RESUMO
A new anthranilic acid derivative (1) was isolated from a Philippine sponge, Oscarella stillans (Bergquist and Kelly). The structure of compound 1, named oscarellin, was determined as 2-amino-3-(3'-aminopropoxy)benzoic acid from spectroscopic data and confirmed by synthesis. We examined the immunomodulating effect of compound 1 and its mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Our data indicated that the expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were significantly reduced by the pretreatment of 1 (0.1-10 µM) for 2 h. In addition, compound 1 suppressed activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-termimal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK) in LPS-stimulated RAW 264.7 cells. Compound 1 abrogated LPS-induced nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activities, whereas the induction of activating transcription factor-3 (ATF-3) was increased. Taken together, our results suggest that compound 1 attenuates pro-inflammatory cytokines via the suppression of JNK, ERK, AP-1, and NF-κB and the activation of the ATF-3 signaling pathway.
Assuntos
Aminas/farmacologia , Benzoatos/farmacologia , Citocinas/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Aminas/química , Aminas/isolamento & purificação , Animais , Benzoatos/química , Benzoatos/isolamento & purificação , Citocinas/química , Interleucina-6/química , Proteínas Quinases JNK Ativadas por Mitógeno/química , Lipopolissacarídeos/química , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/química , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/química , Estrutura Molecular , NF-kappa B/química , Óxido Nítrico Sintase Tipo II/química , Filipinas , Poríferos , Fator de Necrose Tumoral alfa/química , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
Effects of artekeiskeanol A, a newly isolated coumarin derivative from Artemisa keiskeana Miq. (Compositae), the extract of which is used for treatment of rheumatoid arthritis as a folk medicine, on the antigen-induced activation of RBL-2H3 cells were examined. RBL-2H3 cells were sensitized with dinitrophenol (DNP)-specific IgE, and then stimulated with the antigen DNP-conjugated human serum albumin (DNP-HSA). Artekeiskeanol A at 10 to 100 microM inhibited the antigen-induced degranulation in a concentration-dependent manner, the IC(50) value being 38.0 + or - 0.2 microM. Degranulation induced by thapsigargin or A23187 also was inhibited by artekeiskeanol A at 10 to 100 microM. The antigen-induced increase in the levels of mRNA for tumor necrosis factor (TNF)-alpha and interleukin (IL)-13 and phosphorylations of Akt, p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p44/42 MAPK were also suppressed by artekeiskeanol A. Our findings suggested that the effectiveness of the extract of A. keiskeana might partly be due to the inhibition of mast cell activation by artekeiskeanol A.
Assuntos
Artemisia/química , Degranulação Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Fatores Imunológicos/farmacologia , Mastócitos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Terpenos/farmacologia , Animais , Antígenos/metabolismo , Calcimicina/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Imunoglobulina E , Concentração Inibidora 50 , Interleucina-13/genética , Interleucina-13/metabolismo , Mastócitos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Albumina Sérica , Tapsigargina/farmacologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Three new chlorinated diterpenes, 6-8, along with five known ones, 1-5, were isolated from the molluscs Pleurobranchus albiguttatus and P. forskalii collected in the Philippines. These diterpenes are presumably metabolites of a Lissoclinum species of ascidian on which the molluscs have fed. The structures of the new compounds were determined by interpretation of their spectral data. Compounds 1 and 2 were found to be potent cytotoxins in the National Cancer Institute's screening panel of 60 tumor cell lines and showed some selectivity for melanomas. Two other samples exhibited solid tumor selectivity in a soft agar disk diffusion assay.
Assuntos
4-Butirolactona/análogos & derivados , Antineoplásicos/isolamento & purificação , Diterpenos/isolamento & purificação , Hidrocarbonetos Clorados/isolamento & purificação , Moluscos/química , Succinimidas/isolamento & purificação , 4-Butirolactona/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Hidrocarbonetos Clorados/química , Hidrocarbonetos Clorados/farmacologia , Melanoma/tratamento farmacológico , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Filipinas , Succinimidas/química , Succinimidas/farmacologia , Células Tumorais CultivadasRESUMO
The fascaplysin class of compounds have been further investigated from six organisms consisting of four sponge collections (Fascaplysinopsis reticulata) and two tunicate collections (Didemnum sp.). This work is an extension of an earlier communication and reports the isolation of 12 new fascaplysin derivatives: 10-bromofascaplysin (7), 3,10-dibromofascaplysin (8), homofascaplysate A (9), homofascaplysin B-1 (11), 3-bromohomofascaplysins B (12), B-1 (13), and C (15), 7,14-dibromoreticulatine (17), reticulatol (20), 14-bromoreticulatol (21), and 3-bromosecofascaplysins A (22) and B (23), along with known compounds: fascaplysin (1), reticulatine (4), 3-bromofascaplysin (6), and homofascaplysin C (14). Selected compounds were screened in a cell-based cytotoxicity assay with compounds 1, 6, and fascaplysin A (24) also screened in the NCI 60 cell line panel. A biogenetic pathway for the brominated fascaplysins and brominated related alkaloids is proposed and discussed.
