RESUMEN
Erythraline, isolated from the bark of Erythrina crista-galli which are used as Brazilian medicine plant for the treatment of inflammation diseases, suppressed nitric oxide (NO) production and induction of inducible nitric oxide synthase (iNOS) expression in RAW264.7 cells stimulated by lipopolysaccharide (LPS). Because of Toll-like receptor (TLR) 4 and its signal transduction are indispensable to the production of NO and iNOS expression by LPS, we investigated the effects of erythraline on TLR signaling molecules. Western blot analysis revealed that the degradation of inhibitor of nuclear factor (NF)-κB (IκB) by LPS was suppressed by erythraline. Moreover, erythraline inhibited not only LPS-induced phosphorylation of IκB kinase (Ikk) but also phosphorylation of mitogen-activated protein kinases (MAPKs). However, it showed no effect on LPS -induced phosphorylation of transforming growth factor (TGF)-ß-activated kinase (TAK) 1 that exists upstream of Ikk and MAPKs, and is required for the activation of these signaling molecules on TLR signaling pathway. These results suggested that erythraline might have inhibited the kinase activity of TAK1. Furthermore, these results were supported from the inhibitory pattern of erythraline on TLR signaling molecules when the cells were stimulated by TLR2 ligand, peptidoglycan which activates the same pathway as LPS on TLR signal transduction.
Asunto(s)
Antiinflamatorios/farmacología , Erythrina , Alcaloides Indólicos/farmacología , Quinasas Quinasa Quinasa PAM/metabolismo , Receptores Toll-Like/metabolismo , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Lipopolisacáridos , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peptidoglicano , Corteza de la Planta , Transducción de Señal/efectos de los fármacosRESUMEN
Three new indole alkaloids (1-3), named grandilodines A-C, and five known ones were obtained from the Malayan Kopsia grandifolia. The structures were established using NMR and MS analyses and, in the case of 1 and 2, were confirmed by X-ray diffraction analyses. Alkaloids 1, 3, and lapidilectine B (8) were found to reverse multidrug resistance in vincristine-resistant KB cells.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Apocynaceae/química , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Vincristina/farmacología , Antineoplásicos Fitogénicos/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Células KB , Estructura MolecularRESUMEN
Four new bisindole alkaloids of the Strychnos-Strychnos type, leucoridines A-D (1-4), were isolated from the stem-bark extract of Leuconotis griffithii. Alkaloids 1-4 showed moderate cytotoxicity against drug-sensitive and vincristine-resistant human KB cells.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Apocynaceae/química , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Plantas Medicinales/química , Strychnos/química , Antineoplásicos Fitogénicos/química , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Células KB , Malasia , Resonancia Magnética Nuclear Biomolecular , Corteza de la Planta/química , Vincristina/farmacologíaRESUMEN
A total of 25 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia spatulata, of which five are new alkaloids of the strychnan type (alstolucines A-E, 1-5) and the other, a new alkaloid of the secoangustilobine A type (alstolobine A, 6). The structures of these alkaloids were established using NMR and MS analysis and, in the case of alstolucine B (2), also confirmed by X-ray diffraction analysis. A reinvestigation of the stereochemical assignment of scholaricine (13) by NMR and X-ray analyses indicated that the configuration at C-20 required revision. Alkaloids 1, 2, 6, 7, 9, 10, and 13 reversed multidrug resistance in vincristine-resistant KB cells.
Asunto(s)
Alstonia/química , Alcaloides Indólicos/aislamiento & purificación , Cristalografía por Rayos X , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Células KB , Malasia , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Corteza de la Planta/química , Hojas de la Planta/química , Vincristina/farmacologíaRESUMEN
Two new Erythrinan alkaloids, cristanines A and B (1, 2), were isolated from the bark of Erythrina crista-galli L. together with nine known Erythrinan alkaloids (3-5, 7-12) and an indole alkaloid (13). The structures of the compounds, cristanines A (1) and B (2), were elucidated by spectroscopic methods. Three of the twelve compounds isolated showed significant inhibitory activity on lipopolysaccharide induced nitric oxide (NO) production.
Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Erythrina/química , Óxido Nítrico/biosíntesis , Extractos Vegetales/química , Extractos Vegetales/farmacología , Tallos de la Planta/química , Alcaloides/aislamiento & purificación , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ratones , Estructura Molecular , EstereoisomerismoRESUMEN
A new Erythrinan alkaloid (1), erythodine N-oxide, was isolated from the seeds of Erythrina velutina together with seven known Erythrinan alkaloids (2-7, 9) and an indole alkaloid (8). The structure of new compound (1) was elucidated by spectroscopic methods. Six of the nine compounds showed enhanced activity when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Erysotrine (4) did not show cytotoxic activity by itself, but exhibited significant cytotoxicity when combined with TRAIL.
Asunto(s)
Alcaloides/farmacología , Erythrina/química , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Alcaloides/aislamiento & purificación , Alcaloides/uso terapéutico , Antineoplásicos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Alcaloides Indólicos , Células Jurkat , Estructura Molecular , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéuticoRESUMEN
Seven new indole alkaloids of the Strychnos type, leuconicines A-G (1-7), and a new eburnan alkaloid, (-)-eburnamaline (8), were isolated from the stem-bark extract of two Malayan Leuconotis species. The structures of these alkaloids were established using NMR and MS analysis and in the case of 8 also by partial synthesis. Alkaloids 1-5 reversed multidrug resistance in vincristine-resistant KB cells.
Asunto(s)
Alcaloides Indólicos/aislamiento & purificación , Resistencia a Múltiples Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Células KB , Malasia , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Corteza de la Planta/química , Tallos de la Planta/química , Estereoisomerismo , Vincristina/farmacologíaRESUMEN
A new cycloartane, monocarpinine (1), incorporating a fused tetrahydrofuranyl ring, and a cytotoxic tetracyclic lactam, monomarginine (2), were isolated from a stem bark extract of the Malayan species Monocarpia marginalis. The structures of these compounds were determined using NMR and MS analysis. Monomarginine (2) showed appreciable cytotoxicity toward human KB (both drug-sensitive and drug-resistant) and Jurkat cells.
Asunto(s)
Annonaceae/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Furanos/aislamiento & purificación , Furanos/farmacología , Lactamas/aislamiento & purificación , Lactamas/farmacología , Plantas Medicinales/química , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Antineoplásicos Fitogénicos/química , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Furanos/química , Humanos , Células Jurkat , Células KB , Lactamas/química , Malasia , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Triterpenos/química , Vincristina/farmacologíaRESUMEN
Seven new indole alkaloids of the Aspidosperma type, jerantinines A-G (1-7), were isolated from a leaf extract of the Malayan Tabernaemontana corymbosa. The structures were established using NMR and MS analysis. Five of the alkaloids isolated and two derivatives (1-5, 8, 9) displayed pronounced in vitro cytotoxicity against human KB cells (IC50 < 1 microg/mL).
Asunto(s)
Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Plantas Medicinales/química , Tabernaemontana/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Células KB , Malasia , Estructura Molecular , Hojas de la Planta/químicaRESUMEN
There is increasing evidence that more than 70% of cancers including pancreatic, breast and prostate cancers as well as neurofibromatosis (NF) are highly addicted to abnormal activation of the Ser/Thr kinase PAK1 for their growth. So far FK228 is the most potent among the HDAC (histone deacetylase) inhibitors that block the activation of both PAK1 and another kinase AKT, downstream of PI-3 kinase. However, FK228 is still in clinical trials (phase 2) for a variety of cancers (but not for NF as yet), and not available for most cancer/NF patients. Thus, we have been exploring an alternative which is already in the market, and therefore immediately useful for the treatment of those desperate cancer/NF patients. Here we provide the first evidence that extracts of Chinese/ Japanese peppercorns (Zanthoxyli Fructus) from the plant Zanthoxylum piperitum called "Hua Jiao"/"Sansho", block selectively the key kinase PAK1, leading to the downregulation of cyclin D1. Unlike FK228, these extracts do not inhibit AKT activation at the concentrations that block either cancer growth or PAK1 activation. The Chinese pepper extract selectively inhibits the growth of NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells, without affecting the growth of normal fibroblasts, and suppresses the growth of NF1-deficient human breast cancer (MDA-MB-231) xenograft in mice. Our data suggest that these peppercorn extracts would be potentially useful for the treatment of PAK1-dependent NF such as MPNST, in addition to a variety of PAK1-dependent cancers including breast cancers.
