specimens from patients with neonatal GBS disease revealed detectable levels of TNF alpha (7 to 424 pg/ml) in the serum of 5 of 10 patients with sepsis, in 5 of 5 urine samples from infants with sepsis, and in the cerebrospinal fluid of 1 patient with meningitis. These results suggest both a major role for TNF alpha in the pathogenesis of human neonatal GBS sepsis and shock and a potential role for immunotherapy directed against this cytokine in this fulminant neonatal bacterial infection.
Assuntos
Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Infecções Estreptocócicas/metabolismo , Streptococcus agalactiae , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Células Cultivadas , Humanos , Recém-Nascido , Infecções Estreptocócicas/etiologiaRESUMO
The interaction of the vanadyl(IV) cation with oxidized glutathione (GSSG) in solution has been investigated using spectrophotometric techniques. Two complexes, stable at different metal-to-ligand ratios, could be identified at pH = 7. A solid 2:1 VO2+:GSSG complex could also be isolated at pH = 4.5 and characterized by chemical analysis and infrared and electronic spectroscopies. Its thermal behavior was investigated through TG and DTA measurements.
Assuntos
Glutationa/análogos & derivados , Vanadatos/química , Glutationa/química , Dissulfeto de Glutationa , Soluções , Espectrofotometria , Espectrofotometria InfravermelhoRESUMO
The interactions of VO2+ with phytate to form both soluble and insoluble complexes, have been studied by electronic absorption spectroscopy. A soluble 1:1 VO2+:phytate complex is formed at pH < 1. At higher pH-values insoluble complexes are produced. Two different solid complexes, obtained respectively at pH = 2 and 4, were isolated and characterized. The maximal bonding ratio of VO2+:phytate was found to be 4, on the basis of a pH binding profile.
Assuntos
Ácido Fítico/química , Vanádio/química , Eletroquímica , Concentração de Íons de Hidrogênio , Fosfatos/química , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
The interaction of the vanadyl (IV) cation with reduced glutathione (GSH) has been investigated by electronic absorption spectroscopy, at different metal-to-ligand ratios and pH values. The interaction depends strongly on the initial VO2+/GSH ratio. Starting with a tenfold GSH excess, coordination takes place through the two carboxylate groups of the ligand, generating (at pH = 7) a blue 1:2 VO2+/GSH complex; this stoichiometry could be confirmed by photometric titration experiments. Higher GSH concentrations produce a violet complex, which can also be obtained by addition of GSH to the blue species. Some measurements with the three component amino acids of GSH, as well as results obtained from the VO3-/GSH system, allowed a wider insight into the characteristics of this violet complex, in which the cation interacts with S and N atoms of the peptide.