RESUMEN
A novel tripeptide, 1, was isolated from the extracellular extract of a Pseudomonas-Alteromonas bacterium that was associated with the Black Sea sponge Dysidea fragilis. Compound 1 contains the novel beta-aminopimelic acid described for the first time from a natural product. The structure of 1 is suggested on the basis of the analysis of spectroscopic data and chemical degradation.
Asunto(s)
Alteromonas/química , Oligopéptidos/aislamiento & purificación , Poríferos/microbiología , Pseudomonas/química , Aminoácidos/química , Animales , Oligopéptidos/químicaRESUMEN
Cacospongionolide F (4a), a new bioactive cacospongionolide-related sesterterpene, has been isolated from the Northern Adriatic sponge Fasciospongia cavernosa. The structure was proposed on the basis of spectroscopic data and chemical transformations. The absolute configuration was established using the modified Mosher's method. A molecular mechanics study of the dehydrodecalin ring explained the observed differences in dynamic behavior between cacospongionolide F and mamanuthaquinone, a related compound. Antimicrobial activity, brine shrimp and fish lethalities of this new compound are reported.
Asunto(s)
4-Butirolactona/análogos & derivados , Antiinfecciosos/aislamiento & purificación , Poríferos/química , Piranos/aislamiento & purificación , 4-Butirolactona/química , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piranos/química , Piranos/farmacología , Análisis EspectralRESUMEN
1. Cacospongionolide B is a novel marine metabolite isolated from the sponge Fasciospongia cavernosa. In in vitro studies, this compound inhibited phospholipase A2 (PLA2), showing selectivity for secretory PLA2 (sPLA2) versus cytosolic PLA2 (cPLA2), and its potency on the human synovial enzyme (group II) was similar to that of manoalide. 2. This activity was confirmed in vivo in the 8 h zymosan-injected rat air pouch, on the secretory enzyme accumulating in the pouch exudate. Cacospongionolide B, that is bioavailable when is given orally, reduced the elevated levels of sPLA2 present in paw homogenates of rats with adjuvant arthritis. 3. This marine metabolite showed topical anti-inflammatory activity on the mouse ear oedema induced by 12-O-tetradecanoylphorbol acetate (TPA) and decreased carrageenin paw oedema in mice after oral administration of 5, 10 or 20 mg kg(-1). 4. In the mouse air pouch injected with zymosan, cacospongionolide B administered into the pouch, induced a dose-dependent reduction in the levels of eicosanoids and tumour necrosis factor alpha (TNFalpha) in the exudates 4 h after the stimulus. It also had a weak effect on cell migration. 5. The inflammatory response of adjuvant arthritis was reduced by cacospongionolide B, which did not significantly affect eicosanoid levels in serum, paw or stomach homogenates and did not induce toxic effects. 6 Cacospongionolide B is a new inhibitor of sPLA2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation. This marine metabolite was active after oral administration and able to modify TNFalpha levels, and may offer an interesting approach in the search for new anti-inflammatory agents.
Asunto(s)
4-Butirolactona/análogos & derivados , Antiinfecciosos/uso terapéutico , Inflamación/tratamiento farmacológico , Fosfolipasas A/antagonistas & inhibidores , Piranos/uso terapéutico , 4-Butirolactona/química , 4-Butirolactona/farmacología , 4-Butirolactona/uso terapéutico , Enfermedad Aguda , Animales , Antiinfecciosos/farmacología , Artritis Experimental/tratamiento farmacológico , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Oído/patología , Edema/inducido químicamente , Edema/tratamiento farmacológico , Enzimas/efectos de los fármacos , Enzimas/metabolismo , Femenino , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/patología , Masculino , Ratones , Fosfolipasas A/metabolismo , Fosfolipasas A2 , Piranos/química , Piranos/farmacología , Ratas , Ratas Wistar , Líquido Sinovial/enzimología , Células U937RESUMEN
A series of prenyl hydroquinone derivatives synthesized as structural analogs of marine products were tested for their effects on inflammatory responses in vitro and in vivo. 2-Prenyl-1,4-hydroquinone (H1), 2-diprenyl-1,4-hydroquinone (H2), 2-triprenyl-1,4-hydroquinone (H3) and 2-tetraprenyl-1,4-hydroquinone (H4) scavenged reactive oxygen species and inhibited 5-lipoxygenase (5-LO) activity in human neutrophils. The inhibition of 5-LO activity was demonstrated in vivo in the mouse air pouch injected with zymosan and arachidonic acid-induced ear inflammation. The four compounds suppressed the production of tumour necrosis factor alpha (TNFalpha) in J774 cells stimulated with lipopolysaccharide (LPS) and also in vivo in the mouse air pouch injected with zymosan. In addition, all prenyl-hydroquinones inhibited the release of nitrite and PGE2 in LPS-stimulated J774 cells, without direct effects on cyclo-oxygenase-1 (COX-1), cyclo-oxygenase-2 (COX-2) or inducible nitric oxide synthase (iNOS) activities in several cell-free systems. The reduction in the length of the lateral chain in prenyl-hydroquinones (1-4 isoprene units) with respect to their marine analogs (7-8 isoprene units) has improved the anti-inflammatory activity of this class of compounds. Marine natural products may be a model to design new anti-inflammatory agents.
