Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Rearranjo Gênico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Linhagem Celular , Sobrevivência Celular/genética , HumanosRESUMO
BACKGROUND AND OBJECTIVE: Even though herbal medicines have played an important role in disease management and health for many centuries, their present frequent use is challenged by the necessity to determine their complex composition and their multitarget mode of action. In the present study, modern methods were investigated towards their potential in the characterization of herbal substances. As a model the herbal substance Chelidonii herba was used, for which several reports on liver toxicities exist. Extracts of Chelidonii herba with different solvents were characterized phytochemically and functionally by experiments with HepG2 liver cells. METHODS: Chelidonii herba was extracted with four solvents of different polarity (dichloromethane, water, ethanol, and ethanol 50% (V/V); four replicates each). The different extracts were characterized metabolomically by (1)H-NMR fingerprinting analysis and principal component analysis (PCA). The content of alkaloids was additionally determined by RP-HPLC. Functional characterization was achieved by the determination of cell proliferation and by transcriptomics techniques (Whole Genome Gene Expression Microarrays v2, Agilent Technologies) in HepG2 cells after exposure to the different extracts (four experimental replicates each). RESULTS: Based on data from (1)H-NMR fingerprints and RP-HPLC analyses the different extracts showed a divergent composition of constituents depending on the solvent used. HepG2 liver cells responded differentially to the four extracts. Microarray analysis revealed a significant regulation of genes and signal cascades related to biotransformation. Also liver-toxic signal cascades were activated. Neither the activated genes nor the proliferation response could be clearly related to the differing alkaloid content of the extracts. CONCLUSION: Different manufacturing processes lead to different herbal preparations. A systems biology approach combining a metabolomic plant analysis with a functional characterization by gene expression profiling in HepG2 cells is an appropriate strategy to characterize variations in plant extracts. Safety assessments of herbal substances may benefit from such complementary analyses.
Assuntos
Alcaloides/química , Chelidonium/química , Metabolômica , Extratos Vegetais/química , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Perfilação da Expressão Gênica , Células Hep G2 , Humanos , Espectroscopia de Ressonância Magnética , Análise de Sequência com Séries de Oligonucleotídeos , Componentes Aéreos da Planta/química , Plantas Medicinais/químicaRESUMO
Ethnobotanical investigations led to the selection of 19 plant species, used traditionally in Sudan against malaria and other similar tropical diseases, for further studies. Pamianthe peruviana (Amaryllidaceae) exhibited significant activity against a chloroquine-resistant Plasmodium falciparum strain (K1) and a chloroquine-sensitive strain (NF54) with IC(50) values of 0.6 and 1.1 microg/ml, respectively. Additionally, P. peruviana showed considerable activities against Trypanosoma brucei rhodesiense (IC(50) 1.5 microg/ml) and T. cruzi (IC(50) 11.8 microg/ml). The antiplasmodial activity of the different extracts of Salvadora persica (Salvadoraceae) against P. falciparum NF54 strain were found to be 0.6 microg/ml (stems) and 0.7 microg/ml (leaves). Extracts of different parts of Combretum hartmannianum (Combretaceae) possessed significant activity against the chloroquine-sensitive P. falciparum strain (NF54) with IC(50) values of 0.2 microg/ml (bark), 0.4 microg/ml (stem) and 4.3 microg/ml (leaves). Most interestingly, the extracts of the leaves of C. hartmannianum totally inhibited the enzyme HIV-1 reverse transcriptase (HIV-1 RT) at a concentration of 66 microg/ml. A comparably strong activity against p56(lck) tyrosine kinase was also seen for this extract.
