RESUMEN
Three new naphthalenes, designated as syriacusins A-C, were isolated from the root bark of Hibiscus syriacus. These compounds were identified as 2,7-dihydroxy-6-methyl-8-methoxy-1-naphthalenecarbaldehyde, 2-hydroxy-6-hydroxymethyl-7,8-dimethoxy-1-naphthalenecarbaldehyde, 1-carboxy-2,8-dihydroxy-6-methyl-7-methoxynaphthalenecarbolactone (1-->8), respectively, on the basis of various spectral studies. The compounds inhibited lipid peroxidation with IC50s of 0.54, 5.90 and 1.02 micrograms ml-1, respectively. The first compound also showed cytotoxicity against some human cancer cell lines with an ED50 of 1.5-2.4 micrograms ml-1.
Asunto(s)
Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Naftalenos/aislamiento & purificación , Naftalenos/farmacología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Plantas Medicinales/química , Animales , Antioxidantes/química , Humanos , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Naftalenos/química , Resonancia Magnética Nuclear Biomolecular , Extractos Vegetales/química , Raíces de Plantas/química , Ratas , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
Phenazostatins A and B, new diphenazine compounds, were isolated from the culture broth of Streptomyces sp. 833 as new neuronal cell protecting substances which also showed free radical scavenging activity. In the cell assay, phenazostatins A and B inhibited glutamate toxicity in N18-RE-105 cells with EC50 values of 0.34 and 0.33 microM, respectively.
Asunto(s)
Depuradores de Radicales Libres/aislamiento & purificación , Fenazinas/aislamiento & purificación , Piperazinas/aislamiento & purificación , Animales , Fermentación , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Peroxidación de Lípido/efectos de los fármacos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Fenazinas/química , Fenazinas/farmacología , Piperazinas/química , Piperazinas/farmacología , Ratas , StreptomycesRESUMEN
Glutamate, an excitatory amino acid, is known to induce neurotoxicity in central nervous system under abnormal conditions such as ischemia, hypoglycemia, epilepsy, Huntington's chorea, Parkinson's disease and Alzheimer's disease. In our search for neuroprotective agents of microbial origin against excitatory neurotoxins, we have isolated two new bicyclohexapeptides, neuroprotectins A and B, together with a known compound complestatin, from the fermentation broth of Streptomyces sp. Q27107. Neuroprotectins protected primary cultured chick telencephalic neurons from glutamate- and kainate-induced excitotoxicities in a dose-dependant fashion.
Asunto(s)
Glicoproteínas de Membrana/efectos de los fármacos , Proteínas del Tejido Nervioso/efectos de los fármacos , Fármacos Neuroprotectores/aislamiento & purificación , Oligopéptidos/aislamiento & purificación , Animales , Células Cultivadas , Embrión de Pollo , Fermentación , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Oligopéptidos/química , Oligopéptidos/farmacología , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
In the course of our search for neuroprotective agents of microbial origin against kainate-induced neurotoxicity, we have succeeded in the isolation of two new bicyclohexapeptides, neuroprotectins A and B, together with a known compound, complestatin, from the fermentation broth of Streptomyces sp. Q27107. They are closely related in structure to complestatin and possess an oxindolylalanine moiety in place of the tryptophan residue present in complestatin.
Asunto(s)
Fármacos Neuroprotectores/química , Oligopéptidos/química , Estructura Molecular , EstereoisomerismoRESUMEN
These studies were designed to examine the differential effect of nitric oxide (NO) and cGMP on glutamate neurotransmission. In primary cultures of rat cerebellar granule cells, the glutamate receptor agonist N-methyl-D-aspartate (NMDA) stimulates the elevation of intracellular calcium concentration ([Ca2+]i), the release of glutamate, the synthesis of NO and an increase of cGMP. Although NO has been shown to stimulate guanylyl cyclase, it is unclear yet whether NO alters the NMDA-induced glutamate release and [Ca2+]i elevation. We showed that the NO synthase inhibitor, N(G)-monomethyl-L-arginine (NMMA), partially prevented the NMDA-induced release of glutamate and elevation of [Ca2+]i and completely blocked the elevation of cGMP. These effects of NO on glutamate release and [Ca2+]i elevation were unlikely to be secondary to cGMP as the cGMP analogue, dibutyryl cGMP (dBcGMP), did not suppress the effects of NMDA. Rather, dBcGMP slightly augmented the NMDA-induced elevation of [Ca2+]i with no change in the basal level of glutamate or [Ca2+]i. The extracellular NO scavenger hydroxocobalamine prevented the NMDA-induced release of glutamate providing indirect evidence that the effect of NO may act on the NMDA receptor. These results suggest that low concentration of NO has a role in maintaining the NMDA receptor activation in a cGMP-independent manner.
