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1.
Chem Biodivers ; 16(9): e1900266, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31298476

RESUMO

Two new spliceostatin analogs, designed as spliceostatins J and K (1 and 2), were isolated and identified from the culture of Pseudomonas sp., along with two known ones, FR901464 (3) and spliceostatin E (4). Their structures were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS. Spliceostatin J (1) represented the first example of spliceostatins bearing an unusual hexahydrofuro[3,4-b]furan moiety. Biological assay showed all the isolated compounds except 1 displayed potent cytotoxic activities against two cancer cell lines (MDA-MB-231 and A-549). Structure-activity-relationship studies revealed that the tetrahydropyran ring in spliceostatin analogs was necessary for their bioactive retention.


Assuntos
Antineoplásicos/farmacologia , Furanos/farmacologia , Lactonas/farmacologia , Pseudomonas/química , Pironas/farmacologia , Células A549 , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Furanos/isolamento & purificação , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Estrutura Molecular , Piranos/química , Piranos/isolamento & purificação , Piranos/farmacologia , Pironas/química , Pironas/isolamento & purificação , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
2.
Phytochemistry ; 164: 236-242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31185420

RESUMO

Mangiterpenes A-C and 2',3'-seco-manginoid C, four undescribed sesquiterpene/monoterpene-shikimate-conjugated meroterpenoids with spiro ring systems, were isolated from Guignardia mangiferae. The structures and absolute configurations of these compounds were established by comprehensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Mangiterpenes A-C represent the first examples of sesquiterpene-shikimate-conjugated spirocyclic meroterpenoids, and 2',3'-seco-manginoid C features an unexpected 2',3'-seco-manginoids skeleton. Mangiterpene C strongly inhibited the production of NO inducted by LPS, with an IC50 value of 5.97 µM. It showed an anti-inflammatory effect by means of blocking in the NF-κB signaling pathway and decreasing the expression of inflammatory mediators.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Monoterpenos/farmacologia , Ácido Chiquímico/farmacologia , Compostos de Espiro/farmacologia , Terpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Monoterpenos/química , Monoterpenos/isolamento & purificação , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Ácido Chiquímico/química , Ácido Chiquímico/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação
3.
Phytochemistry ; 165: 112041, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203103

RESUMO

Spiroterreusnoids A-F, six undescribed spiro-dioxolane-containing adducts bearing 3,5-dimethylorsellinic acid-based meroterpenoid and 2,3-butanediol moieties were isolated from the endophytic fungus Aspergillus terreus Thom from Tripterygium wilfordii Hook. f. (Celastraceae). The structures of these adducts were established by spectroscopy, single-crystal X-ray diffraction, and experimental electronic circular dichroism (ECD) measurements. Spiroterreusnoids A-F represent the first examples of adducts composed of 3,5-dimethylorsellinic acid-based meroterpenoids. It is noteworthy that spiroterreusnoids A-F possessing a spiro-dioxolane moiety exhibited potential abilities in inhibiting BACE1 (IC50 values ranging from 5.86 to 27.16 µM) and AchE (IC50 values ranging from 22.18 to 32.51 µM), while the other analogues without this fragment displayed no such activities. Taken together, spiroterreusnoids A-F represent the first multitargeted natural adducts that could inhibit BACE1 and AchE, and might provide a new template for the development of new anti-Alzheimer's disease drugs.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Dioxolanos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos de Espiro/farmacologia , Terpenos/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Aspergillus/química , Celastraceae/microbiologia , Dioxolanos/química , Dioxolanos/isolamento & purificação , Enguias , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Terpenos/química , Terpenos/isolamento & purificação
4.
Food Chem ; 294: 104-111, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31126442