Asunto(s)
Antimitóticos/farmacología , Ciclina D1/metabolismo , Neurofibromatosis 1/tratamiento farmacológico , Extractos Vegetales/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Zanthoxylum/química , Animales , Antimitóticos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Neoplasias de la Vaina del Nervio/patología , Neurofibromatosis 1/metabolismo , Neurofibromina 1/genética , Fitoterapia , Extractos Vegetales/uso terapéutico , Transducción de Señal , Trasplante Heterólogo , Quinasas p21 ActivadasRESUMEN
OBJECTIVES: To evaluate the effects of tea catechin inhalation on methicillin-resistant Staphylococcus aureus (MRSA) in disabled elderly patients. DESIGN: Seven days, randomized, prospective study. SETTING: Three hospitals in Japan. PARTICIPANTS: Seventy-two patients aged 78 +/- 11 years (mean age +/- standard deviation) with cerebrovascular diseases, classified as disabled according to the activity of daily living and were either bedridden or required assistance for standing, and showing presence of MRSA in sputum. INTERVENTIONS: Inhalation of 2 mL tea catechin extract solution along with saline (3.7 mg/mL catechins, 43% of catechins are composed of epigallocatechin gallate), or saline alone, 3 times daily using a handheld nebulizer for 7 days. MEASUREMENTS: The endpoint of efficacy was the reduction rates of MRSA in sputum. The safety measure was the adverse events observed during the 7 days of inhalation. RESULTS: The reduction rates calculated as the summation of decrease and disappearance of MRSA in sputum at 7 days were 47% (17 of 36 patients) in the catechin group and 15% (5 of 33 patients) in the control group; the difference in the reduction rates between the 2 groups was statistically significant (P = .014). The disappearance rate of MRSA in sputum was higher in the catechin group (31%; 11 patients) when compared with the control group (12%; 4 patients), however the difference in the disappearance rate between the 2 groups was not statistically significant (P = .091). No adverse events, such as respiratory tract obstruction, allergic bronchial spasm, or skin eruption, including laboratory changes, were observed during the study. CONCLUSION: The catechin inhalation appeared to reduce the MRSA count in sputum. However, the application of tea catechin inhalation as a supplementary treatment for controlling MRSA infection remains controversial.
Asunto(s)
Catequina/uso terapéutico , Personas con Discapacidad , Resistencia a la Meticilina , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus , Té/química , Administración por Inhalación , Anciano , Anciano de 80 o más Años , Catequina/química , Trastornos Cerebrovasculares/complicaciones , Distribución de Chi-Cuadrado , Recuento de Colonia Microbiana , Esquema de Medicación , Femenino , Anciano Frágil , Hospitales Generales , Humanos , Japón , Masculino , Estudios Prospectivos , Método Simple Ciego , Esputo/microbiología , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/etiología , Resultado del TratamientoRESUMEN
Six new indole alkaloids, viz., (3S)-3-cyanocoronaridine (2), (3S)-3-cyanoisovoacangine (3), conolobine A (5), conolobine B (6), conolidine (7), and (3R/3S)-3-ethoxyvoacangine (8), in addition to 36 known ones, were obtained from the stem-bark extract of the Malayan Tabernaemontana divaricata. The structures were determined by NMR and MS analysis. The CN-substituted alkaloids showed appreciable cytotoxicity towards the KB human oral epidermoid carcinoma cell-line.
Asunto(s)
Ibogaína/química , Ibogaína/toxicidad , Tabernaemontana , Línea Celular Tumoral , Humanos , Ibogaína/aislamiento & purificación , Alcaloides Indólicos/química , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/toxicidad , Corteza de la Planta , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Tallos de la PlantaRESUMEN
Fifteen Isodon diterpenoids (1-15) were evaluated for their cytotoxic activity against HeLa and HL-60 human cancer cell lines, and against murine vincristine (VCR)-resistant P388 cells. Kamebanin (14) showed efficient cytotoxic activity against HeLa and HL-60 cells. In addition, although dihydroenmein (2) and trichorabdal B (7) were inactive against several tested cell types, they were found to have cytotoxic-enhancing activity of VCR against VCR-resistant P388 cells.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Diterpenos/química , Diterpenos/farmacología , Isodon/química , Animales , Línea Celular , Humanos , Ratones , Estructura MolecularRESUMEN
A total of 20 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia angustiloba, of which two are hitherto unknown. One is an alkaloid of the angustilobine type (angustilobine C), while the other is a bisindole alkaloid angustiphylline, derived from the union of uleine and secovallesamine moieties. The structures of these alkaloids were established using NMR and MS analysis. Angustilobine C showed moderate cytotoxicity towards KB cells.