Asunto(s)
Calcio/metabolismo , Cerebelo/metabolismo , GMP Cíclico/fisiología , Agonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/metabolismo , N-Metilaspartato/farmacología , Neuronas/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , omega-N-Metilarginina/farmacología , Animales , Células Cultivadas , Cerebelo/citología , Cerebelo/efectos de los fármacos , GMP Dibutiril Cíclico/farmacología , Espacio Extracelular/metabolismo , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-DawleyAsunto(s)
Benzamidas/aislamiento & purificación , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/aislamiento & purificación , Streptomyces/química , Animales , Benzamidas/química , Benzamidas/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/aislamiento & purificación , Depuradores de Radicales Libres/farmacología , Ácido Glutámico/toxicidad , Espectroscopía de Resonancia Magnética , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Ratas , Espectrometría de Masa por Ionización de ElectrosprayAsunto(s)
Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Piperazinas/química , Piperazinas/farmacología , Streptomyces/metabolismo , Animales , Antioxidantes/farmacología , Benzoquinonas/farmacología , Células Cultivadas , Fermentación , Concentración 50 Inhibidora , Peroxidación de Lípido/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/aislamiento & purificación , Piperazinas/aislamiento & purificación , Ratas , Espectrometría de Masa Bombardeada por Átomos Veloces , Ubiquinona/análogos & derivadosAsunto(s)
Antibióticos Antineoplásicos/aislamiento & purificación , Streptomyces/metabolismo , Tiazoles/aislamiento & purificación , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Tiazoles/química , Tiazoles/farmacología , Células Tumorales CultivadasAsunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Macrólidos , Streptomyces/metabolismo , Antibacterianos/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Streptomyces/químicaRESUMEN
A previously undescribed coumarin and a new coumarino-lignan, together with the known compounds scopoletin and cleomiscosins A, C, and D, have been isolated from the root bark of Hibiscus syriacus, and their structures were assigned on the basis of various spectral studies. The coumarin analogue and scopoletin inhibited monoamine oxidase with moderate IC(50) values. The new coumarino-lignan and cleomiscosin C showed lipid peroxidation inhibitory activity comparable to vitamin E.
Asunto(s)
Antioxidantes/aislamiento & purificación , Cumarinas/aislamiento & purificación , Dioxanos/aislamiento & purificación , Lignanos/aislamiento & purificación , Malvaceae/química , Inhibidores de la Monoaminooxidasa/aislamiento & purificación , Animales , Antioxidantes/química , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Cumarinas/química , Cumarinas/farmacología , Dioxanos/química , Dioxanos/farmacología , Técnicas In Vitro , Concentración 50 Inhibidora , Corea (Geográfico) , Lignanos/química , Lignanos/farmacología , Peroxidación de Lípido/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Ratones , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Raíces de Plantas/química , Plantas Medicinales/química , Ratas , Escopoletina/farmacología , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Vitamina E/farmacologíaRESUMEN
Two new indole derivatives were isolated as free radical scavengers from the MeOH extract of Agrocybe cylindracea. The structures of these compounds were determined to be 6-hydroxy-1H-indole-3-carboxaldehyde (1) and 6-hydroxy-1H-indole-3-acetamide (2) on the basis of spectroscopic studies. Compounds 1 and 2 inhibited lipid peroxidation in rat liver microsomes, with IC50 values of 4.1 and 3.9 micrograms/mL, respectively.
Asunto(s)
Basidiomycota/química , Depuradores de Radicales Libres/farmacología , Indoles/química , Animales , Indoles/farmacología , Peroxidación de Lípido/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Ratas , Análisis EspectralRESUMEN
A new lignan named as hibiscuside, (+)-pinoresinol 4-O-[beta-glucopyranosyl (1--->2)-alpha-rhamnoside] (1), and a known lignan, syringaresinol (2) were isolated from the root bark of Hibiscus syriacus together with two feruloyltyramines (3,4) and three known isoflavonoids (5,6,7). The structures of these compounds have been established on the basis of their NMR, mass UV spectra. Among these phenolic compounds, 6"-O-acetyldaidzin (5), 6"-O-acetylgenistin (6), and 3-hydroxydaidzein (7) with IC(50) values of 8.2, 10.6, and 4.1 microM, respectively, significantly inhibited lipid peroxidation in rat liver microsomes. Hibiscuside (1), E- and Z-N-feruloyl tyramines (3,4) exhibited moderate antioxidant activity.