RESUMO

Magnetic solid-phase extraction (MSPE), using a new reversed-phase/weak anion exchange mix-mode mesoporous magnetic SiO2 adsorbent, was assessed as an approach for reducing matrix effects in the analysis of six lipophilic marine biotoxins in shellfish using ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The adsorbent showed greater adsorption capacity and selectivity for the analytes and, thus, the MSPE microspheres reduced the matrix effects significantly in the subsequent analysis. In the UPLC-MS/MS analysis, precursor and product ions of the analytes were monitored quantitatively and qualitatively using multiple reaction monitoring and product ion confirmation modes. The proposed method exhibited a linear correlation of 0.9980-0.9991 in the working range for azaspiracids (2.0-200.0 ng/mL) and okadaic acid and its derivatives dinophysistoxins (4.0-200.0 ng/mL) with satisfactory recoveries (82.8-118.6%, RSD < 12%), lower LODs (0.4-1.0 µg/kg) and LOQs (1.0-4.0 µg/kg) than existing methods. In addition, consumption of the adsorbent was reduced, and the MSPE operation is simple and rapid relative to alternatives. These results suggest the proposed method has potential for use in the analysis of lipophilic marine biotoxins in shellfish samples.


Assuntos
Cromatografia Líquida de Alta Pressão , Magnetismo , Toxinas Marinhas/análise , Microesferas , Ácido Okadáico/análise , Compostos de Espiro/análise , Espectrometria de Massas em Tandem , Óxido Ferroso-Férrico/química , Limite de Detecção , Toxinas Marinhas/isolamento & purificação , Ácido Okadáico/isolamento & purificação , Porosidade , Frutos do Mar/análise , Dióxido de Silício/química , Extração em Fase Sólida , Compostos de Espiro/isolamento & purificação
5.
Fitoterapia ; 135: 5-8, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30914329

RESUMO

Two new spiroketal derivatives with an unprecedented amino group, 2'-aminodechloromaldoxin (1) and 2'-aminodechlorogeodoxin (2), along with one known analogue dechloromaldoxin (3), were isolated from the plant endophytic fungus Pestalotiopsis flavidula. Their structures were elucidated on the basis of extensive spectroscopic analysis. The purification was cytotoxicity-guided which indicated the extract, fractions and compounds were evaluated in vitro for anti-proliferative activity against a panel of human cancer cell lines. The results showed compounds 1 and 2 with moderate cytotoxicity while 3 was inactive, which suggested -NH2 group might play a very important role for their cytotoxicity. This is the first study for P. flavidula and the first time to report the spiroketal derivatives as alkaloids from the Pestalotiopsis genus.


Assuntos
Alcaloides/farmacologia , Furanos/farmacologia , Compostos de Espiro/farmacologia , Xylariales/química , Alcaloides/química , Alcaloides/isolamento & purificação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Furanos/química , Furanos/isolamento & purificação , Humanos , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação
6.
Org Biomol Chem ; 17(8): 2182-2186, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30720839

RESUMO

Versispiroketal A (1), an unprecedented 6/5/5/6 tetracyclic polyketide featuring a rarely encountered bridge-fused spiroketal skeleton, was isolated from the sponge-associated fungus Aspergillus versicolor SCSIO 41013. The structure and absolute configuration of 1 were unequivocally determined by comprehensive spectroscopic analysis, single-crystal X-ray diffraction analysis and quantum chemical ECD calculations. Compound 1 showed weak cytotoxicity against four cancer cell lines. A plausible biosynthetic pathway for 1 was also postulated.


Assuntos
Aspergillus/química , Furanos/química , Poríferos/microbiologia , Compostos de Espiro/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Furanos/isolamento & purificação , Furanos/farmacologia , Humanos , Modelos Moleculares , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia
7.
Nat Prod Res ; 33(3): 386-392, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29569484

RESUMO

Two new phenylspirodrimanes, stachybotrin H (1) and stachybotrysin H (9) together with eleven known analogues (2-8, 10-13) were isolated from deep-sea derived Stachybotrys sp. MCCC 3A00409. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Compounds 9-12 showed weak cytotoxicity against three human cancer cell lines K562, Hela and HL60 with IC50 in the range of 18.5-52.8 µM.