Assuntos
Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Bactérias/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Extratos Vegetais/farmacologia , Plantas Medicinais , Tripanossomicidas/farmacologia , Animais , Células HT29 , Humanos , Leishmania donovani/efeitos dos fármacos , SudãoRESUMO
Five sesquiterpene carbonimide dichlorides (1-5) have been isolated from the dichloromethane extract of the Australian sponge Ulosa spongia. The structures of the two new compounds, ulosins A (1) and B (2), were elucidated by employing spectroscopic techniques (NMR, MS, UV, and IR). The chemotaxonomic significance of our data is discussed.
Assuntos
Hidrocarbonetos Clorados/isolamento & purificação , Poríferos/química , Sesquiterpenos/isolamento & purificação , Animais , Austrália , Cromatografia Líquida de Alta Pressão , Hidrocarbonetos Clorados/química , Hidrocarbonetos Clorados/classificação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Poríferos/classificação , Sesquiterpenos/química , Sesquiterpenos/classificação , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
A series of terpene isonitriles, isolated from marine sponges, have previously been shown to exhibit antimalarial activities. Molecular modeling studies employing 3D-QSAR with receptor modeling methodologies performed with these isonitriles showed that the modeled molecules could be used to generate a pharmacophore hypothesis consistent with the experimentally derived biological activities. It was also shown that one of the modeled compounds, diisocyanoadociane (4), as well as axisonitrile-3 (2), both of which have potent antimalarial activity, interacts with heme (FP) by forming a coordination complex with the FP iron. Furthermore, these compounds were shown to inhibit sequestration of FP into beta-hematin and to prevent both the peroxidative and glutathione-mediated destruction of FP under conditions designed to mimic the environment within the malaria parasite. By contrast, two of the modeled diterpene isonitriles, 7-isocyanoamphilecta-11(20),15-diene (12) and 7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene (13), that displayed little antimalarial activity also showed little inhibitory activity in these FP detoxification assays. These studies suggest that the active isonitrile compounds, like the quinoline antimalarials, exert their antiplasmodial activity by preventing FP detoxification. Molecular dynamics simulations performed with diisocyanoadociane (4) and axisonitrile-3 (2) allowed their different binding to FP to be distinguished.
Assuntos
Antimaláricos/química , Heme/química , Nitrilas/química , Poríferos/química , Pirenos/química , Compostos de Espiro/química , Terpenos/química , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Heme/metabolismo , Hemeproteínas/química , Hemeproteínas/metabolismo , Espectrometria de Massas , Modelos Moleculares , Nitrilas/isolamento & purificação , Nitrilas/farmacologia , Oceanos e Mares , Pirenos/farmacologia , Relação Quantitativa Estrutura-Atividade , Compostos de Espiro/farmacologia , Terpenos/isolamento & purificação , Terpenos/farmacologiaRESUMO
From the lipophilic extract of the soft coral Parerythropodium fulvum a new sesquiterpene with an aromadendrane-type carbon skeleton, 3-acetoxyspathulenol (1), was isolated, and the known compounds spathulenol (2) and tridensenone (3) were identified. The structure of the new compound was determined by interpretation of its spectroscopic data, including 1D and 2D (1)H and (13)C NMR (COSY, HMQC, HMBC) and MS.
Assuntos
Cnidários/química , Sesquiterpenos/isolamento & purificação , Animais , Fatores Biológicos/química , Fatores Biológicos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Sesquiterpenos/químicaRESUMO
From the hydrophilic extract of the ascidian Polycarpa aurata three new compounds, N-(4-methoxybenzoyl)-N'-methylguanidine (1), butyl 2-(4-methoxyphenyl)-2-oxoacetate (2), and 2-(4-methoxyphenyl)-N-methyl-2-oxoacetamide (3), together with the known compounds methyl 2-(4-methoxyphenyl)-2-oxoacetate (4) and 4-methoxybenzoic acid were isolated. The structures of all isolates were determined from their spectroscopic data (NMR, MS, IR, UV).
