RESUMEN
Two new tryptophan derivatives, N-sulfonyl-L-tryptophan (tryptorheedei A) (1) and 3-(N-sulfonylindolyl)-D-lactic acid (tryptorheedei B) (2) together with the known 5-O-ß-D-glucopyranosyl-2-hydroxyphenylacetic acid (3), 1-O-methylglucopyranoside, entadamide A, homogentisic acid and 3-O-ß-D-glucopyranosyl-ß-sitosterol, were isolated from the seed kernels of Entada rheedei (Mimosaceae). Their structures were established using 1D and 2D NMR spectroscopy, mass spectrometry and by comparison with spectroscopic data reported in the literature. Compounds 1 and 2 showed no toxicity to TZM and Human PBMC cells. Both compounds 1 and 2 were found to promote early infection events in HIV, likely by inhibiting the enzyme indolamine 2,3-dioxygenase (IDO) and preventing tryptophan depletion. Inhibition of IDO acutely in HIV infection inhibits viral replication, but chronic activation of IDO leads to immune impairment in AIDS. IDO is also the gatekeeper enzyme for kynurenine metabolism, a pathway involved in serotonin and melatonin biosynthesis and the regulation of glutamate and dopamine levels in the brain. Therefore inhibition of IDO might explain both the reported medicinal and neuropsychiatric effects of E. rheedei.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Fabaceae/química , Infecciones por VIH , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Psicotrópicos/farmacología , Triptófano/análogos & derivados , Síndrome de Inmunodeficiencia Adquirida/inmunología , Encéfalo/metabolismo , Línea Celular , Dopamina/metabolismo , Ácido Glutámico/metabolismo , VIH/efectos de los fármacos , VIH/patogenicidad , Infecciones por VIH/enzimología , Infecciones por VIH/virología , Humanos , Quinurenina/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Melatonina/biosíntesis , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Psicotrópicos/química , Psicotrópicos/aislamiento & purificación , Semillas/química , Serotonina/biosíntesis , Triptófano/química , Triptófano/aislamiento & purificación , Triptófano/metabolismo , Triptófano/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
A series of stilbenoid analogues of resveratrol (trans-3,4',5-trihydroxystilbene) with a stilbenic or a bibenzylic skeleton have been prepared by partial synthesis from resveratrol and dihydroresveratrol. The synthesized compounds have been evaluated for their ability to modulate voltage-gated channels.
Asunto(s)
Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Estilbenos , Animales , Ratones , Estructura Molecular , Ratas , Resveratrol , Estereoisomerismo , Estilbenos/síntesis química , Estilbenos/química , Estilbenos/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The prenylated phloroglucinol hyperforin, thought to be an essential component for the anti-depressant activity of St. John's Wort (Hypericum perforatum), is unstable. The facile oxidative degradation of hyperforin poses serious problems for standardisation, and may also dramatically affect the pharmacological activity of the extracts. Hyperforin was dissolved in hexane and stored at room temperature for 3 days and yielded various closely related degradation products which, although difficult to isolate on the preparative scale, have been analysed by on-flow and stop-flow HPLC-NMR and HPLC-MS/MS. From on-line spectroscopic data, and with the aid of complementary in-mixture standard NMR two-dimensional correlation experiments, the different oxidised forms of hyperforin were found to be phloroglucinol derivatives in which a hydroxy-dihydrofuran ring is formed involving the enol OH at C-7 or C-9 (tautomeric form) and the prenyl chain at C-8 of the core nucleus of hyperforin. The strategy followed for the on-line identification of these constituents is discussed.
