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1.
Int Immunopharmacol ; 100: 108090, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34507108

RESUMO

BACKGROUND: Immunomodulatory therapies are claimed to enhance antimicrobial immunity and counterbalance antimicrobial resistance mechanisms of pathogenic bacteria. PURPOSE: To investigate whether caffeine can be useful for control of inflammation derived from experimental systemic infection with Listeria monocytogenes. METHODS: Peritoneal macrophages (pMØ) from Swiss mice were cultured with caffeine in 96-well plates, and then infected with virulent L. monocytogenes 619. In another experiment, the pMØ were first infected with the bacterium and then treated with caffeine. Swiss mice were inoculated intraperitoneally with L. monocytogenes and then treated intravenously with caffeine (0.05; 0.5 or 5 mg/Kg). RESULTS: Caffeine did not exert direct antibacterial activity in vitro against L. monocytogenes. Macrophages exposed to caffeine before or after infection with L. monocytogenes had increased cell viability, although the intracellular bacterial loads were similar to the control groups. Caffeine treatments of Swiss mice reduced leukocyte infiltration into the peritoneal cavity after L. monocytogenes infection. However, the bacterial burden was reduced in the spleen and liver. The mRNA expressions of IL-1ß, IL-6 and the enzyme inducible nitric oxide synthase (iNOS) were reduced whereas IL-10 was increased. CONCLUSION: Caffeine has an anti-infectious potential and ameliorated infection-derived inflammation following experimental infection with L. monocytogenes.


Assuntos
Anti-Inflamatórios/farmacologia , Cafeína/farmacologia , Inflamação/tratamento farmacológico , Listeria monocytogenes/patogenicidade , Listeriose/tratamento farmacológico , Macrófagos Peritoneais/efeitos dos fármacos , Animais , Cafeína/análogos & derivados , Células Cultivadas , Quimiotaxia de Leucócito/efeitos dos fármacos , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/microbiologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Listeria monocytogenes/imunologia , Listeriose/imunologia , Listeriose/metabolismo , Listeriose/microbiologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/microbiologia , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Virulência
2.
Bioorg Chem ; 111: 104900, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33894429

RESUMO

Due to their unique pharmacological characteristics, methylxanthines are known as therapeutic agents in a fascinating range of medicinal scopes. In this report, we aimed to examine some biological effects of previously synthesized 8-alkylmercaptocaffeine derivatives. Cytotoxic and antioxidative activity of 8-alkylmercaptocaffeine derivatives were measured in malignant A549, MCF7, and C152 cell lines. Assessment of cGMP levels and caspase-3 activity were carried out using a colorimetric competitive ELISA kit. Computational approaches were employed to discover the inhibitory mechanism of synthesized compounds. Among the twelve synthesized derivatives, three compounds (C1, C5, and C7) bearing propyl, heptyl, and 3-methyl-butyl moieties showed higher and more desirable cytotoxic activity against all the studied cell lines (IC50 < 100 µM). Furthermore, C5 synergistically enhanced cisplatin-induced cytotoxicity in MCF-7 cells (CI < 1). Both C5 and C7 significantly increased caspase-3 activity and intracellular cGMP levels at specific time intervals in all studied cell lines (P < 0.05). However, these derivatives did not elevate LDH leakage (P > 0.05) and exhibited no marked ameliorating effects on oxidative damage (P > 0.05). Computational studies showed that H-bond formation between the nitrogen atom in pyrazolo[4,3-D] pyrimidine moiety with Gln817 and creating a hydrophobic cavity result in the stability of the alkyl group in the PDE5A active site. We found that synthesized 8-alkylmercaptocaffeine derivatives induced cell death in different cancer cells through the cGMP pathway. These findings will help us to get a deeper insight into the role of methylxanthines as useful alternatives to conventional cancer therapeutics.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Cafeína/farmacologia , Simulação de Acoplamento Molecular , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Cafeína/análogos & derivados , Cafeína/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade
3.
Chemistry ; 26(67): 15528-15537, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32902006

RESUMO

The organometallic AuI bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)2 ]+ (AuTMX2 ) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometry-based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal-based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.