Assuntos
Hidroxibenzoatos/isolamento & purificação , Metilguanidina/isolamento & purificação , Urocordados/química , Acetamidas , Animais , Austrália , Benzamidas , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Cromatografia Gasosa-Espectrometria de Massas , Éteres de Hidroxibenzoatos , Hidroxibenzoatos/química , Espectrometria de Massas , Metilguanidina/análogos & derivados , Metilguanidina/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Éteres Fenílicos , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Relação Estrutura-AtividadeRESUMO
From the green alga Ulva sp., the endophytic and obligate marine fungus Ascochyta salicorniae was isolated. A. salicorniae was mass cultivated and found to produce the unprecedented and structurally unusual tetramic acid containing metabolites ascosalipyrrolidinones A (1) and B (2). Additionally, the new natural product ascosalipyrone (3) and the known metabolites 4 and 5 were obtained. Ascosalipyrrolidinone A (1) has antiplasmodial activity toward Plasmodium falciparum strains K1 and NF 54, as well as showing antimicrobial activity and inhibiting tyrosine kinase p56lck.
Assuntos
Antibacterianos/química , Ascomicetos/química , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Bactérias/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Testes de Sensibilidade Microbiana , Plasmodium falciparum/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/química , Pirróis/isolamento & purificação , Pirróis/farmacologia , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/isolamento & purificação , Tetra-Hidronaftalenos/farmacologia , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação , Tripanossomicidas/farmacologiaRESUMO
From the dichloromethane solubles of the tropical marine sponge Dactylospongia elegans, a new aromatic substituted sesquiterpene, pelorol (1), and the known sesquiterpene, ilimaquinone (2), were isolated. The structures of 1 and 2 were deduced from their spectroscopic data. The biological activities of compounds 1 and 2 were assessed in a variety of bioassays, and both compounds were found to have weak antitrypanosomal and antiplasmodial effects.
Assuntos
Antiprotozoários/isolamento & purificação , Poríferos/química , Quinonas/isolamento & purificação , Sesquiterpenos/isolamento & purificação , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Bioensaio , Cromatografia em Gel , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Cromatografia Gasosa-Espectrometria de Massas , Espectroscopia de Ressonância Magnética , Rotação Ocular , Queensland , Quinonas/química , Quinonas/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
Three distinct samples of the sea hare Aplysia dactylomela from two different locations around Tenerife (Spain) were investigated for their secondary metabolite content. The investigation resulted in the isolation of five new natural products (1, 2, 5-7), a number of compounds known from red algae of the genera Laurencia (4, 8-14) and Plocamium (17-19), and three known sea-hare metabolites (3, 15, 16). This is the first report of monoterpenes (17-19) from A. dactylomela. All structures were determined mainly by spectroscopic methods (1D and 2D NMR, MS, IR). Compounds 11, 14, 15, and 17 demonstrated significant cytotoxicity toward three cancer cell lines (HM02, HEP G2, and MCF 7; IC(50) for 11, 7.0 to <1.0 microg/mL; 14, <1.0 microg/mL; 15, 17 to <1.0 microg/mL; 17, 1.0 to 1.5 microg/mL). Compounds 3, 8, 9, 11, 15, 18, and 19 exhibited activity in a brine shrimp bioassay in the range of 100% lethality within 24 h to 40% after 48 h. Metabolites 11, 14, 15, and 19 showed moderate antimicrobial activities (2-25 mm total/growth inhibition of several organisms), with 19 also being strongly algicidal (MIC 7-11 microg/filter disk).
Assuntos
Aplysia/química , Fatores Biológicos/isolamento & purificação , Animais , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Fatores Biológicos/metabolismo , Fatores Biológicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Análise Espectral , Células Tumorais CultivadasRESUMO
A series of mainly marine derived natural products were tested for their activities against Mycobacterium tuberculosis and M. avium. Of the thirty-nine compounds tested fifteen demonstrated minimum inhibition concentrations (MICs) of 32 micrograms/ml or less, and eleven had MICs of 16 micrograms/ml or less. The most active compound found in this study was the sponge derived metabolite axisonitrile-3 (MIC 2 micrograms/ml).
