RESUMO
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.
Assuntos
Iodo , Glândula Tireoide , Lactoperoxidase/metabolismo , Lactoperoxidase/farmacologia , Acetilcarnitina/metabolismo , Acetilcarnitina/farmacologia , Peróxido de Hidrogênio/farmacologia , Iodo/química , Modelos TeóricosRESUMO
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.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias Pulmonares , Antineoplásicos/química , Antioxidantes/farmacologia , Cátions , Complexos de Coordenação/química , Cobre/química , Flavanonas , Dissulfeto de Glutationa , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Fenantrolinas/farmacologia , Espécies Reativas de Oxigênio , Soroalbumina Bovina/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Flavonoides/farmacologia , Soroalbumina Bovina/metabolismo , Compostos de Vanádio/farmacologia , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Humanos , Estrutura Molecular , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Soroalbumina Bovina/química , Compostos de Vanádio/química , Compostos de Vanádio/metabolismoRESUMO
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.
Assuntos
5-Hidroxitriptofano/síntese química , Antineoplásicos/síntese química , Antioxidantes/síntese química , Cobre/química , Citotoxinas/síntese química , Fármacos Neuroprotetores/síntese química , 5-Hidroxitriptofano/farmacologia , Células A549 , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cobre/farmacologia , Citotoxinas/farmacologia , Relação Dose-Resposta a Droga , Células HCT116 , Células HeLa , Humanos , Fármacos Neuroprotetores/farmacologiaRESUMO
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.
Assuntos
Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Losartan/farmacologia , Zinco/farmacologia , Células A549 , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Caspase 3/metabolismo , Complexos de Coordenação/química , Glutationa/metabolismo , Humanos , Losartan/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Zinco/química , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismoRESUMO
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.
Assuntos
Antineoplásicos , Antioxidantes , Complexos de Coordenação , Flavonoides , Neoplasias Pulmonares/tratamento farmacológico , Vanadatos , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/química , Flavonoides/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Espécies Reativas de Oxigênio/metabolismo , Vanadatos/síntese química , Vanadatos/química , Vanadatos/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Modelos Animais de Doenças , Luteolina/farmacologia , Vanádio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Luteolina/química , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vanádio/químicaRESUMO
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.
Assuntos
Antidepressivos/farmacologia , Cisteína/análogos & derivados , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Zinco/química , Animais , Antidepressivos/química , Cisteína/química , Cisteína/farmacologia , Inibidores Enzimáticos/química , Sequestradores de Radicais Livres/química , Masculino , Ratos , Ratos Wistar , NataçãoRESUMO
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.
Assuntos
Antineoplásicos/química , Antioxidantes/química , Luteolina/química , Soroalbumina Bovina/química , Compostos de Vanádio/química , Espectroscopia de Ressonância de Spin Eletrônica , Ligação Proteica , Espectrofotometria UltravioletaRESUMO
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.