Assuntos
Antineoplásicos , Ouro , Compostos Organometálicos , Neoplasias Ovarianas , Antineoplásicos/farmacologia , Cafeína/análogos & derivados , Cafeína/química , Cafeína/farmacologia , Linhagem Celular Tumoral , Feminino , Ouro/química , Ouro/farmacologia , Humanos , Metano/análogos & derivados , Metano/química , Metano/farmacologia , Compostos Organometálicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Proteômica
4.
Neuroscience ; 422: 32-43, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678341

RESUMO

A stroke-like event follows seizures which may be responsible for the postictal state and a contributing factor to the development of seizure-induced brain abnormalities and behavioral dysfunction associated with epilepsy. Caffeine is the world's most popular drug with ∼85% of people in the USA consuming it daily. Thus, persons with epilepsy are likely to have caffeine in their body and brain during seizures. This preclinical study investigated the effects of acute caffeine on local hippocampal tissue oxygenation pre and post seizure. We continuously measured local oxygen levels in the CA1 region of the hippocampus and utilized the electrical kindling model in rats. Rats were acutely administered either caffeine, or one of its metabolites, or agonists and antagonists at adenosine sub-receptor types or ryanodine receptors prior to the elicitation of seizures. Acute caffeine administration caused a significant drop in pre-seizure hippocampal pO2. Following a seizure, caffeine, as well as two of its metabolites paraxanthine, and theophylline, increased the time below the severe hypoxic threshold (10 mmHg). Likewise, the specific A2A receptor antagonist, SCH-58261, mimicked caffeine by causing a significant drop in pre-seizure pO2 and the area and time below the severe hypoxic threshold. Moreover, the A2A receptor agonist, CGS-21680 was able to prevent the effect of both caffeine and SCH-58261 adding further evidence that caffeine is likely acting through the A2A receptor. Clinical tracking and investigations are needed to determine the effect of caffeine on postictal symptomology and blood flow in persons with epilepsy.


Assuntos
Cafeína/efeitos adversos , Hipóxia/fisiopatologia , Receptores A2 de Adenosina/fisiologia , Convulsões/fisiopatologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Região CA1 Hipocampal/metabolismo , Cafeína/análogos & derivados , Cafeína/antagonistas & inibidores , Relação Dose-Resposta a Droga , Hipóxia/complicações , Excitação Neurológica/efeitos dos fármacos , Masculino , Oxigênio/metabolismo , Fenetilaminas/farmacologia , Pirimidinas/antagonistas & inibidores , Pirimidinas/farmacologia , Ratos , Receptores A2 de Adenosina/efeitos dos fármacos , Convulsões/complicações , Triazóis/antagonistas & inibidores , Triazóis/farmacologia
5.
Rapid Commun Mass Spectrom ; 33(23): 1792-1803, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351020

RESUMO

RATIONALE: Novel bifunctional compounds composed of a caffeine scaffold attached to nicotine (C8 -6-N), 1-aminoindan (C8 -6-I), or caffeine (C8 -6-C8 ) were designed as therapeutics or diagnostics for Parkinson's disease (PD). In order to probe their pharmacological and toxicological profile, an appropriate analytical method is required. The goal of this study is to establish a tandem mass spectrometric fingerprint for the development of quantitative and qualitative methods that will aid future assessment of the in vitro and in vivo absorption, distribution, metabolism, excretion (ADME) and pharmacokinetic properties of these lead bifunctional compounds for PD. METHODS: Accurate mass measurement was performed using a hybrid quadrupole orthogonal time-of-flight mass spectrometer while multistage MS/MS and MS3 analyses were conducted using a triple quadrupole linear ion trap mass spectrometer. Both instruments are equipped with an electrospray ionization (ESI) source and were operated in the positive ion mode. The source and compound parameters were optimized for all three tested bifunctional compounds. RESULTS: The MS/MS analysis indicates that the fragmentation of C8 -6-N and C8 -6-I is driven by the dissociation of the nicotine and 1-aminoindan moieties, respectively, but not caffeine. A significant observation in the MS/MS fragmentation of C8 -6-C8 suggests that a previously reported loss of acetaldehyde during caffeine dissociation is instead a loss of CO2 . CONCLUSIONS: The collision-induced tandem mass spectrometry (CID-MS/MS) analysis of these novel bifunctional compounds revealed compound-specific diagnostic product ions and neutral losses for all three tested bifunctional compounds. The established MS/MS fingerprint will be applied to the future development of qualitative and quantitative methods.