Asunto(s)
Hypericum/química , Terpenos/química , Compuestos Bicíclicos con Puentes , Cromatografía Líquida de Alta Presión/métodos , Isomerismo , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos , Estructura Molecular , Oxidación-Reducción , Floroglucinol/análogos & derivados , Análisis Espectral , Terpenos/normasRESUMEN
Excessive breakdown of extracellular matrix by metalloproteinases (MMPs) occurs in many pathological conditions, and thus inhibition of MMP activity might have therapeutic potential. The methanolic extract and the identified compounds from the bark of Tristaniopsis calobuxus Brongniart & Gris (Myrtaceae) were tested on the activity, production, and gene expression of MMP-9. The extract produced a concentration-dependent inhibition (50-95% at 10-50 microg/ml) of MMP-9 activity. The inhibitory activity was retained in the ethyl acetate-soluble fraction (50-95% inhibition at 10-50 microg/ml) which also reduced the release of MMP-9 by mouse peritoneal macrophages up to 80%. In the ethyl acetate-soluble fraction, two active fractions, 5A and 5B were identified. HPLC-MS and NMR analyses of these fractions indicated the presence of gallocatechin, ellagic acid, and its glycoside derivatives. Since the absolute configuration of gallocatechin was not determined, in the next experiments both (+)-gallocatechin (2R,3S) and (-)-gallocatechin (2S,3R) were tested, and (-)-epigallocatechin (2R,3R) was included for comparison. 5A and 5B inhibited MMP-9 secretion, an observation which correlated with the decrease of MMP-9 promoter activity and the downregulation of mRNA levels. All compounds decreased MMP-9 mRNA levels and secretion. Ellagic acid, (+)-gallocatechin and (-)-epigallocatechin, but not (-)gallocatechin inhibited promoter-driven transcription. Thus configuration at C2 (R) of the flavanol seem to be critical for the interaction with the promoter.
Asunto(s)
Flavonoides , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz , Myrtaceae/química , Fenoles/aislamiento & purificación , Fenoles/farmacología , Corteza de la Planta/química , Polímeros/aislamiento & purificación , Polímeros/farmacología , Animales , Genes Reporteros , Cinética , Macrófagos Peritoneales/enzimología , Espectroscopía de Resonancia Magnética , Metaloproteinasa 9 de la Matriz/genética , Ratones , Fenoles/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Polímeros/química , Polifenoles , Regiones Promotoras Genéticas , ARN Mensajero/genética , Proteínas Recombinantes/antagonistas & inhibidores , Virus 40 de los Simios/genética , TransfecciónRESUMEN
Hodgkinsine, a trimeric pyrrolidinoindoline type alkaloid, present as a major constituent of Psychotria spp. (Rubiaceae), has shown to produce dose-dependent, naloxone reversible, analgesic effect in thermal models of nociception and in the capsaicin-induced pain. SAR studies have been initiated by synthesizing the three diastereomeric dimers (chimonanthines) (11-13) which were evaluated in vitro and in vivo along with the synthetic intermediates. Strong binding affinities for mu opioid receptors were found for (-)- and (+)-chimonanthine monourethanes (9 and 10), whereas (-)-, (+)- and (meso)-chimonanthine (11-13) and hodgkinsine displayed low affinity. In vivo data have shown that only (+)-chimonanthine (12) and calycosidine resemble the analgesic profile found for hodgkinsine.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/farmacología , Analgésicos/síntesis química , Analgésicos/farmacología , Pirroles/química , Alcaloides/química , Analgésicos/químicaRESUMEN
From Astragalus peregrinus, four cycloartane-type saponins have been isolated and their structures elucidated by spectral means as 20(R),24(S)-epoxy-9 beta,19-cyclolanostane-3 beta,6 alpha,16 beta,25-tetrol 3-O-beta-D-glucopyranoside (1), 20(R),24(S)-epoxy-9 beta,19-cyclolanostane-3 beta,6 alpha,16 beta,25-tetrol 3-O-alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranoside (2), 20(R),24(S)-epoxy-9 beta,19-cyclolanostane-3 beta,6 alpha,16 beta,25-tetrol 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside (3) and 20(R),25-epoxy-9 beta,19-cyclolanostane-3 beta,6 alpha,16 beta,24(S)-tetrol (24-O-acetyl)- 3-O-alpha-L-rhamnopyranosyl-(1-->2)-(6'-O-acetyl)-beta-D-glucopyranoside (4). Compounds 2 and 3 showed to stimulate the proliferation of mouse splenocytes and were not significantly cytotoxic.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Fabaceae , Linfocitos/efectos de los fármacos , Fitoterapia , Extractos Vegetales/farmacología , Saponinas/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Animales , Femenino , Humanos , Ratones , Ratones Endogámicos , Extractos Vegetales/uso terapéutico , Estructuras de las Plantas , Saponinas/uso terapéutico , Bazo/citología , Bazo/efectos de los fármacos , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
We have previously reported that the alkaloid extract of Psychotria colorata (Willd. ex R. & S.) Muell. Arg., had marked dose-dependent, opioid-like activity. Phytochemical analyses of P. colorata flowers and leaves identified several pyrrolidinoindoline alkaloids, including psychotridine. To further investigate the activity and mechanism of action of Psychotria alkaloids, we studied the effects of psychotridine on thermal and chemical models of analgesia. In the tail-flick model, psychotridine presents a dose-dependent analgesic effect; the effect is not reversed by prior treatment with naloxone. Psychotridine dose-dependently decreased capsaicin-induced pain. Performance in the rotarod test showed that psychotridine does not induce motor deficits at doses effective in analgesia models. Psychotridine inhibited [3H]MK-801 (dizocilpine) binding to cortex membranes in a dose-dependent manner. Binding is completely abolished at 300 nM. The data rule out opioid activity, and the inhibition of capsaicin-induced pain and of radioligand binding strongly suggest the participation of NMDA receptors in psychotridine-induced analgesia.
