RESUMO
A new unique sesquiterpene lactone, bicyclolamellolactone A (1), was isolated together with two known monocyclofarnesol-type sesquiterpenes, lamellolactones A (2) and B (3), from the Indonesian marine sponge Lamellodysidea sp. (cf. L. herbacea). The planar structure of 1 was assigned based on its spectroscopic data (1D and 2D NMR, HRESIMS, UV, and IR spectra). The relative and absolute configuration of 1 was determined by comparison of its calculated and experimental electronic circular dichroism spectra in combination with NOESY correlations. Compounds 1-3 inhibited bone morphogenic protein (BMP)-induced alkaline phosphatase activity in mutant BMP receptor-carrying C2C12 cells with IC50 values of 51, 4.6, and 20 µM, respectively.
Assuntos
Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Lactonas/farmacologia , Osteoblastos/efeitos dos fármacos , Poríferos/química , Sesquiterpenos/farmacologia , Fosfatase Alcalina/antagonistas & inibidores , Fosfatase Alcalina/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Indonésia , Lactonas/química , Lactonas/isolamento & purificação , Camundongos , Estrutura Molecular , Osteoblastos/metabolismo , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder with heterotopic ossification (HO) in soft tissues. The abnormal activation of bone morphogenetic protein (BMP) signaling by a mutant activin receptor-like kinase-2 (ALK2) leads to the development of HO in FOP patients, and, thus, BMP signaling inhibitors are promising therapeutic applications for FOP. In the present study, we screened extracts of 188 Indonesian marine invertebrates for small molecular inhibitors of BMP-induced alkaline phosphatase (ALP) activity, a marker of osteoblastic differentiation in a C2C12 cell line stably expressing ALK2(R206H) (C2C12(R206H) cells), and identified five marine sponges with potent ALP inhibitory activities. The activity-guided purification of an EtOH extract of marine sponge Dysidea sp. (No. 256) resulted in the isolation of dysidenin (1), herbasterol (2), and stellettasterol (3) as active components. Compounds 1-3 inhibited ALP activity in C2C12(R206H) cells with IC50 values of 2.3, 4.3, and 4.2 µM, respectively, without any cytotoxicity, even at 18.4-21.4 µM. The direct effects of BMP signaling examined using the Id1WT4F-luciferase reporter assay showed that compounds 1-3 did not decrease the reporter activity, suggesting that they inhibit the downstream of the Smad transcriptional step in BMP signaling.
Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Diferenciação Celular/efeitos dos fármacos , Dysidea/metabolismo , Inibidores Enzimáticos/farmacologia , Mioblastos Esqueléticos/efeitos dos fármacos , Miosite Ossificante/tratamento farmacológico , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Esteróis/farmacologia , Tiazóis/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Proteína Morfogenética Óssea 4/toxicidade , Linhagem Celular , Inibidores Enzimáticos/isolamento & purificação , Indonésia , Camundongos , Estrutura Molecular , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/patologia , Miosite Ossificante/metabolismo , Miosite Ossificante/patologia , Osteoblastos/metabolismo , Osteoblastos/patologia , Esteróis/isolamento & purificação , Relação Estrutura-Atividade , Tiazóis/isolamento & purificaçãoRESUMO
Callyspongiamides A (1) and B (2), two new sterol O-acyltransferase (SOAT) inhibitors, were isolated from the Indonesian marine sponge Callyspongia sp. together with a known congener, dysamide A (3). The structures of 1 and 2 were elucidated to be polychlorine-containing modified dipeptides based on their spectroscopic data. Compounds 1-3 inhibited both of the SOAT isozymes, SOAT1 and SOAT2, in cell-based and enzyme-based assays.
Assuntos
Callyspongia/química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Callyspongia/metabolismo , Dipeptídeos/química , Dipeptídeos/isolamento & purificação , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Indonésia , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Esterol O-Aciltransferase/metabolismoRESUMO
Agelasine G (1), a known bromine-containing diterpene alkaloid, was isolated as a new type of protein tyrosine phosphatase (PTP) 1B inhibitor together with ageline B (2), an inactive debromo-derivative of 1, from the marine sponge Agelas nakamurai collected at Iriomote Island in Okinawa, Japan. Further biological evaluations revealed that compound 1 exhibited selective inhibitory activity against PTP1B over T-cell PTP and CD45 phosphatase. Compound 1 also enhanced the insulin-stimulated phosphorylation levels of Akt in Huh-7 cells more strongly than compound 2. The results obtained in this study suggest that compound 1 activates the insulin signaling pathway by inhibiting PTP1B activity.