Assuntos
Stachybotrys/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Análise Espectral , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação
8.
Org Biomol Chem ; 16(48): 9430-9439, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30511067

RESUMO

Four pairs of new spiropyrrolizidine oxindole enantiomers (1a/1b-4a/4b) were isolated from the leaves of Isatis indigotica Fortune. Their structures and absolute configurations were elucidated by a combination of NMR spectroscopic analyses, experimental and calculated electronic circular dichroism (ECD) and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Notably, all the isolated spiropyrrolizidine oxindoles are reported as natural products for the first time. The biosynthetic pathway of these unique structures was proposed to be formed by cycloaddition reaction. In addition, all the compounds were evaluated for their inhibitory effects on ß-amyloid aggregation by ThT assay, and the optically pure compounds 1a/1b and 2a/2b exhibited better Aß1-42 aggregation inhibition potency (85.8% and 73.6%, 71.5% and 75.8%, respectively) at a concentration of 20 µM, compared with the positive control curcumin (57.0%). The difference of the inhibitory pattern caused by chirality was also explained by molecular docking studies.


Assuntos
Isatis/química , Oxindois/química , Alcaloides de Pirrolizidina/química , Compostos de Espiro/química , Peptídeos beta-Amiloides/metabolismo , Humanos , Simulação de Acoplamento Molecular , Oxindois/isolamento & purificação , Oxindois/farmacologia , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Alcaloides de Pirrolizidina/isolamento & purificação , Alcaloides de Pirrolizidina/farmacologia , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Estereoisomerismo
9.
Mar Drugs ; 16(11)2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30441860

RESUMO

Cyclic imine toxins are neurotoxic, macrocyclic compounds produced by marine dinoflagellates. Mass spectrometric screenings of extracts from natural plankton assemblages revealed a high chemical diversity among this toxin class, yet only few toxins are structurally known. Here we report the structural characterization of four novel cyclic-imine toxins (two gymnodimines (GYMs) and two spirolides (SPXs)) from cultures of Alexandrium ostenfeldii. A GYM with m/z 510 (1) was identified as 16-desmethylGYM D. A GYM with m/z 526 was identified as the hydroxylated degradation product of (1) with an exocyclic methylene at C-17 and an allylic hydroxyl group at C-18. This compound was named GYM E (2). We further identified a SPX with m/z 694 as 20-hydroxy-13,19-didesmethylSPX C (10) and a SPX with m/z 696 as 20-hydroxy-13,19-didesmethylSPX D (11). This is the first report of GYMs without a methyl group at ring D and SPXs with hydroxyl groups at position C-20. These compounds can be conceived as derivatives of the same nascent polyketide chain, supporting the hypothesis that GYMs and SPXs are produced through common biosynthetic genes. Both novel GYMs 1 and 2 were detected in significant amounts in extracts from natural plankton assemblages (1: 447 pg; 2: 1250 pg; 11: 40 pg per mL filtered seawater respectively).


Assuntos
Dinoflagelados/química , Compostos Heterocíclicos com 3 Anéis/química , Hidrocarbonetos Cíclicos/química , Iminas/química , Toxinas Marinhas/química , Fitoplâncton/química , Compostos de Espiro/química , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Hidrocarbonetos Cíclicos/isolamento & purificação , Iminas/isolamento & purificação , Toxinas Marinhas/isolamento & purificação , Estrutura Molecular , Compostos de Espiro/isolamento & purificação
10.
Mar Drugs ; 16(12)2018 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-30477099

RESUMO

Two new bromotyrosine alkaloids, ceratinadins E (1) and F (2), were isolated from an Okinawan marine sponge Pseudoceratina sp. as well as a known bromotyrosine alkaloid, psammaplysin F (3). The gross structures of 1 and 2 were elucidated on the basis of spectroscopic data. The absolute configurations of 1 and 2 were assigned by comparison of the NMR and ECD data with those of a known related bromotyrosine alkaloid, psammaplysin A (4). Ceratinadins E (1) and F (2) are new bromotyrosine alkaloids possessing an 8,10-dibromo-9-methoxy-1,6-dioxa-2-azaspiro[4.6]undeca-2,7,9-trien-4-ol unit with two or three 11-N-methylmoloka'iamine units connected by carbonyl groups, respectively. Ceratinadin E (1) exhibited antimalarial activities against a drug-resistant and a drug-sensitive strains of Plasmodium falciparum (K1 and FCR3 strains, respectively).


