RESUMEN
The development of new anticancer compounds is one of the challenges of bioinorganic and medicinal chemistry. Naringenin and its metal complexes have been recognized as promising inhibitors of cell proliferation, having enormous potential to act as an antioxidant and antitumorigenic agent. Lung cancer is the second most commonly diagnosed type of cancer. Therefore, this study is devoted to investigate the effects of Cu(II), naringenin (Nar), binary Cu(II)-naringenin complex (CuNar), and the Cu(II)-naringenin containing bathophenanthroline as an auxiliary ligand (CuNarBatho) on adenocarcinoma human alveolar basal epithelial cells (A549 cells) that are used as models for the study of drug therapies against lung cancer. The ternary complex shows selectivity being high cytotoxic against malignant cells. The cell death generated by CuNarBatho involves ROS production, loss of mitochondrial membrane potential, and depletion of GSH level and GSH/GSSG ratio. The structure-relationship activity was assessed by comparison with the reported Cu(II)-naringenin-phenanthroline complex. The CuNarBatho complex was synthesized and characterized by elemental analysis, molar conductivity, mass spectrometry, thermogravimetric measurements and UV-VIS, FT-IR, EPR, Raman and 1H-NMR spectroscopies. In addition, the binding to bovine serum albumin (BSA) was studied at the physiological conditions (pH = 7.4) by fluorescence spectroscopy.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Neoplasias Pulmonares , Antineoplásicos/química , Antioxidantes/farmacología , Cationes , Complejos de Coordinación/química , Cobre/química , Flavanonas , Disulfuro de Glutatión , Humanos , Ligandos , Neoplasias Pulmonares/tratamiento farmacológico , Fenantrolinas/farmacología , Especies Reactivas de Oxígeno , Albúmina Sérica Bovina/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
The anticancer and antimetastatic behavior of the flavonoid luteolin and its oxidovanadium(IV) complex [VO(lut)(H2O)2]Na·3H2O (VOlut) has been investigated. Considering that the complex displayed strong anticancer activity on MDAMB231 human breast cancer cell line we herein determined through in vitro assays that the complex would probably reduce breast cancer cell metastasis in a higher extent than the natural antioxidant. In the CT26 colon cancer cell line a stronger anticancer effect has also been determined for the complex (IC50 0.9µM) and in addition it did not exert toxic effects on normal colon epithelial cells at concentrations up to 10µM. Working with a murine model of highly aggressive, orthotopic colon cancer model (CT26 cancer cell lines) it has been determined that the complex might prevent metastatic dissemination of the colon cancer cells to the liver. The flavonoid luteolin also exerted anticancer effects (at a low degree, IC50 5.9µM) on CT26 cell line and produced a 24% reduction of colon cancer liver metastasis.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Modelos Animales de Enfermedad , Luteolina/farmacología , Vanadio/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/patología , Luteolina/química , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas , Vanadio/químicaRESUMEN
The antidepressant effect of simple Zn(II) salts has been proved in several animal models of depression. In this study, a coordination metal complex of Zn(II) having a sulfur containing ligand is tested as antidepressant for the first time. Forced swimming test method on male Wistar rats shows a decrease in the immobility and an increase in the swimming behavior after treatment with [Zn(S-Met)2] (S-Met=S-methyl-l-cysteine) being more effective and remarkable than ZnCl2. The thiobarbituric acid and the pyranine consumption (hydroxyl and peroxyl radicals, respectively) methods were applied to evaluate the antioxidant activity of S-Met and [Zn(S-Met)2] showing evidence of attenuation of hydroxyl but not peroxyl radicals activities. UV-vis studies on the inhibition of acid phosphatase enzyme (AcP) demonstrated that S-methyl-l-cysteine did not produce any effect but, in contrast, [Zn(S-Met)2] complex behaved as a moderate inhibitor. Finally, bioavailability studies were performed by fluorescence spectroscopy denoting the ability of the albumin to transport the complex.