Assuntos
Agelas/química , Alcaloides/química , Diterpenos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Agelas/metabolismo , Alcaloides/isolamento & purificação , Alcaloides/toxicidade , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Diterpenos/isolamento & purificação , Diterpenos/toxicidade , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/toxicidade , Humanos , Insulina/metabolismo , Japão , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fosforilação/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Pirróis/química , Transdução de Sinais/efeitos dos fármacosRESUMO
Three new dimeric 3-alkyl pyridinium alkaloids, named haliclocyclamines A-C (1-3), were isolated together with five known congeners, cyclostellettamines A (4), B (5), C (6), E (7), and F (8), from the Indonesian marine sponge Haliclona sp. The structures of 1-3 were assigned based on their spectroscopic data (1D and 2D NMR, HRFABMS, ESIMS/MS, UV, and IR). Compounds 1-8 exhibited antimicrobial activities against Mycobacterium smegmatis with inhibition zones of 17, 10, 13, 14, 8, 8, 12, and 12mm, respectively, at 10µg/disc. Compounds 3 and 8 also modestly inhibited the activity of vaccinia H-1-related phosphatase (VHR), a dual-specificity phosphatase, at 17-18µM.
Assuntos
Alcaloides/farmacologia , Antibacterianos/farmacologia , Haliclona/química , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium smegmatis/efeitos dos fármacos , Compostos de Piridínio/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Indonésia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Compostos de Piridínio/química , Compostos de Piridínio/isolamento & purificaçãoRESUMO
Protein tyrosine phosphatase (PTP) 1B negatively regulates the insulin and leptin signaling pathways, and, thus, the clinical application of PTP1B inhibitors to the prevention and treatment of type 2 diabetes and obesity is expected. During our studies on PTP1B inhibitors, two furanosesterterpenes and a C21 furanoterpene were obtained as new types of PTP1B inhibitors from two Indonesian marine sponges. (7E, 12E, 20Z, 18S)-Variabilin (1) and (12E, 20Z, 18S)-8-hydroxyvariabilin (2) from Ircinia sp. and furospongin-1 (3) from Spongia sp. inhibited PTP1B activity with IC50 values of 1.5, 7.1, and 9.9µM, respectively. The inhibitory activity of compound 1 against T-cell PTP (TCPTP) was approximately 2-fold that against PTP1B, whereas the vaccinia H-1-related phosphatase (VHR) inhibitory effects of 1 were 4-fold weaker than that of its PTP1B inhibitory activity. Compounds 1-3 at 50µM did not show cytotoxicity against two human cancer cell lines, hepatoma Huh-7 and bladder carcinoma EJ-1. Compound 1 did not enhance the phosphorylation level of Akt, a key downstream effector of the cascade, in Huh-7 cells.
Assuntos
Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Poríferos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteínas/farmacologia , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 1/genéticaRESUMO
Protein tyrosine phosphatase 1B (PTP1B) plays an important role as a negative regulator of the insulin and leptin signaling pathways. Therefore, this enzyme is regarded as an attractive therapeutic target for the treatment of type 2 diabetes and obesity. Our screening program for PTP1B inhibitors led to the isolation of four sesquiterpenes and sterol: N,N'-bis[(6R,7S)-7-amino-7,8-dihydro-α-bisabolen-7-yl]urea (1), (6R,7S)-7-amino-7,8-dihydro-α-bisabolene (2), (1R,6S,7S,10S)-10-isothiocyanato-4-amorphene (3), axinisothiocyanate J (4), and axinysterol (5) from the marine sponge Axinyssa sp. collected at Iriomote Island. Of these, compound 1 was the most potent inhibitor of PTP1B activity (IC50=1.9µM) without cytotoxicity at 50µM in two human cancer cell lines, hepatoma Huh-7 and bladder carcinoma EJ-1 cells. Compound 1 also moderately enhanced the insulin-stimulated phosphorylation levels of Akt in Huh-7 cells. Therefore, compound 1 has potential as a new type of anti-diabetic drug candidate possessing PTP1B inhibitory activity.
Assuntos
Hipoglicemiantes/farmacologia , Poríferos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sesquiterpenos/farmacologia , Ureia/análogos & derivados , Actinas/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Estereoisomerismo , Esteróis/isolamento & purificação , Esteróis/farmacologia , Ureia/química , Ureia/isolamento & purificação , Ureia/farmacologiaRESUMO
Three new sesquiterpene hydroquinones, avapyran (1), 17-O-acetylavarol (2), and 17-O-acetylneoavarol (3), were isolated from a Dysidea sp. marine sponge collected in Okinawa together with five known congeners: avarol (4), neoavarol (5), 20-O-acetylavarol (6), 20-O-acetylneoavarol (7), and 3'-aminoavarone (8). The structures of 1-3 were assigned on the basis of their spectroscopic data. Compounds 1-3 inhibited the activity of protein tyrosine phosphatase 1B with IC50 values of 11, 9.5, and 6.5 µM, respectively, while known compounds 4-8 gave IC50 values of 12, >32, 10, 8.6, and 18 µM, respectively. In a preliminary investigation on structure-activity relationships, six ester and methoxy derivatives (9-14) were prepared from 4 and 5.