Asunto(s)
Antiinflamatorios/uso terapéutico , Hidroquinonas/uso terapéutico , Inflamación/tratamiento farmacológico , Leucotrieno B4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Ácido Araquidónico/toxicidad , Células Cultivadas , Depresión Química , Dinoprostona/biosíntesis , Edema/inducido químicamente , Humanos , Inflamación/metabolismo , Mediciones Luminiscentes , Masculino , Ratones , Nitritos/metabolismoRESUMEN
A new inhibitor of human secretory phospholipase A2 (PLA2), cacospongionolide E (4a), has been isolated from the Tyrrhenian sponge Fasciospongia cavernosa. The structure was proposed on the basis of spectroscopic data and by chemical transformations. The absolute configuration of cacospongionolides 2a-4a was established using the modified Mosher's method. Cacospongionolide E was the most potent inhibitor toward human synovial PLA2, showing higher potency than the reference compound manoalide and exerting no signs of toxicity on human neutrophils. It showed high activity in the Artemia salina bioassay and moderate toxicity in the fish (Gambusia affinis) lethality assay.
Asunto(s)
Inhibidores Enzimáticos/aislamiento & purificación , Furanos/aislamiento & purificación , Fosfolipasas A/antagonistas & inhibidores , Poríferos/química , Piranos/aislamiento & purificación , Animales , Ciprinodontiformes , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Furanos/farmacología , Furanos/toxicidad , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Conformación Molecular , Páncreas/enzimología , Fosfolipasas A2 , Piranos/farmacología , Piranos/toxicidad , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Líquido Sinovial/enzimología , Ponzoñas/enzimologíaRESUMEN
The beta-D-glucoside, gentiobioside and 6-O-alpha-L-arabinosyl-beta-D-glucoside of benzyl alcohol, androsin and a new simple aliphatic glycoside, isopentylgentiobioside, have been found in the cell cultures of Lycopersicon esculentum. Their structures were elucidated from chemical and spectroscopic evidence.
Asunto(s)
Disacáridos/química , Glicósidos/química , Solanum lycopersicum , Secuencia de Carbohidratos , Células Cultivadas , Medios de Cultivo , Disacáridos/aislamiento & purificación , Glicósidos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
Cacospongionolide B [2a], a new cacospongionolide-related sesterterpene, has been isolated from the Adriatic sponge Fasciospongia cavernosa. The structure was elucidated by spectral and chemical means. The antimicrobial activity and brine shrimp and fish lethalities of 2a are reported.
Asunto(s)
4-Butirolactona/análogos & derivados , Antibacterianos/farmacología , Ciprinodontiformes/fisiología , Poríferos/química , Piranos/farmacología , 4-Butirolactona/química , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Acetilación , Animales , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Artemia/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Dosificación Letal Mediana , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Piranos/química , Piranos/aislamiento & purificaciónRESUMEN
Three 2-polyprenyl-1,4-hydroquinone derivatives (2-heptaprenyl-1,4-hydroquinone: IS1, 2-octaprenyl-1,4-hydroquinone: IS2 and 2-[24-hydroxy]-octaprenyl-1,4-hydroquinone: IS3) isolated from the Mediterranean sponge Ircinia spinosula, were evaluated for effects on phospholipase A2 activity of different origin (Naja naja venom, human recombinant synovial fluid and bee venom), as well as on human neutrophil function and mouse ear oedema induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). IS1 interacted minimally with these responses. In contrast, IS2 and IS3 inhibited human recombinant synovial phospholipase A2 in a concentration-dependent manner, with minor effects on the rest of the enzymes. Both compounds slightly affected superoxide generation and degranulation in human neutrophils, whereas they decreased thromboxane B2 and leukotriene B4 synthesis and release in a mixed suspension of human platelets and neutrophils stimulated by ionophore A23187, with IC50 values in the microM range. IS3 was the most effective inhibitor of the synthesis of thromboxane B2 by human platelet microsomes and of leukotriene B4 by high speed supernatants from human neutrophils. IS2 and IS3 showed topical anti-inflammatory activity against the TPA-induced ear inflammation in mice, with similar effects on oedema and a higher inhibition of IS3 on leukocyte migration, estimated as myeloperoxidase activity in supernatants of ear homogenates. Some structure-activity relationships were established since differences in the prenylated chain attached to the hydroquinone moiety result in important modifications of these inflammatory responses.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Hidroquinonas/farmacología , Fosfolipasas A/antagonistas & inhibidores , Poríferos/metabolismo , Animales , Plaquetas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Edema/inducido químicamente , Edema/prevención & control , Humanos , Hidroquinonas/aislamiento & purificación , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Leucotrieno B4/biosíntesis , Ratones , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Neutrófilos/metabolismo , Elastasa Pancreática/metabolismo , Fosfolipasas A2 , Superóxidos/metabolismo , Acetato de Tetradecanoilforbol , Tromboxano B2/sangreRESUMEN