Asunto(s)
Antidepresivos/farmacología , Cisteína/análogos & derivados , Inhibidores Enzimáticos/farmacología , Depuradores de Radicales Libres/farmacología , Zinc/química , Animales , Antidepresivos/química , Cisteína/química , Cisteína/farmacología , Inhibidores Enzimáticos/química , Depuradores de Radicales Libres/química , Masculino , Ratas , Ratas Wistar , NataciónRESUMEN
L-Acetylcarnitine (ALC), a versatile compound, has demonstrated beneficial effects in depression, Alzheimer's disease, cognitive impairment, and other conditions. This study focuses on its antithyroid activity. The precursor molecule, L-carnitine, inhibited the uptake of triiodothyronine (T3) and thyroxine (T4), and it is possible that ALC may reduce the iodination process of T3 and T4. Currently, antithyroid drugs are used to control the excessive production of thyroid hormones (TH) through various mechanisms: (i) forming electron donor-acceptor complexes with molecular iodine, (ii) eliminating hydrogen peroxide, and (iii) inhibiting the enzyme thyroid peroxidase. To understand the pharmacological properties of ALC, we investigated its plausible mechanisms of action. ALC demonstrated the ability to capture iodine (Kc = 8.07 ± 0.32 x 105 M-1), inhibit the enzyme lactoperoxidase (LPO) (IC50 = 17.60 ± 0.76 µM), and scavenge H2O2 (39.82 ± 0.67 mM). A comprehensive physicochemical characterization of ALC was performed using FTIR, Raman, and UV-Vis spectroscopy, along with theoretical DFT calculations. The inhibition process was assessed through fluorescence spectroscopy and vibrational analysis. Docking and molecular dynamics simulations were carried out to predict the binding mode of ALC to LPO and to gain a better understanding into the inhibition process. Furthermore, albumin binding experiments were also conducted. These findings highlight the potential of ALC as a therapeutic agent, providing valuable insights for further investigating its role in the treatment of thyroid disorders.
Asunto(s)
Yodo , Glándula Tiroides , Lactoperoxidasa/metabolismo , Lactoperoxidasa/farmacología , Acetilcarnitina/metabolismo , Acetilcarnitina/farmacología , Peróxido de Hidrógeno/farmacología , Yodo/química , Modelos TeóricosRESUMEN
We have previously synthesized and characterized the chrysin coordination complex with the oxidovanadium(IV) cation (VIVO(chrys)2) and characterized in ethanolic solution and in solid state. Because suitable single crystals for X-ray diffraction determinations could not be obtained, in the present work, we elucidate the geometrical parameters of this complex by computational methodologies. The optimization and vibrational investigation were carried out both in ethanolic solution and in gas phase. The computational results support the experimentally proposed geometries of the VIVO(chrys)2 complex, thus leading to the conclusion that the complex exists as conformers with trans-octahedral geometry in ethanolic solution and as conformers with cis-octahedral geometry in the solid state. The complex also exists as conformers with trans-octahedral geometry in aqueous media. The active species formed after dissolution in DMSO showed anticancer and antimetastatic behavior in human lung cell line A549 with moderate binding (Kaca. 105 M-1) to bovine serum albumin (BSA). The interaction through hydrogen bonding and van der Waals forces resulted in a spontaneous process. Site marker competitive experiments showed binding sites for chrysin mainly located in site II (subdomain IIIA) and in site I (subdomain IIIA) for the complex. FT-IR spectral measurements showed evidences of the alterations of protein secondary structure in the presence of chrysin and VIVO(chrys)2.