Assuntos
Alcaloides/farmacologia , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Poríferos , Tirosina/análogos & derivados , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Antimaláricos/química , Antimaláricos/isolamento & purificação , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Tirosina/química , Tirosina/isolamento & purificação , Tirosina/farmacologia
11.
Org Lett ; 20(22): 7341-7344, 2018 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-30394758

RESUMO

Purpurolide A (1), an unprecedent sesquiterpene lactone with a rarely encountered 5/5/5 spirocyclic skeleton, along with two new 6/4/5/5 tetracyclic sesquiterpene lactones (2 and 3), were isolated from the cultures of the endophytic fungus Penicillium purpurogenum IMM003. The structures and absolute configurations of 1-3 were established by spectroscopic analysis, single-crystal X-ray diffraction, and calculations of the 13C NMR and ECD data. Compounds 1-3 showed significant inhibitory activity against pancreatic lipase.


Assuntos
Inibidores Enzimáticos/isolamento & purificação , Lactonas/isolamento & purificação , Penicillium/metabolismo , Sesquiterpenos/isolamento & purificação , Compostos de Espiro/isolamento & purificação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lactonas/química , Lactonas/farmacologia , Lipase/antagonistas & inibidores , Estrutura Molecular , Penicillium/isolamento & purificação , Folhas de Planta/microbiologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Thymelaeaceae/microbiologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-30189375

RESUMO

Papaver species, well known for their alkaloids, have been used for the treatment of several diseases, such as inflammation, diarrhea, depression, and sleep disorders in certain parts of Anatolia. In this study, four Papaver species (P. lacerum, P. syriacum, P. glaucum and P. rhoeas) were collected from different localities of Turkey. Methanolic extracts were prepared from the aerial parts of the plants. A rapid analytical method was developed for the simultaneously quantitative analysis of two alkaloids, pronuciferine and roemerine, using liquid chromatography tandem mass spectrometry. Multiple reaction monitoring in the positive ionization mode was used for detection. Pronuciferine and roemerine were analyzed on a C18 column (2.1 × 50 mm, 3 µm) with the mobile phase run in the gradient mode with 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile at a flow rate of 0.3 mL/min. The transitions 312.1→283.1 m/z and 280.0→249.0 m/z were used to monitor pronuciferine and roemerine, respectively. The assay was linear in the concentration range of 0.01 µg/mL to 1 µg/mL (r = 0.996 for roemerine, r = 0.998 for pronuciferine). The validation studies revealed that the method was linear, sensitive, accurate, precise, selective, repeatable, robust, and rugged. Finally, the developed method was applied to quantify pronuciferine and roemerine in the selected species. The amounts of pronuciferine and roemerine were respectively found as 8.5 to 48 µg/g and 4.4 to 43,000 µg/g.


Assuntos
Alcaloides/análise , Cromatografia Líquida/métodos , Papaver/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Compostos de Espiro/análise , Alcaloides/química , Alcaloides/isolamento & purificação , Limite de Detecção , Modelos Lineares , Extratos Vegetais/química , Reprodutibilidade dos Testes , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Espectrometria de Massas em Tandem/métodos
13.
Electrophoresis ; 39(17): 2195-2201, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29947080

RESUMO

A sensitive, fast, and effective method, field-amplified sample stacking (FASS) in capillary electrophoresis, has been established for the separation and determination of corynoxine and corynoxine B. Hydroxypropyl-ß-CD (HP-ß-CD) and tetrabutylammonium-L-glutamic acid (TBA-L-Glu) were used as additives in the separation system. Electrokinetic injection was chosen to introduce sample from inlet at 10 kV for 50 s after a water plug (0.5 psi, 4 s) was injected to permit FASS. The running buffer (pH 6.1) was composed of 40 mM sodium dihydrogen phosphate solution, 130 mM HP-ß-CD, and 10 mM TBA-L-Glu and the separation voltage was 20 kV. Under the optimum conditions, corynoxine and corynoxine B were successfully enriched and separated within 12 min and the sensitivity was improved approximately by 700-900 folds. Calibration curves were in a good linear relationship within the range of 62.5-5.00 × 103  ng/mL for both corynoxine and corynoxine B. The limits of detection (S/N = 3) and quantitation (S/N = 10) were 14.9, 45.2 ng/mL for corynoxine and 11.2, 34.5 ng/mL for corynoxine B, respectively. Finally, this method was successfully applied for the determination of corynoxine and corynoxine B in the stems with hooks of Uncaria rhynchophylla and its formulations.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Eletroforese Capilar/métodos , Indóis/análise , Compostos de Espiro/análise , Concentração de Íons de Hidrogênio , Indóis/isolamento & purificação , Líquidos Iônicos/química , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Compostos de Espiro/isolamento & purificação , Estereoisomerismo
14.
Bioorg Chem ; 80: 216-222, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29957490