Assuntos
Cafeína/análogos & derivados , Indanos/química , Nicotina/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Espectrometria de Massas por Ionização por Electrospray/métodos
6.
J Inorg Biochem ; 198: 110749, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31200320

RESUMO

Three Pt(II) complexes containing the natural ligands curcumin and caffeine, namely [Pt(curc)(PPh3)2]Cl (1), [PtCl(curc)(DMSO)] (2) (curc = deprotonated curcumin) and trans-[Pt(caffeine)Cl2(DMSO)] (3), were synthesized and fully characterized. The data obtained suggest that, for both 1 and 2, the anion of curcumin is coordinated to the platinum ion via the oxygen atoms of the ß-diketonate moiety. Spectroscopic features reveal that in 2 and 3, a DMSO molecule is S-bonded to the metal centre. For 3, all data indicate a square-planar geometry formed by a 9-N bonded caffeine, two trans chloride anions and a DMSO. The three complexes undergo changes in solution upon incubation for 24 h; 1 and 2 release curcumin while 3 isomerizes from trans to cis configuration. The DNA-binding and cytotoxic properties of 1-3 were evaluated in vitro. Despite their structural similarity, curcuminate-containing 1 and 2 exhibit distinct DNA interactions. While 1 appears to intercalate between nucleobase pairs, inducing the oxidative degradation of the biomolecule, 2 behaves as a groove binder, by means of electrostatic forces. Caffeine-containing 3 exhibits a behaviour that is comparable to that of 2. Complexes 1 and 2 showed moderate to high cytotoxicity and selectivity against several cancer cell lines, while 3 is inactive. Compounds 1 and 2 can be further activated by visible-light irradiation.


Assuntos
Antineoplásicos/farmacologia , Cafeína/farmacologia , Complexos de Coordenação/farmacologia , Curcumina/farmacologia , DNA/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Cafeína/análogos & derivados , Cafeína/síntese química , Cafeína/metabolismo , Bovinos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Curcumina/análogos & derivados , Curcumina/síntese química , Curcumina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Platina/química
7.
Molecules ; 23(11)2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30380600

RESUMO

The antioxidant activity of molecules constitutes an important factor for the regulation of redox homeostasis and reduction of the oxidative stress. Cells affected by oxidative stress can undergo genetic alteration, causing structural changes and promoting the onset of chronic diseases, such as cancer. We have performed an in silico study to evaluate the antioxidant potential of two molecules of the zinc database: ZINC08706191 (Z91) and ZINC08992920 (Z20). Molecular docking, quantum chemical calculations (HF/6-31G**) and Pearson's correlation have been performed. Molecular docking results of Z91 and Z20 showed both the lower binding affinity (BA) and inhibition constant (Ki) values for the receptor-ligand interactions in the three tested enzymes (cytochrome P450-CP450, myeloperoxidase-MP and NADPH oxidase-NO) than the control molecules (5-fluorouracil-FLU, melatonin-MEL and dextromethorphan-DEX, for each receptor respectively). Molecular descriptors were correlated with Ki and strong correlations were observed for the CP450, MP and NO receptors. These and other results attest the significant antioxidant ability of Z91 and Z20, that may be indicated for further analyses in relation to the control of oxidative stress and as possible antioxidant agents to be used in the pharmaceutical industry.


Assuntos
Antioxidantes/química , Cafeína/análogos & derivados , Cafeína/química , Enzimas/química , Domínio Catalítico , Simulação por Computador , Enzimas/metabolismo , Febuxostat/química , Fluoruracila/química , Hidroxiureia/análogos & derivados , Hidroxiureia/química , Simulação de Acoplamento Molecular , Teoria Quântica
8.
ChemMedChem ; 13(22): 2408-2414, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30203922

RESUMO

Three new gold(I)-coumarin-based trackable therapeutic complexes and two non-trackable analogues have been synthesised and fully characterised. They all display anti-proliferative properties on several types of cancer cell lines, including those of colon, breast, and prostate. Two complexes displayed significant anti-inflammatory effects; one displayed pro-inflammatory behaviour; this highlights the impact of the position of the fluorophore on the caffeine scaffold. Additionally, the three coumarin derivatives could be visualised in vitro by two-photon microscopy.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Cafeína/análogos & derivados , Cafeína/farmacologia , Complexos de Coordenação/farmacologia , Cumarínicos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/efeitos da radiação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Cafeína/síntese química , Cafeína/efeitos da radiação , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/efeitos da radiação , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Corantes Fluorescentes/efeitos da radiação , Ouro/química , Células HEK293 , Humanos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Raios Ultravioleta
9.
Free Radic Res ; 52(6): 724-736, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29669446

