RESUMO
P2X7 receptor promotes inflammatory response and neuropathic pain. New drugs capable of impairing inflammation and pain-reducing adverse effects extracted from plant extracts have been studied. Physalis angulate L. possesses traditional uses and exhibits antiparasitic, anti-inflammatory, antimicrobial, antinociceptive, antimalarial, antileishmanial, immunosuppressive, antiasthmatic. diuretic, and antitumor activities. The most representative phytochemical constituents identified with medicinal importance are the physalins and withanolides. However, the mechanism of anti-inflammatory action is scarce. Although some physalins and withanolides subtypes have anti-inflammatory activity, only four physalins subtypes (B, D, F, and G) have further studies. Therefore, we evaluated the crude ethanolic extract enriched with physalins B, D, F, and G from P. angulata leaves, a pool containing the physalins B, D, F, G, and the physalins individually, as P2X7 receptor antagonists. For this purpose, we evaluated ATP-induced dye uptake, macroscopic currents, and interleukin 1-ß (IL-1ß) in vitro. The crude extract and pool dose-dependently inhibited P2X7 receptor function. Thus, physalin B, D, F, and G individually evaluated for 5'-triphosphate (ATP)-induced dye uptake assay, whole-cell patch-clamp, and cytokine release showed distinct antagonist levels. Physalin D displayed higher potency and efficacy than physalin B, F, and G for all these parameters. In vivo mice model as ATP-induced paw edema was potently inhibited for physalin D, in contrast to physalin B, F, and G. ATP and lipopolysaccharide (LPS)-induced pleurisy in mice were reversed for physalin D treatment. Molecular modeling and computational simulation predicted the intermolecular interactions between the P2X7 receptor and physalin derivatives. In silico results indicated physalin D and F as a potent allosteric P2X7 receptor antagonist. These data confirm physalin D as a promisor source for developing a new P2X7 receptor antagonist with anti-inflammatory action.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Physalis/química , Extratos Vegetais/farmacologia , Secoesteroides/farmacologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Simulação por Computador , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Camundongos , Modelos Moleculares , Extratos Vegetais/administração & dosagem , Folhas de Planta , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/isolamento & purificação , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Secoesteroides/isolamento & purificaçãoRESUMO
Extracellular adenosine 5'-triphosphate (ATP) triggers the P2X7 receptor (P2X7R) ionic channel to stimulate the release of the interleukin-IL-1ß cytokine into macrophages. The current study explored the reaction of six structurally diverse triazole derivatives on P2X7-mediated dye uptake into murine peritoneal macrophages. P2X7R activity determined by ATP-evoked fluorescent dye uptake. Triazole derivatives toxicity measured using dextran rhodamine exclusion based colorimetric assay. A740004 and BBG, both P2X7R antagonist, inhibited ATP-induced dye uptake. In contrast, the derivatives 5a, 5b, 5e, and 5f did not diminish P2X7R activity in concentrations until 100⯵M. 5c and 5d analogs caused a potent inhibitory activity on P2X7-induced dye uptake. Dextran Rhodamine exclusion measurements after 24â¯h of continuous treatment with triazole derivatives indicated a moderated toxicity for all molecules. In conclusion, this study showed that a series of new hybrid 1,2,3-triazolic naphthoquinones reduces P2X7R-induced dye uptake into murine macrophages. In silico analysis indicates a good pharmacokinetic profile and molecular docking results of these analogs indicate the potential to bind into an allosteric site located into the P2X7R pore and juxtaposed with the ATP binding pocket. In this manner, the compounds 5c and 5d may be used as a scaffold for new P2X7R inhibitors with reduced toxicity, and good anti-inflammatory activity.
Assuntos
Naftoquinonas/química , Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X7/metabolismo , Triazóis/química , Sítio Alostérico , Animais , Sítios de Ligação , Células CACO-2 , Linhagem Celular , Corantes/metabolismo , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Permeabilidade/efeitos dos fármacos , Estrutura Terciária de Proteína , Antagonistas do Receptor Purinérgico P2X/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/química , Triazóis/metabolismo , Triazóis/farmacologiaRESUMO
AIM: Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N'-substitutedphenylmethylene-1H-pyrazolo[3,4-b]pyridine-carbohydrazide derivatives (3a-3k). METHODS: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPARTAN' 08 program, in silico ADMET screening and the Lipinski " rule of five " using Osiris Property Explorer and molinspiration on-line programs. RESULTS: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c - IC(50)=61 microM and 68 microM respectively) almost 5-fold more potent than aspirin (IC(50)=300 microM). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. CONCLUSION: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases.
Assuntos
Plaquetas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Trombose/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Trombose/patologiaRESUMO
El osteosarcoma es el tumor óseo primario más frecuente habiendo dos picos de incidencia, uno en torno a los 15 años (adolescentes) y otro en ancianos. Caso clínico: Paciente de 14 años con clínica de dolor en región proximal de perné. Se diagnosticó mediante estudios radiológicos y biopsia osteosarcoma localizado con infiltración de cortical y periostio y extensión hacia epífisis de peroné. Tras quimioterapia preoperatorio se realizó exéresis tumoral con márgenes de 5cm. Siguiendo criterios de Enneking (cirurgia de salvación del miembro). Completamos varios ciclos de quimioterapia postoperatoria. La paciente está libre de enfermedad a los diecisiete años. Discusión: Años atrás en el tratamiento del osteosarcoma localizado se procedía a la amputación radical por norma. Actualmente debido al avance de las técnicas quirurgicas y diagnósticas (capaces de detectar precozmente la diseminación local y a distancia del tumor) es posible efectuar otras modalidades terapéuticas que preservan el miembro hasta en terapéuticas que preservan el miembro hasta en el 90% de los pacientes. Gracias al uso de la quimioterapia la tasa de supervivencia hoy dia se aproxima al 70% en aquellos casos diagnosticados previamente a la aparición de metástasis. Actualmente en quellos casos en los cuales la enfermedad esté localizada, el tamaño tumoral sea reducido y haya una buena respuesta a la quimioterapia preoperatoria es más aconsejable optar por una cirugía de salvación del miembro haciendo una prudente resección a distancia de los márgenes de la tumoración y acompañándola de ciclos de quimioterapia combinada.
Osteosarcoma is the most frequent primary bony tumor with two picks of incidence, one around the 15 years (adolescents) and another in old people. CLINICAL CASE: Patient of 14 years with pain clinic in proximal fibula. It was diagnosed by radiological studies and biopsy of located osteosarcoma with infiltration of cortical and periostium and extension toward fibula epiphysis. After preoperatory chemotherapy she was carried out tumoral resection with margins of 5 cm. following approaches of Enneking (surgery of salvation of the member). Several cycles of chemotherapy were completed after surgery. The patient, after seventeen years, is free of illness. DISCUSSION: Traditionally in the treatment of the located osteosarcoma you proceeded to the radical amputation for norm. At the moment due to the advances of the surgical and diagnostic techniques (able to detect precociously the local and distant dissemination of the tumor) it is possible to make other therapeutic modalities that preserve the member until in 90% of the patients. Thanks to the use of the chemotherapy the rate of survival nowadays approaches to 70% in those cases diagnosed previously to the metastasis appearance. At the moment in those cases in which the illness is located, the tumoral size is reduced and have a good answer to the preoperatroy chemotherapy, it is more advisable to opt for a surgery of salvation of the limb making a wise resection at distance of the margins of the tumor and accompanying it of cycles of combined chemotherapy.