Asunto(s)
Alstonia/química , Antineoplásicos Fitogénicos/uso terapéutico , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Alcaloides/química , Alcaloides/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Corteza de la Planta/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Tallos de la Planta/químicaRESUMEN
Leucofoline and leuconoline, representing the first members of the aspidospermatan-aspidospermatan and eburnane-sarpagine subclasses of the bisindole alkaloids, respectively, were isolated from the Malayan Leuconotis griffithii. The structures of these bisindole alkaloids were established using NMR and MS analysis, and in the case of leuconoline, confirmed by X-ray diffraction analysis. Both alkaloids showed weak cytotoxicity towards human KB cells.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Apocynaceae/química , Alcaloides Indólicos/aislamiento & purificación , Plantas Medicinales/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Células KB , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , EstereoisomerismoRESUMEN
A cytotoxic bisindole alkaloid possessing an unprecedented structure constituted from the union of an eburnan half and a novel vinylquinoline alkaloid has been isolated from Leuconotis griffithii. The structure was established by analysis of the spectroscopic data and confirmed by X-ray diffraction analysis. A possible biogenetic pathway to the novel quinolinic coupling partner is presented from an Aspidosperma precursor.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Apocynaceae/química , Alcaloides Indólicos/síntesis química , Alcaloides Indólicos/farmacología , Plantas Medicinales/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/aislamiento & purificación , Células KB , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Corteza de la Planta/química , Vincristina/farmacología , Difracción de Rayos XRESUMEN
A cytotoxic bisindole alkaloid possessing an unprecedented structure in which two indole moieties are bridged by an aromatic spacer unit has been isolated from Alstonia angustifolia. The structure was established by analysis of the spectroscopic data and confirmed by X-ray diffraction analysis. A possible biogenetic pathway from pyrocatechuic acid and pleiocarpamine is presented.
Asunto(s)
Alstonia/química , Alcaloides Indólicos/química , Humanos , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Células Jurkat , Células KB , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Corteza de la Planta/química , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Difracción de Rayos XRESUMEN
Ten new indole alkaloids of the aspidofractinine type, in addition to several recently reported indole alkaloids and 20 other known alkaloids, were obtained from the leaf and stem-bark extract of the Malayan Kopsia singapurensis, viz., kopsimalines A-E (1-5), kopsinicine (6), kopsofinone (7), and kopsiloscines H-J (8-10). The structures of these alkaloids were determined using NMR and MS analysis. Kopsimalines A (1), B (2), C (3), D (4), and E (5) and kopsiloscine J (10) were found to reverse multidrug-resistance in vincristine-resistant KB cells, with 1 showing the highest potency.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Apocynaceae/química , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Plantas Medicinales/química , Vincristina/farmacología , Antineoplásicos Fitogénicos/química , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Células KB , Malasia , Estructura Molecular , Corteza de la Planta/química , Hojas de la Planta/químicaRESUMEN
Four new indole alkaloids were obtained from two Kopsia species, 6-oxoleuconoxine (1) from the leaf extract of K. griffithii and kopsinitarine E (2), kopsijasminine (3), and kopsonoline (4) from the stem-bark extract of K. teoi. The structures of these alkaloids were determined using NMR and MS analysis. Kopsijasminine (3) showed moderate activity in reversing multidrug resistance in vincristine-resistant KB cells.
Asunto(s)
Antineoplásicos Fitogénicos , Apocynaceae/química , Alcaloides Indólicos/aislamiento & purificación , Alcaloides de Triptamina Secologanina/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Células KB , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Alcaloides de Triptamina Secologanina/química , Alcaloides de Triptamina Secologanina/farmacología , Vincristina/farmacologíaRESUMEN
Nine new indole alkaloids, rhazinoline (1), 19(S)-methoxytubotaiwine (2), 19(R)-methoxytubotaiwine (3), kopsamidine A (4), kopsamidine B (5), kopsinidine A (6), kopsinidine B (7), paucidactine C (8), and pericine N-oxide (9), in addition to several recently reported novel indoles and 34 other known ones, were obtained from the stem-bark extract of the Malayan Kopsia arborea. The structures were determined using NMR and MS analysis. Valparicine (12) showed pronounced cytotoxic effects against KB and Jurkat cells (IC(50) 13.0 and 0.91 microM, respectively).