Asunto(s)
Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Flavonoides/farmacología , Albúmina Sérica Bovina/metabolismo , Compuestos de Vanadio/farmacología , Células A549 , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Sitios de Unión , Bovinos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Humanos , Estructura Molecular , Unión Proteica , Conformación Proteica/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Albúmina Sérica Bovina/química , Compuestos de Vanadio/química , Compuestos de Vanadio/metabolismoRESUMEN
A new complex of the oxovanadium(IV) cation with the flavolignan silibinin has been synthesized and characterized. Vanadium compounds show interesting biological and pharmacological properties and some of them display antitumoral actions. Flavonoids are part of a larger group of antioxidant compounds called polyphenols which may inhibit the proliferation and growth of cancer cells. The antioxidant and antitumoral effects of silibinin and its oxovanadium(IV) complex were investigated. Silibinin acted as a very strong antioxidant and its complexation with oxovanadium(IV) improved this behavior. Besides, the generation of reactive oxygen species (ROS) by this compound was favored in tumoral (UMR106) cells and correlated with the deleterious behavior in the proliferation of this cell line. Conversely, silibinin did not exert any effect on the proliferation of normal osteoblasts (MC3T3E1). The cytotoxic action and ROS generation of the oxovanadium(IV) complex was more effective in tumoral cells. This behavior was not consistent with cleaving DNA of plasmid DNA pA1 because no significant cleaving activity was observed in both cases. These results suggest that the main deleterious mechanisms may take place through cytotoxic effects more than genotoxic actions. A comparison with our own findings on the behavior of other flavonoids and their vanadyl(IV) complex has also been performed.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , División del ADN/efectos de los fármacos , Compuestos Organometálicos/farmacología , Silimarina/farmacología , Vanadatos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Espectroscopía de Resonancia por Spin del Electrón , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Plásmidos/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Silibina , Silimarina/química , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Relación Estructura-Actividad , Vanadatos/químicaRESUMEN
BACKGROUND: Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and more than 90 % of mortality is due to metastasis-related deaths. Flavonoids are considered nutraceuticals due to the variety of pharmacological properties. In this paper, we studied the effects of baicalin, silibinin, apigenin, luteolin, and its oxidovanadium(IV) cation complexes on the viability, adhesion to fibronectin, invasion, and migration on human lung cancer cell line A549. In addition, in order to complete the study of the interaction of VOflavonoids and bovine serum albumin (BSA), the binding ability of silibinin and VOsil to the protein was evaluated. METHOD: To establish the non-cytotoxic concentration range of the tested compounds, the cancer cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Cell migration and invasion assays were performed using Boyden chambers and adhesion assay using MTT method. The interaction of compounds with BSA were investigated in physiological buffer (pHâ¯=â¯7.4) by fluorescence spectroscopy. RESULTS: All complexes inhibited the metastatic cascade steps to a greater extent than their respective ligands. Likewise, based on binding constant values (Kb) for BSA-silibinin and BSA-VOsil, we can suggest that both compounds can interact with the protein. CONCLUSION: Although all the complexes suppressed cell adhesion, invasion and migration, VOlut can be considered as a good candidate to continue the trials because it presented encouraging results as a potential antitumor and antimetastatic agent, and can be transported by BSA.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Flavonoides/farmacología , Vanadatos/farmacología , Células A549 , Animales , Antineoplásicos/química , Bovinos , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/química , Humanos , Estructura Molecular , Albúmina Sérica Bovina/metabolismo , Células Tumorales Cultivadas , Vanadatos/químicaRESUMEN
Methimazole (MeimzH) is an anti-thyroid drug and the first choice for patients with Grave's disease. Two new copper(II) complexes of this drug: [Cu(MeimzH)(2)(NO(3))(2)]*0.5H(2)O and [Cu(MeimzH)(2)(H(2)O)(2)](NO(3))(2)*H(2)O were synthesized and characterized by elemental analysis, dissolution behavior, thermogravimetric analysis and UV-vis, diffuse reflectance, FTIR and EPR spectroscopies. As it is known that copper(II) cation can act as an inhibitor of alkaline phosphatase (ALP), the inhibitory effect of methimazole and its copper(II) complexes on ALP activity has also been investigated.