Asunto(s)
Alcaloides/farmacología , Analgésicos/farmacología , Indoles/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Rubiaceae/química , Analgésicos/química , Analgésicos Opioides/farmacología , Animales , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Indoles/química , Masculino , Ratones , Estructura Molecular , Morfina/farmacología , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Estructuras de las PlantasRESUMEN
Screening of plants from New Caledonia for antiplasmodial activity against Plasmodium falciparum revealed that methanolic extracts of the leaves and bark of Tristaniopsis calobuxus, T. yateensis, and T.glauca inhibited the growth of chloroquine-sensitive and -resistant clones. Ellagic acid and the new compound 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-D-glucopyranoside were identified as the active constituents (IC50 0.5 and 3.2 microM, respectively). The growth inhibition of both clones was comparable. The compounds showed negligible or very low cytotoxicity to human skin fibroblasts and Hep G2 cells when tested at concentrations ranging from 0.5 to 100 microM.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Ácido Elágico/química , Ácido Elágico/farmacología , Glucósidos/aislamiento & purificación , Glucósidos/farmacología , Plantas Medicinales/química , Plasmodium/efectos de los fármacos , Animales , Antimaláricos/aislamiento & purificación , Ácido Elágico/aislamiento & purificación , Humanos , Espectroscopía de Resonancia Magnética , Nueva Caledonia , Epidermis de la Planta/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Células Tumorales CultivadasRESUMEN
Three oxygenated analogues of the prenylated phloroglucinol hyperforin (3-5) were isolated from the aerial parts of Hypericum perforatum and their structures elucidated by spectroscopic methods.
Asunto(s)
Hypericum/química , Plantas Medicinales , Compuestos Bicíclicos con Puentes , Estructura Molecular , Floroglucinol/análogos & derivados , Análisis Espectral , Terpenos/química , Terpenos/aislamiento & purificaciónRESUMEN
To further understand the mechanism of analgesic activity and structural requirements of pyrrolidinoindoline alkaloids identified in Psychotria colorata, we here report the analgesic activity of the trimer hodgkinsine on thermal and chemical models of analgesia. Results show that hodgkinsine produces a dose-dependent naloxone reversible analgesic effect in thermal models of nociception, suggesting that activation of opioid receptors participates in hodgkinsine's mode of action. Hodgkinsine shows a potent dose-dependent analgesic activity against capsaicin-induced pain, indicating the participation of NMDA receptors in hodgkinsine-induced analgesia. Such a dual mechanism of action may be of interest for developing innovative analgesics.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Indoles/farmacología , Rubiaceae/química , Analgésicos no Narcóticos/química , Analgésicos no Narcóticos/aislamiento & purificación , Animales , Indoles/química , Indoles/aislamiento & purificación , Masculino , Ratones , Estructura MolecularRESUMEN
The phytochemical investigation of members of the genus Protea afforded a series of polyphenolic compounds (1-5) that were identified by 1D and 2D NMR experiments. Of these, 2-5 are new compounds. Chemical syntheses of 1-3 were performed in order to confirm the structures and to prepare additional material for biological evaluation.