RESUMO

A series of new di- and polyamine-caffeine analogues were synthesised and characterised by NMR, FT-IR, and MS spectroscopic methods. To access the stability of the investigated caffeine analogues, molecular dynamic simulations were performed in NAMD 2.9 assuming CHARMM36 force field. To evaluate the antioxidant capacity of new compounds, three different antioxidant assays were used, namely 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH•) scavenging activity, ferrous ions (Fe2+) chelating activity, and Fe3+→Fe2+reducing ability. In vitro, the ability of new derivatives to protect human erythrocytes against oxidative haemolysis induced by free radical from 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH) was estimated. The cytotoxic activity was tested using MCF-7 breast cancer cells and human erythrocytes. All compounds showed the antioxidant capacity depending mostly on their ferrous ions chelating activity. In the presence of AAPH, some derivatives were able to effectively inhibit the oxidative haemolysis. Two derivatives, namely 8-(methyl(2-(methylamino)ethyl)-amino)caffeine and 8-(methyl(3-(methylamino)propyl)amino)caffeine, showed cytotoxic activity against MCF-7 breast cancer cells but not against human erythrocytes. Therefore, it is concluded that the selected di- and polyamine caffeine analogues, depending on their chemical structure, were able to minimise the oxidative stress and to inhibit the tumour cell growth. The confirmed antioxidant and cytotoxic properties of some caffeine derivatives make them attractive for potential applications in food or pharmaceutical industries.


Assuntos
Antioxidantes/farmacologia , Cafeína/farmacologia , Quelantes/farmacologia , Citotoxinas/farmacologia , Oxidantes/antagonistas & inibidores , Amidinas/antagonistas & inibidores , Amidinas/farmacologia , Antioxidantes/síntese química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Cafeína/análogos & derivados , Cafeína/síntese química , Sobrevivência Celular/efeitos dos fármacos , Quelantes/síntese química , Citotoxinas/síntese química , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ferro/química , Células MCF-7 , Especificidade de Órgãos , Oxidantes/farmacologia , Oxirredução , Picratos/antagonistas & inibidores , Picratos/química , Poliaminas/química , Relação Estrutura-Atividade
10.
Curr Pharm Des ; 24(5): 576-594, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28699538

RESUMO

About 132 thousand cases of melanoma (more severe type of skin cancer) were registered in 2014 according to the World Health Organization. This type of cancer significantly affects the quality of life of individuals. Caffeine has shown potential inhibitory effect against epithelial cancer. In this study, it was proposed to obtain new caffeine-based molecules with potential epithelial anticancer activity. For this, a training set of 21 molecules was used for pharmacophore perception procedures. Multiple linear regression analyses were used to propose mono-, bi-, tri-, and tetra-parametric models applied in the prediction of the activity. The generated pharmacophore was used to select 350 molecules available at the ZINCpharmer server, followed by reduction to 24 molecules, after selection using the Tanimoto index, yielding 10 molecules after final selection by predicted activity values > 1.5229. These ten molecules had better pharmacokinetic properties than the other ones used as reference and within the clinically significant limits. Only two molecules show minor hits of toxicity and were submitted to molecular docking procedures, showing BFE (binding free energy) values lower than the reference values. Statistical analyses indicated strong negative correlations between BFE and pharmacophoric properties (high influence on BFE lowering) and practically null correlation between BFE and BBB. The two most promising molecules can be indicated as candidates for further in vitro and in vivo analyzes.


Assuntos
Antineoplásicos/farmacologia , Cafeína/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Desenho de Fármacos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Cafeína/análogos & derivados , Cafeína/química , Carcinoma Epitelial do Ovário/patologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Simulação de Acoplamento Molecular , Neoplasias Ovarianas/patologia , Ratos , Estatística como Assunto
11.
BMC Anesthesiol ; 16(1): 121, 2016 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-27914476