Asunto(s)
Fosfatasa Alcalina/antagonistas & inhibidores , Antitiroideos/síntesis química , Antitiroideos/metabolismo , Antitiroideos/uso terapéutico , Cobre/química , Enfermedad de Graves/tratamiento farmacológico , Metimazol/síntesis química , Metimazol/metabolismo , Metimazol/uso terapéutico , Animales , Antitiroideos/química , Espectroscopía de Resonancia por Spin del Electrón , Humanos , Metimazol/química , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
We report the synthesis and biological evaluation of a ternary copper complex, [Cu(5HTP)(phen)(H2O)](NO3).2H2O, with the antioxidant agent 5-hydroxytryptophan (5-HTP) and phenanthroline (phen, added to improve its lipophilicity and membrane transport). The crystal structure of the complex was determined by X-ray diffraction methods. The complex showed antioxidant, antimicrobial, antitumor and antimetastatic properties with an adequate safety profile. The interaction of the metal with phen promotes cellular copper accumulation and cytotoxicity on human lung A549 cell line (IC50 = 3.6 µM). Furthermore, the viability of the normal human fetal lung fibroblast cell line (MRC-5) is not altered by the complex. An oxidative stress mechanism for the anticancer effect has been determined: cellular increase of reactive oxygen species (ROS), decrease of the glutathione (GSH) and oxidized GSH (GSSG) ratio and alteration of the mitochondrial potential. The complex also displays antimetastatic activities with inhibition of cell adhesion, invasion and migration. It has not mutagenic behavior and no toxicity on Artemia salina indicating its potential to act as an effective and safety antimicrobial and antitumor drug.
Asunto(s)
5-Hidroxitriptófano/química , Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Cobre/química , Neoplasias Pulmonares/tratamiento farmacológico , Fenantrolinas/química , Células A549 , Animales , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antioxidantes/química , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Artemia/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Cobre/farmacología , Humanos , Fenantrolinas/farmacología , Pruebas de ToxicidadRESUMEN
5-Hydroxy-L-tryptophan (5-HTP) is a serotonin pathway metabolite of L-tryptophan in the brain. In the knowledge that the biological properties of some compounds can be modified upon metal complexation, a new solid metal complex, [Cu(5-hydroxytryptophan)2].H2O (Cu5HTP), has been synthesized and characterized to analyze the modification of some biological properties. The conformational investigations (optimized in gas phase at B3LYP/6-311G** theory level) suggest the coexistence of two conformers of Cu5HTP with cis- and trans- arrangements of the amino acids in the equatorial plane. The trans- Cu5HTP1 complex is the most stable conformer. The complexation led to an enhancement of the antioxidant properties of the ligand. The metal complex also improved the anticancer behavior of the ligand (tested in cancer cell lines derived from human lung (A549), cervix (HeLa) and colon (HCT-116)). It did not show toxicity against either the non-malignant human lung fibroblast (MRC-5) cell line or Artemia salina and did not behave as mutagenic agent (Ames test). Cellular reactive oxygen species production may be one of the possible mechanisms of action. Besides, the metal complex exerted neuroprotective action on cortical neurons from embryonic 18 days rats exposed to glutamate.