RESUMEN
The hydroalcoholic extract of Hypericum perforatum L. is an effective antidepressant, although its mechanism of action is still unknown. It inhibits the synaptosomal uptake of serotonin (5-HT), dopamine and noradrenaline, suggesting a biochemical mechanism similar to the synthetic standard antidepressants. In the present study, further investigating this hypothesis, we confirmed that a hydromethanolic extract of H. perforatum inhibited [3H]5-HT accumulation in rat brain cortical synaptosomes with an IC50 value of 7.9 microg/ml. The IC50 of pure hyperforin was 1.8 microg/ml, so the activity of the total extract is not related only to its hyperforin content (<5%). This inhibitory effect, however, is not due to a direct interaction with, and blockade of, the 5-HT transporters since the extract, like hyperforin, did not inhibit [3H]citalopram binding (IC50 > 100 microg/ml and 10 microg/ml, respectively). We also found that 3-10 microg/ml of the extract, or 0.3-1 microg/ml hyperforin, induced marked tritium release from superfused synaptosomes previously loaded with [3H]5-HT. The releasing effect of the extract resembles the releasing effect of a reserpine-like compound (Ro 04-1284), i.e. it was slightly delayed and was 5-HT carrier- and calcium-independent. These data suggest that the hydromethanolic extract of H. peforatum, similarly to Ro 04-1284, rapidly depletes storage vesicles, raising the cytoplasmic concentration of 5-HT, and this increase is presumably responsible for the apparent inhibition of [3H]5-HT uptake. Therefore, our in vitro data do not confirm that the hydromethanolic extract of H. perforatum acts as a classical 5-HT uptake inhibitor but indicate reserpine-like properties. However, the concentrations of the active component(s) effective in vitro as reserpine-like agent(s) (i.e. corresponding to > or =3 microg/ml of the hydromethanolic extract) do not seem to be achieved in the brain after pharmacologically effective doses of the extract, as indicated by the finding that there were no significant changes of rat brain 5-HT and 5-hydroxyindoleacetic acid levels after a schedule of treatment (3 x 300 mg/kgday, orally) active in an animal model predictive of antidepressant-like activity. These data also suggest that the antidepressant effect of H. perforatum extracts is unlikely to be associated with interaction with GABA, benzodiazepine and 5-HT1 receptors since, in receptor binding studies, we found IC50 values higher than 5 microg/ml. Therefore other, still unknown, mechanisms are possibly involved in H. perforatum antidepressant effects.
Asunto(s)
Encéfalo/efectos de los fármacos , Proteínas Portadoras/antagonistas & inhibidores , Corteza Cerebral/efectos de los fármacos , Hypericum , Glicoproteínas de Membrana/antagonistas & inhibidores , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Extractos Vegetales/farmacología , Plantas Medicinales , Animales , Unión Competitiva/efectos de los fármacos , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Citalopram/metabolismo , Dopamina/metabolismo , Dopamina/farmacocinética , Inmovilización , Masculino , Fluidez de la Membrana/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de GABA/efectos de los fármacos , Receptores de GABA/metabolismo , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Factores de Tiempo , TritioRESUMEN
Furohyperforin, an oxygenated analogue of the prenylated phloroglucinol hyperforin, was isolated from the aerial parts of Hypericum perforatum. Its structure was elucidated as 2 on the basis of extensive NMR investigations.
Asunto(s)
Anticarcinógenos/uso terapéutico , Bibencilos/uso terapéutico , Neoplasias/prevención & control , Estilbenos/uso terapéutico , Bibencilos/síntesis química , Bibencilos/aislamiento & purificación , Humanos , Plantas Comestibles , Estilbenos/síntesis química , Estilbenos/aislamiento & purificaciónRESUMEN
Fractionation of an alkaloid extract of Psychotria colorata flowers led to the isolation of six alkaloids, identified by UV, 1D and 2D NMR, and MS as (-)-calycanthine, isocalycanthine, (+)-chimonanthine, hodgkinsine, quadrigemine C, and a new alkaloid (1), whose structure was deduced by X-ray analysis to be (8-8a),(8'-8'a)-tetradehydroisocalycanthine 3a(R), 3'a(R).
RESUMEN
Resveratrol 3-O-beta-D-glucopyranoside (1) has been isolated from the seeds of Erythrophleum lasianthum (Caesalpinioidae, Leguminosae), a South African plant used in traditional medicine, and has shown antiplatelet aggregation activity. The synthesis of 1, related hydroxystilbenes, and their glucosides has been undertaken to provide larger quantities, for further biological evaluation, and has been accomplished via Wittig reactions followed by glucosylation under phase transfer catalysis.