Twenty-three hydroquinone and quinone derivatives were assayed for antimicrobial effects and brine shrimp and fish lethalities, to establish relevant structure-activity relationships (SAR). Linear 2-prenyl-1,4-hydroquinones used for bioassay were obtained either by isolation from the sponge Ircinia spinosula or by synthesis. Corresponding quinones, as well as hydroquinones possessing saturated side-chains composed of one to eight isopentane units, were also synthesized and biologically evaluated. Terpenoid 1,4-benzoquinones displayed moderate antimicrobial activity against three microorganisms, SAR studies indicate the optimum length of the side-chain is in the range of five to fifteen carbon atoms.
Asunto(s)
Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Ciprinodontiformes/fisiología , Hongos/efectos de los fármacos , Hidroquinonas/farmacología , Poríferos/química , Terpenos/farmacología , Animales , Antibacterianos , Antiinfecciosos/química , Antiinfecciosos/toxicidad , Artemia , Ensayos de Selección de Medicamentos Antitumorales , Hidroquinonas/química , Hidroquinonas/toxicidad , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Terpenos/química , Terpenos/toxicidadRESUMEN
A new sesterterpene, 12-deacetoxyscalaradial [2a] has been isolated from the sponge Cacospongia mollior, together with the previously described scalaradial [2b] and furoscalarol [3]. The structure of the new compound, proposed by spectral data, was confirmed by X-ray diffraction analysis. Compound 2a is the first scalarane sesterterpenoid, without a substituent at C-12, to have been identified in nature. It shows high antifeedant activity and is hot to taste for the human tongue. Both 2a and 2b display cytotoxic activity.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Homoesteroides/aislamiento & purificación , Poríferos/química , Terpenos/aislamiento & purificación , Animales , Antineoplásicos/farmacología , Artemia , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Conducta Alimentaria/efectos de los fármacos , Peces , Homoesteroides/farmacología , Homoesteroides/toxicidad , Humanos , Dosificación Letal Mediana , Espectrometría de Masas , Espectrofotometría Ultravioleta , Gusto/efectos de los fármacos , Terpenos/farmacología , Terpenos/toxicidadRESUMEN
1. The Mediterranean sponge Reniera sarai, Pulitzeri-Finali, 1969 (Demospongiae: Haploscleridae: Renieridae) possesses in large amounts a series of unprecedented polycyclic alkaloids, saraines 1-3 and saraines A-C. 2. The structural peculiarities of saraines, their chemical-physical characteristics, along with their relevant abundance in the sponge, prompted a study aimed at investigating their biological properties. 3. Saraines were assayed for their cytotoxic, antibacterial, insecticidal and potential antitumoral activities. These results, along with the growth inhibition of fertilized sea urchin eggs, are reported.
Asunto(s)
Alcaloides/farmacología , Poríferos/química , Aedes , Agrobacterium tumefaciens , Animales , Artemia/efectos de los fármacos , Artrópodos , Insecticidas , Ácaros , Tumores de Planta , Erizos de Mar , Staphylococcus aureus/efectos de los fármacos , Cigoto/efectos de los fármacos , Cigoto/crecimiento & desarrolloRESUMEN
Avarol, a sesquiterpenoid hydroquinone, its quinone avarone, both main secondary metabolites from the marine sponge Dysidea avara and nine of their natural and synthetic derivatives were tested for ability to interact selectively with rat liver microsomal phenobarbital (PB)- or 3-methylcholanthrene (3-MC)-induced cytochrome (cyt.) P-450 isoenzymatic forms. Ethoxy- and pentoxyresorufin, aminopyrine and ethoxycoumarin were the specific substrates used for assaying cyt. P-450-dependent mono-oxygenase activities. All compounds were more effective in inhibiting the enzymatic activities measured in microsomes from PB-induced rat liver than those measured in microsomes from 3-MC-treated rats. Avarol and avarone, which were the most active inhibitors, act as mixed-type inhibitors of pentoxyresorufin-O-dealkylase activity. Mono- and diacetyl-derivatives of avarol, being deacetylated by rat liver microsomes, were almost as effective as the parent compound. Conversely, avarone derivatives, where one or two hydrogen atoms of the quinone ring have been substituted, were less effective inhibitors than the parent compound. The selective inhibition of PB-inducible cyt.P-450IIB by avarol and avarone was confirmed by their ability to inhibit the mutagenic activation of cyclophosphamide, as opposed to that of benzo[a]pyrene, which is activated mainly by the 3-MC-inducible cyt.P-450IA.