Assuntos
Antibacterianos/farmacologia , Mycobacterium avium/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Células Cultivadas , Humanos , Testes de Sensibilidade MicrobianaRESUMO
Inhibitors of HIV reverse transcriptase (RT) are important drugs for the treatment of acquired immuno-deficiency syndrome (AIDS). One approach to identify novel inhibitors of HIV-1-RT is the screening of natural compounds. Many natural products have been shown to be active as RT inhibitors. These compounds belong to a wide range of different structural classes, e.g., coumarins, flavonoids, tannins, alkaloids, lignans, terpenes, naphtho- and anthraquinones, and polysaccharides. The life forms from which the bioactive compounds were isolated are as equally diverse and comprise terrestrial and marine plants, micro-organisms, and marine animals. From the most extensive screening effort, carried out by the NCl, calanolide A, isolated from the terrestrial plant Calophyllum lanigerum (Guttiferae), has been discovered as the most interesting natural RT inhibitor. The promise of this natural product probably relates to a novel mechanism of action. The current review describes natural products from various sources that are able to inhibit HIV-RT.
Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Plantas Medicinais , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/isolamento & purificação , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Humanos , Inibidores da Transcriptase Reversa/uso terapêutico , Relação Estrutura-AtividadeRESUMO
From the lipophilic extract of the marine brown alga Stypopodium zonale (Dictyotaceae) the new terpenoid compound stypoquinonic acid (1) together with the known compounds taondiol (2) and atomaric acid (3) were isolated. The structures of all isolates were determined from their spectroscopic data, including 1- and 2-dimensional NMR methods. The new compound, 1, and atomaric acid (3), showed inhibition of tyrosine kinase (p56lck).
Assuntos
Inibidores Enzimáticos/isolamento & purificação , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Naftalenos/isolamento & purificação , Phaeophyceae/química , Quinonas/isolamento & purificação , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Clorófitas/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Contagem de Colônia Microbiana , Inibidores Enzimáticos/farmacologia , Fungos/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Naftalenos/farmacologia , Quinonas/farmacologiaRESUMO
The polyhalogenated monoterpene content of six samples of the tropical marine red alga Plocamium hamatum, collected from the southern, central and northern regions of The Great Barrier Reef, Australia, was assessed. In all but two of the samples, the polyhalogenated monoterpene content was shown to differ markedly. In total, eleven previously reported compounds were isolated and characterised (1-11). Compound 2 was obtained for the first time as a pure natural product. For compound 4 a single crystal X-ray crystallographic analysis was undertaken which established its absolute configuration as (1S,2S,4R,5R,1'E)-2-bromo-1- bromomethyl-1,4-dichloro-5-(2'-chloroethenyl)-5-methylcyclohexa ne. Complete and unambiguous 1H and 13C NMR data are reported for 2 and 4. For 6-8, some prior 13C NMR assignments are revised. The biological activities of compounds 2-8 and 11 were assessed and indicated 4 to have potent antialgal activity towards Chlorella fusca in an agar diffusion bioassay, as well as being moderately antitubercular and cytotoxic. Compound 6 demonstrated moderate cytotoxicity.
Assuntos
Rodófitas/química , Terpenos/química , Terpenos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Antifúngicos/farmacologia , Chlorella/efeitos dos fármacos , Cristalografia por Raios X , Transcriptase Reversa do HIV/antagonistas & inibidores , Ressonância Magnética Nuclear Biomolecular , Fotossíntese/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Rodófitas/metabolismo , Terpenos/metabolismoRESUMO
The 3-hydroxy-3-methylglutaric acid (HMG) containing flavonoid glucoside chamaemeloside, has been determined to have in vivo hypoglycaemic activity comparable to that of free HMG. An improved isolation scheme for obtaining chamaemeloside from Chamaemelum nobile is presented.