Asunto(s)
Glucósidos/aislamiento & purificación , Inhibidores de Agregación Plaquetaria/aislamiento & purificación , Agregación Plaquetaria/efectos de los fármacos , Estilbenos , Glucósidos/síntesis química , Glucósidos/farmacología , Humanos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Semillas/químicaRESUMEN
Guiera senegalensis J. F. Gmelin (Combretaceae) leaves are used in African traditional medicine for gastrointestinal disorders, cough and topically for wound healing. This paper regards the evaluation of antiradical, antielastase, antimicrobial, genotoxic and antimutagenic activities of the leaf extracts and the determination of chemical structure of the elastase inhibitors. Antimicrobial activity was tested against Gram positive and negative bacteria, moulds and yeasts. Genotoxic potential was assayed with Bacillus subtilis rec -assay and Salmonella-microsome test. The latter was used also for determining antimutagenic activity. Antiradical properties were evaluated as inhibition of ADP-Fe(2+) induced lipoperoxidation in rat liver microsomes. Porcine pancreatic elastase was used to test enzyme inhibition. The methanolic extract was fractionated with dichloromethane, w-butanol and water and these fractions were tested for the above mentioned activities. The crude extract possessed a mild antimicrobial effect only on Gram positive bacteria (MIC 0.8-1.5 mg/ml) and the effect was associated to dichloromethane and n-butanol fractions. The crude extract and the dichloromethane and n-butanol fractions were weakly genotoxic but showed also a significant antimutagenicity. Inhibition of lipoperoxidation was assignable mainly to the n-butanol fraction. Elastase was inhibited (IC(50) 181 µg/ml) and the inhibition was retained in the water soluble fraction (IC(50) 37µg/ml). The compounds responsible for the enzyme inhibition were a mixture of proanthocyanidins constituted predominantly by (-)-epicatechin and (-)-epigallocatechin units. The mean degree of polymerization was 2-6.
RESUMEN
Combretastatin B1, a polyhydroxybibenzyl compound extracted from the fruit of Combretum kraussii, known to contain 'hiccup nut' toxin, reversibly increased the duration, but not the peak or the rate of rise, of the action potential in rat sensory neurones by approximately 300%. This effect was only seen when it was applied to the extracellular side of the membrane. No effects on the resting potential were observed. K+ delayed rectifier currents were inhibited in neurones and in human myotubes with an IC50 of about 300 microM; the HERG-type inward rectifier channels in tumour cells were inhibited to a greater degree. Due to its selective action and the similarity of its blockade to that produced by class III antiarrhythmic drugs, the toxin could be the origin of compounds of potentially significant pharmacological interest.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Bibencilos/farmacología , Ganglios Espinales/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Estilbenos , Animales , Relación Dosis-Respuesta a Droga , Humanos , RatasRESUMEN
Three new cycloartane glycosides, trigonoside I, II and III, and the known astragalosides I and II were isolated from the roots of Astragalus trigonus. The structures of the new glycosides were totally elucidated by high field (600 MHz) NMR analyses as cycloastragenol-6-O-beta-xylopyranoside, cycloastragenol-3-O-[alpha-L-arabinopyranosyl(1-->2)-beta-D- xylopyranosyl]- 6-O-beta-D-xylopyranoside and cycloastragenol-3-O-[alpha-L-arabinopyranosyl (1-->2)-beta-D-(3-O-acetyl)-xylopyranosyl]-6-O-beta-D-xylopyranoside.
Asunto(s)
Fabaceae , Plantas Medicinales , Saponinas/química , Triterpenos/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Datos de Secuencia Molecular , Saponinas/aislamiento & purificación , Triterpenos/aislamiento & purificaciónRESUMEN
Two alkaloids 1 and 2 were isolated from the seeds of Erythrophleum lasianthum. Their structures were assigned by spectroscopic and chemical means as 3 beta-hydroxynorerythrosuamine (1) and its 3-O-beta-D-glucopyranoside (2). In spontaneously beating atria, both compounds 1 and 2 showed a marked and concentration-dependent positive inotropic activity and a weak negative chronotropic activity. The positive inotropic effect induced by 1 and 2 was not modified by propranolol, prazosin, carbachol, and ranitidine plus pyrilamine. Both 1 and 2 were very active in inhibiting the Na+/K(+)-ATPase isolated from bovine cardiac sarcolemmal vesicles.