Asunto(s)
Antioxidantes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Disacáridos/química , Lignanos/química , Malvaceae/química , Animales , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/aislamiento & purificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Disacáridos/aislamiento & purificación , Disacáridos/farmacología , Furanos/química , Furanos/aislamiento & purificación , Glicósidos , Técnicas In Vitro , Lignanos/aislamiento & purificación , Lignanos/farmacología , Peroxidación de Lípido/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , RatasRESUMEN
Two lipid peroxidation inhibitors, designated as betulinans A (1) and B (2), were isolated from the MeOH extract of Lenzites betulina. The structures of these compounds have been determined to be 2,5-diphenyl-3,6-dimethoxy-p-benzoquinone and 2-phenyl-3-methoxy-[1H-2-benzopyran][4,3-e][p]benzoquinone, respectively, on the basis of various spectral data. Betulinans A and B inhibited lipid peroxidation with IC50 values of 0.46 and 2.88 micrograms/mL, respectively.
Asunto(s)
Antioxidantes/aislamiento & purificación , Benzoquinonas/aislamiento & purificación , Polyporaceae/química , Animales , Antioxidantes/farmacología , Benzoquinonas/farmacología , Técnicas In Vitro , Peroxidación de Lípido/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Ratas , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Vitamina E/farmacologíaRESUMEN
Two new triterpene caffeates have been isolated from the root bark of Hibiscus syriacus. Their structures were established through various spectral studies as 3beta,23,28-trihydroxy-12-oleanene 23-caffeate (1) and 3beta,23,28-trihydroxy-12-oleanene 3beta-caffeate (2). Compounds 1 and 2 showed lipid peroxidation inhibitory activity and significant cytotoxicity against a panel of human cancer cell lines.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Malvaceae/química , Triterpenos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Peroxidación de Lípido/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Raíces de Plantas/química , Espectrometría de Masa Bombardeada por Átomos Veloces , Triterpenos/química , Triterpenos/aislamiento & purificación , Células Tumorales CultivadasRESUMEN
Terrein is a bioactive fungal metabolite whose effects are almost unknown. In this study, we found for the first time that terrein has a strong hypopigmentary effect in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment of Mel-Ab cells with terrein (10-100 microM) for 4 days significantly reduced melanin levels in a dose-dependent manner. In addition, terrein at the same concentration also reduced tyrosinase activity. We then investigated whether terrein influences the extracellular signal-regulated protein kinase (ERK) pathway and the expression of microphthalmia-associated transcription factor (MITF), which is required for tyrosinase expression. Terrein was found to induce sustained ERK activation and MITF down-regulation, and luciferase assays showed that terrein inhibits MITF promoter activity in a dose-dependent manner. To elucidate the correlation between ERK pathway activation and a decreased MITF transcriptional level, PD98059, a specific inhibitor of the ERK pathway, was applied before terrein treatment and found to abrogate the terrein-induced MITF attenuation. Terrein also reduced the tyrosinase protein level for at least 72 h. These results suggest that terrein reduces melanin synthesis by reducing tyrosinase production via ERK activation, and that this is followed by MITF down-regulation.
Asunto(s)
Ciclopentanos/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Melaninas/antagonistas & inhibidores , Melaninas/biosíntesis , Monofenol Monooxigenasa/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Animales , Western Blotting , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Proteínas de Unión al ADN/genética , Relación Dosis-Respuesta a Droga , Luciferasas/metabolismo , Melaninas/análisis , Melanoma Experimental , Ratones , Factor de Transcripción Asociado a Microftalmía , Monofenol Monooxigenasa/metabolismo , Penicillium/química , Factores de Transcripción/genéticaRESUMEN
Complestatin, a peptide derived from Streptomyces, was found to protect cultured cortical neurons from excitotoxicity induced by N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or kainate. This neuroprotective behavior of complestatin was attributed to a blockade of Ca2+ ion entry and accumulation, after the activation of NMDA and AMPA/kainate receptors. Complestatin reversibly interfered with NMDA- and AMPA-mediated excitatory synaptic transmission. Complestatin also protected cortical neurons from prolonged deprivation of oxygen and glucose, more effectively than combined antagonists of NMDA and AMPA/kainate receptors. Neurotoxicity, evolving within 1 to 2 days after continuous exposure to combined NMDA and AMPA/kainate antagonists, was not observed in cortical cell cultures that were exposed to complestatin. Finally, complestatin dose dependently prevented neuronal death evolving within the inner nuclear and ganglion cell layers, after transient retinal ischemia. We conclude that complestatin possesses novel pharmacological properties that effectively prevent excitotoxicity under certain pathological conditions.