RESUMO

BACKGROUND: Lidocaine is an approved local anesthetic and Class 1B antiarrhythmic with a number of ancillary properties. Our aim was to investigate lidocaine's vasoreactivity properties in intact versus denuded rat thoracic aortic rings, and the effect of inhibitors of nitric oxide (NO), prostenoids, voltage-dependent Kv and KATP channels, membrane Na+/K+ pump, and A2a and A2b receptors. METHODS: Aortic rings were harvested from adult male Sprague Dawley rats and equilibrated in an organ bath containing oxygenated, modified Krebs-Henseleit solution, pH 7.4, 37 °C. The rings were pre-contracted sub-maximally with 0.3 µM norepinephrine (NE), and the effect of increasing lidocaine concentrations was examined. Rings were tested for viability after each experiment with maximally dilating 100 µM papaverine. The drugs 4-aminopyridine (4-AP), glibenclamide, 5-hydroxydecanoate, ouabain, 8-(3-chlorostyryl) caffeine and PSB-0788 were examined. RESULTS: All drugs tested had no significant effect on basal tension. Lidocaine relaxation in intact rings was biphasic between 1 and 10 µM (Phase 1) and 10 and 1000 µM (Phase 2). Mechanical removal of the endothelium resulted in further relaxation, and at lower concentrations ring sensitivity (% relaxation per µM lidocaine) significantly increased 3.5 times compared to intact rings. The relaxing factor(s) responsible for enhancing ring relaxation did not appear to be NO- or prostacyclin-dependent, as L-NAME and indomethacin had little or no effect on intact ring relaxation. In denuded rings, lidocaine relaxation was completely abolished by Kv channel inhibition and significantly reduced by antagonists of the MitoKATP channel, and to a lesser extent the SarcKATP channel. Curiously, A2a subtype receptor antagonism significantly inhibited lidocaine relaxation above 100 µM, but not the A2b receptor. CONCLUSIONS: We show that lidocaine relaxation in rat thoracic aorta was biphasic and significantly enhanced by endothelial removal, which did not appear to be NO or prostacyclin dependent. The unknown factor(s) responsible for enhanced relaxation was significantly reduced by Kv inhibition, 5-HD inhibition, and A2a subtype inhibition indicating a potential role for crosstalk in lidocaine's vasoreactivity.


Assuntos
Aorta Torácica/efeitos dos fármacos , Canais KATP/antagonistas & inibidores , Lidocaína/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Vasodilatação/efeitos dos fármacos , 4-Aminopiridina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Cafeína/análogos & derivados , Cafeína/farmacologia , Ácidos Decanoicos/farmacologia , Relação Dose-Resposta a Droga , Epoprostenol/antagonistas & inibidores , Glibureto/farmacologia , Hidroxiácidos/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , Lidocaína/antagonistas & inibidores , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/antagonistas & inibidores , Norepinefrina/farmacologia , Ouabaína/farmacologia , Papaverina/farmacologia , Ratos , Receptor Cross-Talk/efeitos dos fármacos , Receptor A2A de Adenosina/efeitos dos fármacos
12.
Am J Ther ; 23(3): e757-65, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-24368612

RESUMO

Defibrotide is a polydisperse mixture of single-stranded oligonucleotides with many pharmacologic properties and multiple actions on the vascular endothelium. Responses to defibrotide and other vasodepressor agents were evaluated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure. Lobar arterial pressure was increased to a high steady level with the thromboxane A2 analog U-46619. Under increased-tone conditions, defibrotide caused dose-dependent decreases in lobar arterial pressure without altering systemic arterial and left atrial pressures. Responses to defibrotide were significantly attenuated after the administration of the cyclooxygenase inhibitor sodium meclofenamate. Responses to defibrotide were also significantly attenuated after the administration of both the adenosine 1 and 2 receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine and 8-(3-chlorostyryl)caffeine. Responses to defibrotide were not altered after the administration of the vascular selective adenosine triphosphate-sensitive potassium channel blocker U-37883A, or after the administration of the nitric oxide synthase inhibitor L-N-(1-iminoethyl)-ornithine. These data show that defibrotide has significant vasodepressor activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to defibrotide are partially dependent on both the activation of the cyclooxygenase enzyme and adenosine 1 and 2 receptor pathways and independent of the activation of adenosine triphosphate-sensitive potassium channels or the synthesis of nitric oxide in the pulmonary vascular bed of the cat.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Polidesoxirribonucleotídeos/farmacologia , Circulação Pulmonar/efeitos dos fármacos , Vasodilatadores/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Adamantano/análogos & derivados , Adamantano/farmacologia , Adenosina/antagonistas & inibidores , Animais , Cafeína/análogos & derivados , Cafeína/farmacologia , Gatos , Inibidores de Ciclo-Oxigenase/farmacologia , Diuréticos/farmacologia , Feminino , Masculino , Ácido Meclofenâmico/farmacologia , Morfolinas/farmacologia , Óxido Nítrico , Óxido Nítrico Sintase/antagonistas & inibidores , Ornitina/análise , Ornitina/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Circulação Pulmonar/fisiologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Teofilina/análogos & derivados , Teofilina/farmacologia , Resistência Vascular , Vasoconstritores/farmacologia
13.
Bioorg Med Chem Lett ; 26(2): 540-544, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26646217