RESUMO

Lambertellin (1) and ergosta-5,7,22-trien-3-ol (2) were isolated from the solid rice fermentation of the plant pathogenic fungus Pycnoporus sanguineus MUCL 51321. Their structures were elucidated using comprehensive spectroscopic methods. The isolated compounds were tested on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. Lambertellin (1) exhibited promising inhibitory activity against nitric oxide (NO) production with IC50 value of 3.19 µM, and it significantly inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2). Lambertellin (1) also decreased the expression of pro-inflammatory cytokines IL-6 and IL-1ß. The study of the mechanistic pathways revealed that lambertellin (1) exerts its anti-inflammatory effect in LPS-stimulated RAW 264.7 macrophage cells by modulating the activation of the mitogen activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. Therefore, lambertellin (1) could be a promising lead compound for the development of new anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Naftalenos/química , Pycnoporus/química , Compostos de Espiro/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Naftalenos/isolamento & purificação , Naftalenos/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Pycnoporus/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia
15.
Phytochemistry ; 153: 138-146, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29929080

RESUMO

Four undescribed 23,24-O-isopropylidene-19(18 → 17)-abeo-28-noroleanane-derived spirocyclic triterpenoids and an undescribed 28-noroleanane-derived spirocyclic triterpenoid, together with five known 28-noroleanane-derived spirocyclic triterpenoids, were isolated and identified. In addition, three undescribed iridoid glucosides and four known ones were also identified. All the isolates were identified using spectroscopic techniques, and the absolute configurations of 28-noroleanane-derived spirocyclic triterpenoids were determined by CD method for the first time. Additionally, the alkaline hydrolysis method and HPLC analysis were applied to confirm the moieties of the iridoid glucosides. The fraction and isolates were evaluated for cytotoxic activity on cervical cancer (Hela), human promyelocytic leukemia (HL-60), and breast cancer (MCF-7) cell lines. Among them, phlomisu E possessed an aldehyde group showed the most potent cytotoxic effect with IC50 value less than 10 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Glucosídeos Iridoides/farmacologia , Lamiaceae/química , Raízes de Plantas/química , Compostos de Espiro/farmacologia , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Células HeLa , Humanos , Glucosídeos Iridoides/química , Glucosídeos Iridoides/isolamento & purificação , Células MCF-7 , Conformação Molecular , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificação
16.
Biomed Pharmacother ; 99: 697-703, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29710467