Assuntos
Dysidea/química , Hidroquinonas/isolamento & purificação , Hidroquinonas/farmacologia , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Animais , Hidroquinonas/química , Concentração Inibidora 50 , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sesquiterpenos/química , Relação Estrutura-AtividadeRESUMO
Four new haliclonadiamine analogues, (10Z,12E)-haliclonadiamine (1), (10E,12Z)-haliclonadiamine (2), and halichondriamines A (3) and B (4), were isolated from the Okinawan marine sponge Halichondria panicea together with haliclonadiamine (5) and papuamine (6). The structures of 1-4 were elucidated on the basis of their spectroscopic data by comparisons with those for 5 and 6. Further separation of the remaining fraction led to the isolation of a new bicyclic guanidine alkaloid, 6-epi-monanchorin (7), along with monanchorin (8). Compound 7 is the epimer of 8 at the 6 position. Compounds 1-6 inhibited the growth of Mycobacterium smegmatis with inhibition zones of 12, 7, 8, 7, 16, and 12 mm at 10 µg/disc, respectively. Compounds 2-4 exhibited weak cytotoxicities against the Huh-7 (hepatoma) human cancer cell line and were 2-fold less active than 5 and 6. Compounds 7 and 8 were not active against M. smegmatis at 20 µg/disc or the cancer cell line at 10 µM.
Assuntos
Alcaloides/isolamento & purificação , Antineoplásicos/isolamento & purificação , Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Guanidinas/isolamento & purificação , Poríferos/química , Alcaloides/química , Alcaloides/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Guanidina , Guanidinas/química , Guanidinas/farmacologia , Humanos , Japão , Biologia Marinha , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacosRESUMO
A new meroditerpene, 26-O-ethylstrongylophorine-14 (1), was isolated from the Okinawan marine sponge Strongylophora strongilata together with six known strongylophorines: 26-O-methylstrongylophorine-16 (2) and strongylophorines-2 (3), -3 (4), -8 (5), -15 (6), and -17 (7). The structure of 1 was assigned on the basis of its spectroscopic data. Compound 1 inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 8.7 µM, while known compounds 2-8 gave IC50 values of 8.5, >24.4, 9.0, 21.2, 11.9, and 14.8 µM, respectively. Oleanolic acid, a positive control, inhibited PTP1B activity at 0.7 µM (IC50). The inhibitory activities of strongylophorines possessing the acetal moiety at C-26 (1, 2, and 6) were stronger than those of the lactone derivatives (3 and 5). This is the first study to demonstrate that meroditerpenes inhibit PTP1B activity.
Assuntos
Diterpenos/farmacologia , Inibidores Enzimáticos/farmacologia , Poríferos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Ilhas , Conformação Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Two unique sesterterpenes, hyattellactones A (1) and B (2), together with two known sesterterpenes, phyllofolactones F (3) and G (4), were isolated from the Indonesian marine sponge Hyattella sp. The structures of the two new compounds, 1 and 2 were assigned based on their spectroscopic data. Hyattellactone A (1) was a scalarane sesterterpene with an α,ß-unsaturated-γ-lactone ring and C-ethyl group, while B (2) was an epimer of 1 at the C-24 position. Compounds 1 and 3 inhibited PTP1B activity with IC50 values of 7.45 and 7.47µM, respectively. On the other hand, compounds 2 and 4 (24S-isomers of 1 and 3, respectively) showed much reduced activity than the 24R-isomers.
Assuntos
Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Lactonas/isolamento & purificação , Lactonas/farmacologia , Poríferos/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Animais , Dicroísmo Circular , Inibidores Enzimáticos/química , Lactonas/químicaRESUMO
Three new N-methyladenine-containing diterpenes, 2-oxoagelasines A (1) and F (2) and 10-hydro-9-hydroxyagelasine F (3), were isolated from the Okinawan marine sponge Agelas nakamurai Hoshino together with eight known agelasine derivatives, 2-oxoagelasine B (4), agelasines A (5), B (6), D (7), E (8), F (9), and G (10), and ageline B (11). The structures of 1-3 were assigned on the basis of their spectroscopic data and their comparison with those of the literature. Compounds 3 and 5-11 inhibited the growth of Mycobacterium smegmatis with inhibition zones of 10, 14, 15, 18, 14, 20, 12, and 12 mm at 20 µg/disc, respectively. All compounds were inactive (IC50 > 10 µM) against Huh-7 (hepatoma) and EJ-1 (bladder carcinoma) human cancer cell lines. Three 2-oxo derivatives (1, 2, and 4) exhibited markedly reduced biological activity against M. smegmatis. Moreover, compound 10 inhibited protein tyrosine phosphatase 1B (PTP1B) activity with an IC50 value of 15 µM.