RESUMO

The effects of different adenosine receptor antagonists and cyclic nucleotide phosphodiesterase (PDE) inhibitors on monoclonal antibody (mAb) titer and cell viability of murine hybridoma cells in culture were measured as part of our investigations to discover additives that enhance mAb production. Specific adenosine receptor antagonists and PDE inhibitors were found to enhance or decrease the titer of immunoglobulin G1 (IgG1) mAbs relative to negative controls, depending on the specific compound and cell line employed. The observed enhancements or decreases in IgG1 mAb titer appeared to be mainly due to an increase or decrease in specific productivity rates (ngmAb/cell), respectively. The different effects of the selective adenosine antagonists suggest that antagonism at the level of the adenosine A2A and A1 or the adenosine A3 receptors result in either enhancement or suppression of IgG1 mAb production by hybridoma cells. Overall, these studies have identified hitherto unknown activities of specific adenosine antagonists and PDE inhibitors which indicate they may have valuable roles as cell culture additives in industrial biomanufacturing processes designed to enhance the yields of mAbs or other recombinant proteins produced by mammalian cell culture procedures.


Assuntos
Anticorpos Monoclonais Murinos/biossíntese , Imunoglobulina G/biossíntese , Inibidores de Fosfodiesterase/farmacologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Animais , Anticorpos Monoclonais Murinos/farmacologia , Cafeína/análogos & derivados , Cafeína/farmacologia , Sobrevivência Celular , Hibridomas , Camundongos
14.
Curr Med Chem ; 22(8): 975-88, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25544641

RESUMO

The current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson's disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson's disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson's disease.


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Cafeína/análogos & derivados , Cafeína/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Cafeína/farmacologia , Desenho de Fármacos , Humanos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/metabolismo
15.
Neurochem Res ; 40(3): 531-41, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25503480

RESUMO

(E)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeine (HOEC), a naturally caffeic ester isolated from Incarvillea mairei, has been reported to possess anti-inflammatory activity by targeting 5-lipoxygenase. However, its other potential activities have yet to be explored. In this study, we measured antioxidant activity of HOEC using the DPPH free radical-scavenging assay. Then, we exposed rat pheochromocytoma (PC12) cells to hydrogen peroxide (H2O2)-induced damage and investigated the antioxidant activity of HOEC. Cell viability, lactate dehydrogenase (LDH) release, cellular morphology, Hoechst 33342 fluorescent staining, and apoptosis of the PC12 cells were assessed after treatment with 0.3-10 µM HOEC for 2 h and exposure to 600 µM H2O2. Additionally, glutathione reductase (GR), superoxide dismutase (SOD), lipid peroxidation malondialdehyde (MDA), and intracellular reactive oxygen species (ROS) accumulation were assayed after the PC12 cells were exposed to H2O2. To investigate mechanism, apoptosis-related protein were evaluated, including cleaved caspase 3/7, cleaved PARP, Bcl-2, Bcl-XL, and cytochrome c. The results showed that HOEC possessed potent antioxidant activity and pre-treatment with HOEC prior to H2O2 exposure significantly increased cell viability, reduced the release of LDH, ameliorated changes in cell morphology, and inhibited apoptosis. Further, HOEC did the following: reduced intracellular accumulation of ROS and MDA; rescued loss of SOD and GR activities; inhibited activated caspase-3 and caspase-7, cleaved PARP, and cytochrome c release; up-regulated the antiapoptosis-related protein Bcl-2 and Bcl-XL; and down-regulated the apoptosis-related proteins Bax and Bad. These findings suggested that HOEC may be a therapeutic agent for treating oxidative stress-derived neurodegenerative disorders.