RESUMO

This study aimed to investigate the potential effect of plumieride, an iridoid glycoside isolated from Alamanda cathartica L. flowers, against dextran sulfate sodium (DSS)-induced colitis in mice. Colitis was induced in female swiss mice by adding DSS 3% to the drinking water. The animals were treated with vehicle (water), 5-aminosalicylic acid (100?mg/kg) or plumieride (10, 30 and 100?mg/kg) once a day, during 7 days. The body weight progression and the disease activity index was evaluated daily. On the eighth day, colons were collected for the measurement of the size, histological, histochemical, biochemical and inflammatory analysis. The cytotoxicity of plumieride on intestinal epithelial cell (IEC-6 cell line) was also evaluated. Plumieride, at dose of 100?mg/kg, significantly attenuated the mice weight loss, showed lower score in the disease activity index, diminished the colon shortening, improved the histological damage and avoided mucosa intestinal mucus depletion when compared with vehicle-treated only group. Moreover, plumieride was able to reduce the amount of colonic lipid hydroperoxides, while augmented reduced glutathione levels and superoxide dismutase activity. Although DSS intake stimulated an increase in myeloperoxidase activity and in tumor necrosis factor content on the colon tissue of the vehicle-treated group, the colons obtained from mice treated with plumieride did not present any of these changes. Taking together, the results of the present study disclose that plumieride exhibited a significant efficacy in attenuating the parameters of experimental ulcerative colitis, which may be mediated by an antioxidant and anti-inflammatory effect.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Colite/tratamento farmacológico , Furanos/farmacologia , Compostos de Espiro/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/administração & dosagem , Antioxidantes/isolamento & purificação , Apocynaceae/química , Linhagem Celular , Colite/patologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Furanos/administração & dosagem , Furanos/isolamento & purificação , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mesalamina/farmacologia , Camundongos , Ratos , Compostos de Espiro/administração & dosagem , Compostos de Espiro/isolamento & purificação , Fator de Necrose Tumoral alfa/metabolismo
17.
ACS Chem Neurosci ; 9(7): 1652-1662, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29672015

RESUMO

In search for novel antiseizure drugs (ASDs), the European FP7-funded PharmaSea project used zebrafish embryos and larvae as a drug discovery platform to screen marine natural products to identify promising antiseizure hits in vivo for further development. Within the framework of this project, seven known heterospirocyclic γ-lactams, namely, pseurotin A, pseurotin A2, pseurotin F1, 11- O-methylpseurotin A, pseurotin D, azaspirofuran A, and azaspirofuran B, were isolated from the bioactive marine fungus Aspergillus fumigatus, and their antiseizure activity was evaluated in the larval zebrafish pentylenetetrazole (PTZ) seizure model. Pseurotin A2 and azaspirofuran A were identified as antiseizure hits, while their close chemical analogues were inactive. Besides, electrophysiological analysis from the zebrafish midbrain demonstrated that pseurotin A2 and azaspirofuran A also ameliorate PTZ-induced epileptiform discharges. Next, to determine whether these findings translate to mammalians, both compounds were analyzed in the mouse 6 Hz (44 mA) psychomotor seizure model. They lowered the seizure duration dose-dependently, thereby confirming their antiseizure properties and suggesting activity against drug-resistant seizures. Finally, in a thorough ADMET assessment, pseurotin A2 and azaspirofuran A were found to be drug-like. Based on the prominent antiseizure activity in both species and the drug-likeness, we propose pseurotin A2 and azaspirofuran A as lead compounds that are worth further investigation for the treatment of epileptic seizures. This study not only provides the first evidence of antiseizure activity of pseurotins and azaspirofurans, but also demonstrates the value of the zebrafish model in (marine) natural product drug discovery in general, and for ASD discovery in particular.


Assuntos
Anticonvulsivantes/farmacologia , Lactamas/farmacologia , Pirrolidinonas/farmacologia , Compostos de Espiro/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/isolamento & purificação , Aspergillus fumigatus , Encéfalo/efeitos dos fármacos , Linhagem Celular , Descoberta de Drogas , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Estimulação Elétrica , Humanos , Oceano Índico , Lactamas/química , Lactamas/isolamento & purificação , Masculino , Camundongos , Estrutura Molecular , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Distribuição Aleatória , Convulsões/tratamento farmacológico , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Peixe-Zebra
18.
BMC Biotechnol ; 18(1): 22, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29642881