Assuntos
Agelas/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Animais , Antibacterianos/química , Diterpenos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Japão , Biologia Marinha , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidoresRESUMO
During the search for new protein tyrosine phosphatase (PTP) 1B inhibitors, EtOH extracts from the aerial parts of Lantana camara L. (lantana) collected at Manado (Indonesia) and two subtropical islands in Japan (Ishigaki and Iriomote Islands, Okinawa) exhibited potent inhibitory activities against PTP1B in an enzyme assay. Four previously undescribed oleanane triterpenes were isolated together with known triterpenes and flavones from the Indonesian lantana. The EtOH extracts of lantana collected in Ishigaki and Iriomote Islands exhibited different phytochemical profiles from each other and the Indonesian lantana. Triterpenes with a 24-OH group were isolated from the Indonesian lantana only. Five known triterpene compounds were detected in the Ishigaki lantana, and two oleanane triterpenes with an ether linkage between 3ß and 25 were the main components together with five known triterpenes as minor components in the Iriomote lantana. The structures of previously undescribed compounds were assigned on the basis of their spectroscopic data. Among the compounds obtained in this study, oleanolic acid exhibited the most potent activity against PTP1B, and is used as a positive control in studies on PTP1B.
Assuntos
Inibidores Enzimáticos/farmacologia , Lantana/química , Ácido Oleanólico/análogos & derivados , Componentes Aéreos da Planta/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Indonésia , Japão , Estrutura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-AtividadeRESUMO
In the course of our studies on anti-mycobacterial substances from marine organisms, the known dimeric sphingolipid, leucettamol A (1), was isolated as an active component, together with the new bromopyrrole alkaloid, 5-bromophakelline (2), and twelve known congeners from the Indonesian marine sponge Agelas sp. The structure of 2 was elucidated based on its spectroscopic data. Compound 1 and its bis TFA salt showed inhibition zones of 12 and 7 mm against Mycobacterium smegmatis at 50 µg/disk, respectively, while the N,N'-diacetyl derivative (1a) was not active at 50 µg/disk. Therefore, free amino groups are important for anti-mycobacterial activity. This is the first study to show the anti-mycobacterial activity of a bisfunctionalized sphingolipid. Compound 13 exhibited weak PTP1B inhibitory activity (29% inhibition at 35 µM).
Assuntos
Agelas/química , Antibacterianos/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Pirróis/isolamento & purificação , Esfingolipídeos/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Indonésia , Estrutura Molecular , Mycobacterium smegmatis/crescimento & desenvolvimento , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Pirróis/química , Pirróis/farmacologia , Esfingolipídeos/química , Esfingolipídeos/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
A seco-cucurbitane triterpene and two aristolane sesquiterpenes, named (24E)-3,4-seco-cucurbita-4,24-diene-3-hydroxy-26,29-dioic acid, (+)-1,2-didehydro-9-hydroxy-aristlone, and (+)-12-hydroxy-aristlone, were isolated from fruiting bodies of the medicinal mushroom Russula lepida, together with (24E)-3,4-seco-cucurbita-4,24-diene-3,26,29-trioic acid and (+)-aristlone. The structures of the first three compounds, including their absolute configurations, were assigned on the basis of their NMR and ECD spectra. Two seco-cucurbitane triterpenes, (24E)-3,4-seco-cucurbita-4,24-diene-3-hydroxy-26,29-dioic acid and (24E)-3,4-seco-cucurbita-4,24-diene-3,26,29-trioic acid, inhibited the activity of protein tyrosine phosphatase 1B (PTP1B), with IC50 values of 20.3 and 0.4µM, respectively. All isolated compounds did not show cytotoxicity against human cancer cell lines, Huh-7 (hepatoma) and EJ-1 (bladder), at 50µM.
Assuntos
Agaricales/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Carpóforos/química , Glicosídeos/química , Humanos , Japão , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Sesquiterpenos/química , Triterpenos/químicaRESUMO
Two new indole derivatives, 5-hydroxy-1H-indole-3-carboxylic acid ethyl ester (1) and 5-hydroxy-1H-indole-3-glyoxylate ethyl ester (2), and seven known indole alkaloids, dragmacidonamine B (3), gesashidine A (4), hyrtiosulawesine (5), hyrtiomanzamine (6), hyrtimomine D (7), hyrtiosine A (8), and 5-hydroxy-1H-indole-3-carbaldehyde (9), were isolated from a marine sponge Ircinia sp., Irciniidae, collected at Iriomote Island. The structures of 1 and 2 were elucidated on the basis of their spectroscopic data. Compound 1 has previously been reported as a synthetic intermediate and this is the first time that it has been obtained from a natural source.