RESUMO
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.
Assuntos
Anti-Inflamatórios/farmacologia , Erythrina , Alcaloides Indólicos/farmacologia , MAP Quinase Quinase Quinases/metabolismo , Receptores Toll-Like/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Lipopolissacarídeos , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Peptidoglicano , Casca de Planta , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Isodon/química , Animais , Linhagem Celular , Humanos , Camundongos , Estrutura MolecularRESUMO
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.
Assuntos
Alstonia/química , Antineoplásicos Fitogênicos/uso terapêutico , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/uso terapêutico , Neoplasias/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Caules de Planta/químicaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Vincristina/farmacologia , Antineoplásicos Fitogênicos/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Células KB , Estrutura MolecularRESUMO
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.
Assuntos
Alstonia/química , Alcaloides Indólicos/isolamento & purificação , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Células KB , Malásia , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Folhas de Planta/química , Vincristina/farmacologiaRESUMO
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.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Erythrina/química , Óxido Nítrico/biossíntese , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Caules de Planta/química , Alcaloides/isolamento & purificação , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Camundongos , Estrutura Molecular , EstereoisomerismoRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Strychnos/química , Antineoplásicos Fitogênicos/química , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Células KB , Malásia , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Vincristina/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Células KB , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , EstereoisomerismoRESUMO
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.
Assuntos
Alcaloides Indólicos/isolamento & purificação , Resistência a Múltiplos Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Células KB , Malásia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Caules de Planta/química , Estereoisomerismo , Vincristina/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Células KB , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Vincristina/farmacologia , Difração de Raios XRESUMO
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.
Assuntos
Alcaloides/farmacologia , Erythrina/química , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/uso terapêutico , Antineoplásicos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Alcaloides Indólicos , Células Jurkat , Estrutura Molecular , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêuticoRESUMO
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).
Assuntos
Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Tabernaemontana/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Células KB , Malásia , Estrutura Molecular , Folhas de Planta/químicaRESUMO
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.
Assuntos
Alstonia/química , Alcaloides Indólicos/química , Humanos , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Células Jurkat , Células KB , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Difração de Raios XRESUMO
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.
Assuntos
Annonaceae/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Furanos/isolamento & purificação , Furanos/farmacologia , Lactamas/isolamento & purificação , Lactamas/farmacologia , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Humanos , Células Jurkat , Células KB , Lactamas/química , Malásia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Triterpenos/química , Vincristina/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Vincristina/farmacologia , Antineoplásicos Fitogênicos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Células KB , Malásia , Estrutura Molecular , Casca de Planta/química , Folhas de Planta/químicaRESUMO
Eleven new indole alkaloids, in addition to the previously reported rhazinal (1), and 14 other known alkaloids, were obtained from the Malayan Kopsia singapurensis, viz., kopsiloscines A-F (2-7), 16-epikopsinine (8), kopsilongine- N-oxide (9), 16-epiakuammiline (10), aspidophylline A (11), and vincophylline (12). The structures of these alkaloids were determined using NMR and MS analyses. Rhazinal (1), rhazinilam (17), and rhazinicine (18) showed appreciable cytotoxicity toward drug-sensitive as well as vincristine-resistant KB cells, while kopsiloscines A (2), B (3), and D (5) and aspidophylline A (11) were found to reverse drug-resistance in drug-resistant KB cells.
Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Plantas Medicinais/química , Alcaloides/química , Alcaloides/classificação , Antineoplásicos Fitogênicos/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indolizinas/química , Indolizinas/isolamento & purificação , Indolizinas/farmacologia , Células KB , Lactamas/química , Lactamas/isolamento & purificação , Lactamas/farmacologia , Malásia , Estrutura MolecularRESUMO
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).
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Células Jurkat , Células KB , Malásia , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Caules de Planta/químicaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides de Triptamina e Secologanina/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Células KB , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/farmacologia , Vincristina/farmacologiaRESUMO
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells; however, not all human tumors respond to TRAIL, potentially limiting its therapeutic utility. Although there is substantial evidence that cytotoxic drugs can augment sensitivity to TRAIL, it has become important to know what kinds of nontoxic drugs can be used together with TRAIL. We thus screened several natural compounds that can overcome resistance to TRAIL and found that a cycloanthranilylproline derivative, Fuligocandin B (FCB), an extract of myxomycete Fuligo candida, exhibited significant synergism with TRAIL. Treatment of the TRAIL-resistant cell line KOB with FCB and TRAIL resulted in apparent apoptosis, which was not induced by either agent alone. FCB increased the production of 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), an endogenous PPAR gamma ligand, through activation of cyclooxygenase-2 (COX-2). This unique mechanism highlighted the fact that 15d-PGJ(2) directly enhanced sensitivity to TRAIL by inhibiting multiple antiapoptotic factors. More importantly, similar effects were observed in other leukemia cell lines irrespective of their origin. The enhancement was observed regardless of PPAR gamma expression and was not blocked even by peroxisome proliferator-activated receptor-gamma (PPAR gamma) siRNA. These results indicate that 15d-PGJ(2) sensitizes TRAIL-resistant cells to TRAIL in a PPAR gamma-independent manner and that the use of 15d-PGJ(2) or its inducers, such as FCB, is a new strategy for cancer therapy.
Assuntos
Apoptose/efeitos dos fármacos , Leucemia/tratamento farmacológico , Prolina/análogos & derivados , Prostaglandina D2/análogos & derivados , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Linhagem Celular Transformada , Ciclo-Oxigenase 2/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/metabolismo , Células K562 , Leucemia/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , PPAR gama/biossíntese , Prolina/agonistas , Prolina/farmacologia , Prolina/uso terapêutico , Prostaglandina D2/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêuticoRESUMO
A new iridoid glycoside, citrifoside (1), and a new anthraquinone, 1,5,15-trimethylmorindol (2), together with 24 known compounds, were isolated from the leaves of Morinda citrifolia. The structures of the new compounds were elucidated by spectral data. 1,5,15-Trimethylmorindol (2) did not show significant cytotoxic activity by itself but showed cytotoxicity when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), while citrifoside (1) did not show any activity even with TRAIL.