RESUMO

BACKGROUND: Violacein is a deep violet compound that is produced by a number of bacterial species. It is synthesized from tryptophan by a pathway that involves the sequential action of 5 different enzymes (encoded by genes vioA to vioE). Violacein has antibacterial, antiparasitic, and antiviral activities, and also has the potential of inducing apoptosis in certain cancer cells. RESULTS: Here, we describe the construction of a series of plasmids harboring the complete or partial violacein biosynthesis operon and their use to enable production of violacein and deoxyviolacein in E.coli. We performed in vitro assays to determine the biological activity of these compounds against Plasmodium, Trypanosoma, and mammalian cells. We found that, while deoxyviolacein has a lower activity against parasites than violacein, its toxicity to mammalian cells is insignificant compared to that of violacein. CONCLUSIONS: We constructed E. coli strains capable of producing biologically active violacein and related compounds, and propose that deoxyviolacein might be a useful starting compound for the development of antiparasite drugs.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Alcaloides Indólicos/farmacologia , Indóis/farmacologia , Compostos de Espiro/farmacologia , Tripanossomicidas/farmacologia , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/metabolismo , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Células COS , Escherichia coli/genética , Células Hep G2 , Humanos , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/metabolismo , Indóis/isolamento & purificação , Indóis/metabolismo , Engenharia Metabólica , Óperon , Plasmídeos/genética , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/metabolismo , Tripanossomicidas/isolamento & purificação , Tripanossomicidas/metabolismo , Trypanosoma cruzi/efeitos dos fármacos
19.
J Nat Prod ; 81(4): 785-790, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29488766

RESUMO

Cyclopiamines C (1) and D (2) were isolated from the extract of Penicillium sp. CML 3020, a fungus sourced from an Atlantic Forest soil sample. Their structures and relative configuration were determined by 1D and 2D NMR, HRMS, and UV/vis data analysis. Cyclopiamines C and D belong to a small subset of rare spiroindolinone compounds containing an alkyl nitro group and a 4,5-dihydro-1 H-pyrrolo[3,2,1- ij]quinoline-2,6-dione ring system. NMR and MS/HRMS data confirmed the presence of an epoxide unit (C-17-O-C-18) and a hydroxy group at C-5, not observed for their known congeners. Cytotoxic and antimicrobial activities were evaluated.


Assuntos
Antibacterianos/química , Compostos de Epóxi/química , Alcaloides Indólicos/química , Penicillium/química , Compostos de Espiro/química , Antibacterianos/isolamento & purificação , Compostos de Epóxi/isolamento & purificação , Alcaloides Indólicos/isolamento & purificação , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Compostos de Espiro/isolamento & purificação
20.
J Agric Food Chem ; 66(11): 2962-2969, 2018 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-29502403

RESUMO

Azaspiracids belong to a family of more than 50 polyether toxins originating from marine dinoflagellates such as Azadinium spinosum. All of the azaspiracids reported thus far contain a 21,22-dihydroxy group. Boric acid gel can bind selectively to compounds containing vic-diols or α-hydroxycarboxylic acids via formation of reversible boronate complexes. Here we report use of the gel to selectively capture and release azaspiracids from extracts of blue mussels. Analysis of the extracts and fractions by liquid chromatography-tandem mass spectrometry (LC-MS) showed that this procedure resulted in an excellent cleanup of the azaspiracids in the extract. Analysis by enzyme-linked immunoasorbent assay (ELISA) and LC-MS indicated that most azaspiracid analogues were recovered in good yield by this procedure. The capacity of boric acid gel for azaspiracids was at least 50 µg/g, making this procedure suitable for use in the early stages of preparative purification of azaspiracids. In addition to its potential for concentration of dilute samples, the extensive cleanup provided by boric acid gel fractionation of azaspiracids in mussel samples almost eliminated matrix effects during subsequent LC-MS and could be expected to reduce matrix effects during ELISA analysis. The method may therefore prove useful for quantitative analysis of azaspiracids as part of monitoring programs. Although LC-MS data showed that okadaic acid analogues also bound to the gel, this was much less efficient than for azaspiracids under the conditions used. The boric acid gel methodology is potentially applicable to other important groups of natural toxins containing diols including ciguatoxins, palytoxins, pectenotoxins, tetrodotoxin, trichothecenes, and toxin glycosides.


Assuntos
Ácidos Bóricos/química , Toxinas Marinhas/isolamento & purificação , Mytilus edulis/química , Frutos do Mar/análise , Extração em Fase Sólida/métodos , Compostos de Espiro/isolamento & purificação , Adsorção , Animais , Cromatografia Líquida , Dinoflagelados/química , Géis/química , Toxinas Marinhas/química , Extração em Fase Sólida/instrumentação , Compostos de Espiro/química , Espectrometria de Massas em Tandem
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