Assuntos
Alcaloides , Indóis , Poríferos/química , Urocordados/química , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Fiji , Humanos , Hidrocarbonetos Bromados/química , Hidrocarbonetos Bromados/isolamento & purificação , Hidrocarbonetos Bromados/farmacologia , Indóis/química , Indóis/isolamento & purificação , Indóis/farmacologia , Indonésia , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Células Tumorais CultivadasRESUMO
Four novel bisulfide bromotyrosine derivatives, psammaplins E (9), F (10), G (11), and H (12), and two new bromotyrosine derivatives, psammaplins I (13) and J (14), were isolated from the sponge Pseudoceratina purpurea, along with known psammaplins A (4), B (6), C (7), and D (8) and bisaprasin (5). The structures of psammaplins E (9) and F (10), which each contain an oxalyl group rarely found in marine organisms, were determined by spectroscopic analysis. Compounds 4, 5, and 10 are potent histone deacetylase inhibitors and also show mild cytotoxicity. Furthermore, compounds 4, 5, and 11 are potent DNA methyltransferase inhibitors. The biogenetic pathway previously proposed for the psammaplins class is also revisited.
Assuntos
Metilases de Modificação do DNA/antagonistas & inibidores , Dissulfetos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Inibidores de Histona Desacetilases , Poríferos/química , Ésteres do Ácido Sulfúrico/isolamento & purificação , Tirosina/análogos & derivados , Tirosina/isolamento & purificação , Animais , Dissulfetos/química , Dissulfetos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Papua Nova Guiné , Ésteres do Ácido Sulfúrico/química , Ésteres do Ácido Sulfúrico/farmacologia , Tirosina/química , Tirosina/farmacologiaRESUMO
Three new sesquiterpene quinols (1, 2, and 5) and two known ones (3 and 4) were isolated along with halistanol sulfate (6) from a marine sponge of the genus Aka collected from Yap Island, Federated States of Micronesia. Their structures were determined from spectral data, and the structure of siphonodictyal C (3) was revised. Sulfates 3 and 6 inhibit CDK4/cyclin D1 complexation, whereas 1 and 4 do not.
Assuntos
Poríferos/química , Proteínas Proto-Oncogênicas , Sesquiterpenos/isolamento & purificação , Animais , Cromatografia Líquida de Alta Pressão , Ciclina D1/efeitos dos fármacos , Quinase 4 Dependente de Ciclina , Quinases Ciclina-Dependentes/efeitos dos fármacos , Concentração Inibidora 50 , Micronésia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Five new diterpenoids, juncins I-M (1-5), of the briarane skeleton have been isolated from the Indian Ocean gorgonian Junceella juncea in addition to four known derivatives, gemmacolides A-C (6-8) and juncin H (9). The structures of 1-5 were established by the interpretation of spectroscopic data.
Assuntos
Cnidários/química , Diterpenos/isolamento & purificação , Animais , Diterpenos/química , Oceano Índico , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
Twelve new briarane diterpenes, designated milolides (1-12), and one known diterpene, 9-deacetylstylatulide lactone (13), were isolated from the Micronesian octocoral Briareum stechei collected at Yap, Federated States of Micronesia. Their structures were determined from spectral data.
Assuntos
Cnidários/química , Diterpenos/isolamento & purificação , Animais , Cromatografia Líquida de Alta Pressão , Diterpenos/química , Micronésia , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Two novel, C-14 epimeric polyhydroxylated 15-keto steroid sulfates, tamosterone sulfate and 14beta-tamosterone sulfate (1 and 2), were isolated from a sponge belonging to a new genus collected in Yap, Federated States of Micronesia. Their structures were assigned by analysis of spectroscopic data and chemical conversions. 14beta-Tamosterone sulfate (2) has the rare naturally occurring C/D cis ring fusion and is the less stable epimer based on equilibration studies. Both compounds possess side-chain substitution patterns not observed previously in marine sterols.
RESUMO
Two new alkaloids, polycarpine (1) and N,N-didesmethylgrossularine-1 (4), have been isolated from extracts of the ascidian Polycarpa aurata collected in Chuuk, Federated States of Micronesia. Three degradation products of 1 were also isolated. The structures of 1, 2, and 4 were determined by X-ray crystallography. The dimeric disulfide 1 inhibited the enzyme inosine monophosphate dehydrogenase, but the inhibition could be reversed by addition of excess dithiothreitol suggesting that 1 reacts with sulfhydryl groups on the enzyme.