Asunto(s)
5-Hidroxitriptófano/síntesis química , Antineoplásicos/síntesis química , Antioxidantes/síntesis química , Cobre/química , Citotoxinas/síntesis química , Fármacos Neuroprotectores/síntesis química , 5-Hidroxitriptófano/farmacología , Células A549 , Antineoplásicos/farmacología , Antioxidantes/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Cobre/farmacología , Citotoxinas/farmacología , Relación Dosis-Respuesta a Droga , Células HCT116 , Células HeLa , Humanos , Fármacos Neuroprotectores/farmacologíaRESUMEN
A new losartan [2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol zinc(II) complex [Zn(Los)Cl], was synthesized and characterized. The crystal structure was determined by x-ray diffraction methods. When aqueous solutions of the ligand and the metal were mixed, the known and more soluble powder [Zn(Los)2].3H2O (ZnLos) complex has been obtained. The interactions with phosphatases showed a concerted mechanism displayed by the Zn ions and ZnLos up to 500 µM concentration: a decrease of the acid phosphatase (AcP) associated with an increase in the alkaline phosphatase (ALP) activities. The complex and ZnSO4 showed a cytotoxic behavior on human lung A549 cancer cell line at concentrations higher than 75 µM with reactive oxygen species (ROS) generation and GSH (and GSH/GSSG ratio) depletion. Apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) method, a mechanism accompanied by upregulation of BAX protein, downregulation of Bcl-XL and release of caspase-3. The BAX/Bcl-XL ratio was found to be significantly higher in cells exposure to ZnLos than cells treated with ZnSO4, in agreement with the higher apoptotic percentage of cells found for the complex. Cell death was found to be produced by apoptosis and no necrosis has been observed. On the contrary, losartan exerted low effects on phosphatases, produced some reduction of cancer cell viability (concentrations > 250 µM, number of apoptotic cells similar to the basal) with low ROS depletion, without alteration of the GSH/GSSG and low BAX/Bcl-XL ratios. In the MRC-5, normal lung fibroblasts cell line only ZnSO4 at concentrations higher than 200 µM displays cytotoxic effects. Graphical abstract Interaction of Zn with losartan. Activation of intrinsic apoptotic signaling pathway in lung cancer cells and effects on alkaline and acid phosphatases.
Asunto(s)
Fosfatasa Ácida/metabolismo , Fosfatasa Alcalina/metabolismo , Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , Losartán/farmacología , Zinc/farmacología , Células A549 , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Caspasa 3/metabolismo , Complejos de Coordinación/química , Glutatión/metabolismo , Humanos , Losartán/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Zinc/química , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismoRESUMEN
Based on the known antioxidant effect of flavonoids, baicalin (baic) found in roots of Scutellaria has been selected. Its coordination complex with the oxidovanadium(IV) cation, Na4[VO(baic)2].6H2O (VIVO(baic)), was synthesized at pH9 in ethanol and characterized by physicochemical methods. Spectrophotometric studies at pH9 showed a ligand: metal stoichiometry of 2:1. By vibrational spectroscopy a coordination mode through the cis 5-OH and 6-OH deprotonated groups is inferred. EPR spectroscopy shows an environment of four aryloxide (ArO-) groups in the equatorial plane of the VO moiety, both in solution and in the solid complex. The antioxidant capacity against superoxide and peroxyl radicals of VIVO(baic) resulted greater than for baicalin and correlated with previous results obtained for other VOflavonoid complexes. The coordination mode produces delocalization of the electron density and the stabilization of the radical formed by interaction with external radicals. The complex and the ligand displayed no toxic (Artemia salina test) and no mutagenic (Ames test) effects. The complex improved the ability of the ligand to reduce cell viability of human lung cancer cell lines (A549) generating reactive oxygen species (ROS) in cells, being this effect reversed by pre-incubation of the cells with antioxidants such as vitamins C and E. The addition of NAC (N-acetyl-l-cysteine, a sequestering agent of free radicals) suppresses the anticancer effect, confirming the oxidative stress mechanism. The complex interacted with bovine serum albumin (BSA) with stronger binding than baicalin and the mechanisms involved H bonding and van der Waals interactions.