Assuntos
Cafeína/análogos & derivados , Cafeína/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Células PC12 , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ratos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
16.
Naunyn Schmiedebergs Arch Pharmacol ; 387(2): 165-73, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24170241

RESUMO

Antagonism of the adenosine A2A receptor (A2AR) has been shown to elicit substantial neuroprotective properties when given immediately after cerebral ischemia. We asked whether the continuous application of a selective A2AR antagonist within a clinically relevant time window will be a feasible and effective approach to treat focal cerebral ischemia. To answer this question, we subjected 20 male spontaneously hypertensive rats to permanent middle cerebral artery occlusion and randomized them equally to a verum and a control group. Two hours after stroke onset, the animals received a subcutaneous implantation of an osmotic minipump filled with 5 mg kg(-1) day(-1) 8-(3-chlorostyryl) caffeine (CSC) or vehicle solution. The serum level of CSC was measured twice a day for three consecutive days. The infarct volume was determined at days 1 and 3 using magnetic resonance imaging. We found the serum level of CSC showing a bell-shaped curve with its maximum at 36 h. The infarct volume was not affected by continuous CSC treatment. These results suggest that delayed and continuous CSC application was not sufficient to treat acute ischemic stroke, potentially due to unfavorable hepatic elimination and metabolization of the pharmaceutical.


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Cafeína/análogos & derivados , Antagonistas do Receptor A2 de Adenosina/sangue , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Cafeína/sangue , Cafeína/farmacocinética , Cafeína/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Ratos , Ratos Endogâmicos SHR
17.
Molecules ; 18(5): 5251-64, 2013 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-23698041

RESUMO

We report the development of a new microwave-based synthetic methodology mediated by Woollins' reagent that allowed an efficient conversion of caffeine into 6-selenocaffeine. A preliminary evaluation on the modulation of antioxidant activity upon selenation of caffeine, using the DPPH assay, indicated a mild antioxidant activity for 6-selenocaffeine, contrasting with caffeine, that exhibited no antioxidant activity under the same experimental conditions. Interestingly, whereas 6-selenocaffeine has revealed to have a low cytotoxic potential in both MCF10A and MCF-7 breast cells (24 h, up to 100 µM, MTT assay), a differential effect was observed when used in combination with the anticancer agents doxorubicin and oxaliplatin in MCF-7 breast cancer cells. The co-treatment of doxorubicin (1 µM) and 6-selenocaffeine (100 µM) resulted in a slight decrease in cellular viability when compared to doxorubicin (1 µM) alone. Conversely, the seleno-caffeine derivative at the same concentration markedly increased the viability of oxaliplatin (100 µM)-treated cells (p < 0.01). Overall, this work highlights an emerging methodology to synthesize organoselenium compounds and points out the differential roles of 6-selenocaffeine in the modulation of the cytotoxicity of anticancer agents.


Assuntos
Antioxidantes , Neoplasias da Mama/tratamento farmacológico , Cafeína , Células Epiteliais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Compostos Organosselênicos , Antibióticos Antineoplásicos/agonistas , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cafeína/agonistas , Cafeína/análogos & derivados , Cafeína/síntese química , Cafeína/química , Cafeína/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/agonistas , Doxorrubicina/farmacologia , Agonismo de Drogas , Células Epiteliais/patologia , Feminino , Humanos , Glândulas Mamárias Humanas/patologia , Compostos Organoplatínicos/agonistas , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Compostos Organosselênicos/agonistas , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Oxaliplatina
18.
J Mol Model ; 19(4): 1835-51, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23315214

RESUMO

The structure, spectral properties and the hydrogen bond interactions of 8-aza analogues of xanthine, theophylline and caffeine have been studied by using quantum chemical methods. The time-dependent density functional theory (TD-DFT) and the singly excited configuration interaction (CIS) methods are employed to optimize the excited state geometries of isolated 8-azaxanthine, 8-azatheophylline tautomers and 8-azacaffeine in both the gas and solvent phases. The solvent phase calculations are performed using the polarizable continuum model (PCM). The absorption and emission spectra are calculated using the time-dependent density functional theory (TD-DFT) method. The results from the TD-DFT calculations reveal that the excitation spectra are red shifted relative to absorption in aqueous medium. These changes in the transition energies are qualitatively comparable to the experimental data. The examination of molecular orbital reveals that the molecules with a small H→L energy gap possess maximum absorption and emission wavelength. The relative stability and hydrogen bonded interactions of mono and heptahydrated 8-azaxanthine, 8-azatheophylline tautomers and 8-azacaffeine have been studied using the density functional theory (DFT) and Møller Plesset perturbation theory (MP2) implementing the 6-311++G(d,p) basis set. The formation of strong N-H...O bond has resulted in the highest interaction energy among the monohydrates. Hydration does not show any significant impact on the stability of heptahydrated complexes. The atoms in molecule (AIM) and natural bonding orbital (NBO) analyses have been performed to elucidate the nature of the hydrogen bond interactions in these complexes.