Assuntos
Asteraceae/química , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Plantas Medicinais/química , Animais , Glicemia/análise , Linhagem Celular , Teste de Tolerância a Glucose , Glucosídeos/química , Glucosídeos/isolamento & purificação , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Masculino , CamundongosRESUMO
From a Maltese sample of the marine sponge Agelas oroides, five compounds: oroidin (1), 2-cyano-4,5-dibromopyrrole (2), 4,5-dibromopyrrole-2-carboxylic acid (3), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (4), and 4 alpha-methyl-5 alpha-cholest-8-en-3 beta-ol (5) have been isolated. For compounds 1-5, completely assigned 1H- and 13C-NMR data are reported for the first time. For 2 a single crystal X-ray crystallographic analysis proved its structure unambiguously. The X-ray analysis of 2 indicated it to crystallise in an unexpected polar space group. Biological activity assessment of all isolates indicate 5 to have moderate antiplasmodial activity, as well as being cytotoxic, and 2 to be moderately cytotoxic towards several cancer cell lines.
Assuntos
Antimaláricos/isolamento & purificação , Antineoplásicos/isolamento & purificação , Plasmodium/efeitos dos fármacos , Poríferos/química , Animais , Antimaláricos/química , Antineoplásicos/química , Cristalografia por Raios X , Análise EspectralRESUMO
Three new terpenoid metabolites (1-3) were isolated from the CH2Cl2 extract of the soft coral Lobophytum crassum together with the eudesmane derivative 4 and the known cembrane (2S,7S,8S)-sarcophytoxide (5). Compound 1 is a new cembrane-based diterpene with an C7-C8-epoxide and a methyl ester functionality at C-16. (3E,5Z)- (2) and (3Z,5E)-2-methyl-6-(4a'-methyl-8'-methylene-trans-perhydr onaphthalen-2'-yl)hepta-3,5-dien-2-ol (3) represent two new carbon-carbon double bond isomers of 4, which has the 3E,5E-configuration. The structures of 1-5 were established by interpretation of their spectroscopic data, mainly 1D and 2D NMR and MS. Biological activity evaluation of compounds 1 and 5 and the crude extracts was carried out using agar diffusion assays toward microbial targets and ELISA assays for investigating the inhibition of HIV-1 reverse transcriptase and p56lck tyrosine kinase.
Assuntos
Cnidários/química , Diterpenos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Transcriptase Reversa do HIV/antagonistas & inibidores , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Inibidores da Transcriptase Reversa/isolamento & purificação , Animais , Bactérias/efeitos dos fármacos , Diterpenos/farmacologia , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Fungos/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
Bioassay guided fractionation of the lipophilic extract of the marine cyanobacterium Phormidium ectocarpi yielded a new natural product hierridin B and the previously described compound 2,4-dimethoxy-6-heptadecyl-phenol. Both structures were secured by extensive spectroscopic analysis (1D and 2D NMR, MS, GC-MS, IR). The isolate (mixture) showed antiplasmodial activity towards Plasmodium falciparum.
Assuntos
Alcanos/isolamento & purificação , Anisóis/isolamento & purificação , Antimaláricos/isolamento & purificação , Cianobactérias/química , Fenol/isolamento & purificação , Alcanos/química , Alcanos/farmacologia , Anisóis/química , Anisóis/farmacologia , Antimaláricos/farmacologia , Estrutura Molecular , Fenol/química , Fenol/farmacologia , Análise EspectralRESUMO
Further investigation into the natural product chemistry of the tropical marine sponge Agelas oroides has yielded the new compound 2,4,6,6-tetramethyl-3(6 H)-pyridone (1), and 2,2,6,6-tetramethyl-4-piperidone (2). Both compounds are volatile. The structures of 1 and 2 were determined from the interpretation of their 1D and 2D NMR, UV, IR, and mass spectral data.