Asunto(s)
Antineoplásicos , Antioxidantes , Complejos de Coordinación , Flavonoides , Neoplasias Pulmonares/tratamiento farmacológico , Vanadatos , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/química , Flavonoides/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Especies Reactivas de Oxígeno/metabolismo , Vanadatos/síntesis química , Vanadatos/química , Vanadatos/farmacologíaRESUMEN
Chemotherapy using metal coordination compounds for cancer treatment is the work of the ongoing research. Continuing our research on the improvement of the anticancer activity of natural flavonoids by metal complexation, a coordination compound of the natural antioxidant flavone luteolin (lut) and the oxidovanadium(IV) cation has been synthesized and characterized. Using different physicochemical measurements some structural aspects of [VO(lut)(H2O)2]Na·3H2O (VOlut) were determined. The metal coordinated to two cis-deprotonated oxygen atoms (ArO(-)) of the ligand and two H2O molecules. Magnetic measurements in solid state indicated the presence of an effective exchange pathway between adjacent vanadium ions. VOlut improved the antioxidant capacity of luteolin only against hydroxyl radical. The antitumoral effects were evaluated on MDAMB231 breast cancer and A549 lung cancer cell lines. VOlut exhibited higher viability inhibition (IC50=17 µM) than the ligand on MDAMB231 cells but they have the same behavior on A549 cells (ca. IC50=60 µM). At least oxidative stress processes were active during cancer cell-killing. When metals chelated through the carbonyl group and one adjacent OH group of the flavonoid an effective improvement of the biological properties has been observed. In VOlut the different coordination may be the cause of the small improvement of some of the tested properties of the flavonoid. Luteolin and VOlut could be distributed and transported in vivo. Luteolin interacted in the microenvironment of the tryptophan group of the serum binding protein, BSA, by means of electrostatic forces and its complex bind the protein by H bonding and van der Waals interactions.
Asunto(s)
Antineoplásicos/química , Antioxidantes/química , Luteolina/química , Albúmina Sérica Bovina/química , Compuestos de Vanadio/química , Espectroscopía de Resonancia por Spin del Electrón , Unión Proteica , Espectrofotometría UltravioletaRESUMEN
Naringenin, a natural antioxidant present in grapefruit, oranges and the skin of tomatoes showed low antioxidant properties among other flavonoids due to its structural characteristics. Since many flavonoids were shown to have cell-killing and antioxidant activities, naringenin was investigated herein. In parallel with its antioxidant activities the flavonoid showed very low cytotoxicity at concentrations up to 100 µM against lung (A549) and breast (SKBr3 and MDAMB231) cancer cell lines. Furthermore, a newly-synthesized and characterized complex of naringenin and oxidovanadium(IV) ([V(IV)O(nar)2] · 2H2O, VOnar, with weak ferromagnetic coupling) was also studied. As a result, VOnar acted as a better compound on cell-killing and antioxidant activities (in vitro) than naringenin. The anti-proliferative effect of VOnar was accompanied by reactive oxygen species (ROS) generation, cell membrane and DNA damages, cell cycle arrest, caspase 3/7 activation and mitochondrial potential reduction. The higher parameters observed for the MDAMB231 cell line have been related to its low glutathione (GSH) content. The assays of the interaction of bovine serum albumin (BSA) with the complex showed the affinity of protein toward it and that there is only one binding site on the BSA molecule. However, metal complexation decreased the binding affinity to BSA of naringenin probably due to a steric hindrance of the complex.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Flavanonas/química , Compuestos Organometálicos/farmacología , Albúmina Sérica Bovina/metabolismo , Vanadio/química , Antineoplásicos/química , Antioxidantes/química , Apoptosis , Sitios de Unión , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Daño del ADN , Células Epiteliales/efectos de los fármacos , Humanos , Compuestos Organometálicos/química , Unión Proteica , Albúmina Sérica Bovina/químicaRESUMEN
A new chlorogenate oxidovanadium complex (Na[VO(chlorog)(H2O)3].4H2O) was synthesized by using Schlenk methodology in the course of a reaction at inert atmosphere in which deprotonated chlorogenic acid ligand binds to oxidovanadium(IV) in a reaction experiment controlled via EPR technique and based in a species distribution diagram. The compound was characterized by FTIR, EPR, UV-visible and diffuse reflectance spectroscopies and thermogravimetric, differential thermal and elemental analyses. The ligand and the complex were tested for their antioxidant effects on DPPH (1,1-diphenyl-2-picrylhydrazyl radical), ABTS(+) (radical cation of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt), O2(-), OH and ROO radicals and their cytotoxic activity on different cancer cell lines (SKBR3, T47D and MDAMB231) and primary human mammary epithelial cells. The complex behaved as good antioxidant agent with strongest inhibitory effects on O2(-), OH and ROO radicals and exhibited selective cytotoxicity against SKBR3 cancer cell line. Albumin interaction experiments denoted high affinity toward the complex and its calculated binding constant was indicative of a strong binding to the protein. Based on this study, it is hypothesized that Na[VO(chlorog)(H2O)3].4H2O would be a promising candidate for further evaluation as an antioxidant and anticancer agent.
Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Depuradores de Radicales Libres/síntesis química , Albúmina Sérica Bovina/química , Animales , Antineoplásicos/farmacología , Compuestos de Bifenilo/química , Neoplasias de la Mama , Bovinos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Complejos de Coordinación/farmacología , Estabilidad de Medicamentos , Femenino , Depuradores de Radicales Libres/farmacología , Radicales Libres/química , Humanos , Oxidación-Reducción , Picratos/química , Unión Proteica , Superóxido Dismutasa/químicaRESUMEN
It is known that flavonoids possess, among others, antioxidant and antitumoral properties that depend on their molecular structure. The central objective if this study was to investigate the potential antioxidant and antiproliferative properties of the flavonol morin and its new oxovanadium(IV) complex (VOmor) that was synthesized in order to modify the morin chemical structure. Two osteoblast (UMR106 and MC3T3E1), two breast tumor (T47D and SKBR3) and breast epithelial cell lines in culture were used for the antitumoral determinations. Additionally, a comparative study of their antioxidant capacities using different radicals (DPPH, ABTS(+), OH, O2(-), ROO) was performed. Selected mechanisms of action were studied using the breast cancer cell lines. Results obtained show that morin and its complex behaved as good antioxidant agents for some of the radicals and that the complexation improved the behavior with respect to OH and O2(-) radicals being morin more effective as ROO scavenger. A considerable variation in sensitivity was observed in the breast cancer cells but non-specificity was found for the treatment of osteosarcoma. Moreover, the compounds did not affect the normal proliferation of the breast epithelial mammal cells. The mechanistic studies demonstrated that the complex did not generate reactive oxygen species in the cells (confirming the in vitro studies) and did not produce any damage of DNA. The plasmatic membrane was observed to be damaged only in the SKBR3 cell line. In contrast, the perturbation of the mitochondrial membrane potential and the activation of caspase 3/7 for the breast tumor cells revealed an apoptotic cell death process. All these results collectively suggested that VOmor complex could serve as promising pharmacologically active substance against breast cancer treatment.
Asunto(s)
Antineoplásicos/química , Antioxidantes/química , Complejos de Coordinación/química , Flavonoides/química , Vanadio/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Espectroscopía de Resonancia por Spin del Electrón , Humanos , Ratones , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Two copper(II) complexes, [Cu(sac)(2)(4-cypy)(2)(H(2)O)], 1 and [Cu(sac)(2)(4-Ampy)(2)(H(2)O)], 2 (4-cypy: 4-cyanopyridine; 4-Ampy: 4-aminopyridine) were prepared. Physicochemical properties of the complexes were studied by spectroscopic (solution UV-vis, diffuse reflectance and IR) techniques. Structural X-ray diffraction data could be obtained only for [Cu(sac)(2)(4-cypy)(2)(H(2)O)] that it crystallized in the tetragonal space group P4cc with a=b=15.313(1), c=13.240(1)A, and Z=4 molecules per unit cell. The complex was cited on a crystallographic C(2)-axis with the Cu(II) ion in a square-pyramidal environment, coordinated at the pyramid basis to the nitrogen atom of two saccharine anions [d(Cu-N)=2.011(3)A] and the pyridine N-atom of two 4-cyanopyridine ligands [d(Cu-N)=2.038(4)A]. The coordination was completed by a water molecule at the pyramid apex [d(Cu-Ow)=2.189(5)A]. Elemental and spectroscopic analyses revealed an O-saccharinate coordination mode for complex 2 and a square-pyramidal structure. Only complex 2 retained its structure in methanolic solution. However, both complexes were able to catalyze the dismutation of superoxide anion (O(2)(-)) (pH 7.5) at micromolar concentrations. Therefore, these complexes behaved as useful SOD-mimetic compounds.