Asunto(s)
Antineoplásicos/toxicidad , Microsomas Hepáticos/efectos de los fármacos , Sesquiterpenos/toxicidad , 7-Alcoxicumarina O-Dealquilasa/antagonistas & inhibidores , 7-Alcoxicumarina O-Dealquilasa/metabolismo , Animales , Ciclohexenos , Citocromo P-450 CYP1A1 , Citocromo P-450 CYP2B1 , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Masculino , Metilcolantreno/toxicidad , Microsomas Hepáticos/enzimología , Pruebas de Mutagenicidad , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/metabolismo , Fenobarbital/toxicidad , Ratas , Ratas Endogámicas , Sesquiterpenos/farmacologíaRESUMEN
A new derivative of avarol, monoacetyl avarol, has been isolated from the sponge Dysidea avara. The structural elucidation and biological activities are reported.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Poríferos/análisis , Sesquiterpenos/farmacología , Animales , Ensayos de Selección de Medicamentos Antitumorales , Espectroscopía de Resonancia Magnética , Estructura Molecular , Sesquiterpenos/aislamiento & purificaciónRESUMEN
Non-induced and phenobarbital (PB) or methylcholanthrene (MC) pretreated rats were injected with 1-nitropyrene (1-NP). Mutagenic activity of urine and feces samples were compared by the Salmonella/microsome assay. The highest, indirect-acting mutagenicity was associated with urines from MC-induced rats; HPLC analysis of organic extracts of urine samples showed that the differences in mutagenic response can be ascribed to different amounts of hydroxy derivatives of N-acetylaminopyrene excreted. Monohydroxy derivatives of 1-NP, being detected in the HPLC profiles of urine from PB-induced rats only, could be responsible of the higher direct-acting mutagenic activity of these samples as compared to urine from non-induced or MC-induced rats. The excretion rate of aminopyrene, the main metabolite of 1-NP identified in rat feces samples, was not affected by inducer pretreatment.
Asunto(s)
Metilcolantreno/farmacología , Mutágenos/aislamiento & purificación , Mutación , Fenobarbital/farmacología , Pirenos/metabolismo , Animales , Biotransformación , Heces/análisis , Cinética , Masculino , Microsomas Hepáticos/metabolismo , Pruebas de Mutagenicidad , Mutágenos/farmacología , Mutágenos/orina , Pirenos/farmacología , Pirenos/orina , Ratas , Ratas Endogámicas , Salmonella typhimurium/efectos de los fármacosRESUMEN
Liver enzymes (S9) of rats induced with various drugs differently affected the mutagenic response of 1-nitropyrene (1-NP) in vitro. The role of inducible enzymes in 1-NP conversion was evaluated by high-performance liquid chromatography (HPLC) analyses of 1-NP metabolites formed during incubation in vitro of the chemical with each S9 fraction. Methylcholanthrene (MC)-induced S9 preferentially results in 1-NP hydroxylation in position 6 or 8. Metabolic interconversions among 1-NP metabolites could be inferred from the HPLC patterns.
Asunto(s)
Sistema Enzimático del Citocromo P-450/fisiología , Hígado/enzimología , Mutágenos/metabolismo , Pirenos/metabolismo , Animales , Biotransformación , Inducción Enzimática , Hidroxilación , Técnicas In Vitro , Masculino , Ratas , Ratas EndogámicasRESUMEN
Los autores refieren un caso de dermatomiositis del niño y uno del adulto, ambos de sexo femenino. Se establecen las características de la afección más notorias en estas dos etapas de la vida y se hace referencia a la clasificación de las miositis de Bohan y colaboradores (AU)
Asunto(s)
Persona de Mediana Edad , Humanos , Femenino , Dermatomiositis/patología , Dermatomiositis/clasificaciónRESUMEN
Los autores refieren un caso de dermatomiositis del niño y uno del adulto, ambos de sexo femenino. Se establecen las características de la afección más notorias en estas dos etapas de la vida y se hace referencia a la clasificación de las miositis de Bohan y colaboradores