Assuntos
Antineoplásicos/química , Antivirais/química , Compostos Aza/química , Cafeína/análogos & derivados , Cafeína/química , Teofilina/análogos & derivados , Teofilina/química , Xantinas/química , Gases , Ligação de Hidrogênio , Cinética , Modelos Químicos , Teoria Quântica , Soluções , Análise Espectral , Estereoisomerismo , Termodinâmica , Água
19.
Chembiochem ; 13(13): 1905-12, 2012 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-22930447

RESUMO

The targeting of higher-order DNA structures has been thoroughly developed with G-quadruplex DNA but not with other structures like branched DNA (also known as DNA junctions). Because these alternative higher-order DNA architectures might be of high biological relevance, we implemented a high-throughput version of the FRET melting assay that enabled us to map the interactions of a candidate with four different DNA structures (duplex- and quadruplex DNA, three- and four-way junctions) in a rapid and reliable manner. We also introduce a novel index, the BONDS (branched and other noncanonical DNA selectivity) index, to conveniently quantify this differential affinity.


Assuntos
Cafeína/farmacologia , DNA/química , Conformação de Ácido Nucleico/efeitos dos fármacos , Compostos Organoáuricos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Sequência de Bases , Cafeína/análogos & derivados , Transferência Ressonante de Energia de Fluorescência , Quadruplex G/efeitos dos fármacos , Modelos Moleculares , Compostos Organoáuricos/química , Bibliotecas de Moléculas Pequenas/química , Termodinâmica
20.
Neurotox Res ; 22(2): 150-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22407500

RESUMO

It has been shown that a decreased vesicular monoamine transporter (VMAT2) function and the disruption of dopamine (DA) storage is an early contributor to oxidative damage of dopamine neurons in Parkinson's disease (PD). In our previous study, we demonstrated that adenosine A(2A) receptor antagonists suppressed oxidative stress in 6-hydroxydopamine-treated rats suggesting that this effect may account for neuroprotective properties of drugs. In the present study, rats were injected with reserpine (10 mg/kg sc) and 18 h later the effect of the adenosine A(2A) receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on extracellular DA, glutamate and hydroxyl radical formation was studied in the rat striatum using in vivo microdialysis. By disrupting VMAT2 function, reserpine depleted DA stores, and increased glutamate and hydroxyl radical levels in the rat striatum. CSC (1 mg/kg) but not ZM 241385 (3 mg/kg) increased extracellular DA level and production of hydroxyl radical in reserpinised rats. Both antagonists decreased the reserpine-induced increase in extracellular glutamate. L-3,4-Dihydroxyphenylalanine (L-DOPA) (25 mg/kg) significantly enhanced extracellular DA, had no effect on reserpine-induced hydroxyl radical production and decreased extracellular glutamate concentration. CSC but not ZM 241385 given jointly with L-DOPA increased the effect of L-DOPA on extracellular DA and augmented the reserpine-induced hydroxyl radical production. CSC and ZM 241385 did not influence extracellular glutamate level, which was decreased by L-DOPA. It seems that by decreasing the MAO-dependent DA metabolism rate, CSC raised cytosolic DA and by DA autoxidation, it induced hydroxyl radical overproduction. Thus, the methylxanthine A(2A) receptor antagonists bearing properties of MAO-B inhibitor, like CSC, may cause a risk of oxidative stress resulting from dysfunctional DA storage mechanism in early PD.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Radical Hidroxila/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Inibidores da Captação Adrenérgica/toxicidade , Animais , Cafeína/análogos & derivados , Cafeína/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/toxicidade , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Ácido Homovanílico/metabolismo , Levodopa/toxicidade , Masculino , Microdiálise , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Reserpina/toxicidade , Triazinas/farmacologia , Triazóis/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/genética
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