RESUMO
Marinobazzanan (1), a new bazzanane-type sesquiterpenoid, was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was elucidated using NMR and mass spectroscopic data, while the relative configurations were established through the analysis of NOESY data. The absolute configurations of 1 were determined by the modified Mosher's method as well as vibrational circular dichroism (VCD) spectra calculation and it was determined as 6R, 7R, 9R, and 10R. It was found that compound 1 was not cytotoxic to human cancer cells, including A549 (lung cancer), AGS (gastric cancer), and Caco-2 (colorectal cancer) below the concentration of 25 µM. However, compound 1 was shown to significantly decrease cancer-cell migration and invasion and soft-agar colony-formation ability at concentrations ranging from 1 to 5 µM by downregulating the expression level of KITENIN and upregulating the expression level of KAI1. Compound 1 suppressed ß-catenin-mediated TOPFLASH activity and its downstream targets in AGS, A549, and Caco-2 and slightly suppressed the Notch signal pathway in three cancer cells. Furthermore, 1 also reduced the number of metastatic nodules in an intraperitoneal xenograft mouse model.
Assuntos
Antineoplásicos , Sesquiterpenos , Humanos , Animais , Camundongos , Células CACO-2 , Transformação Celular Neoplásica , Antineoplásicos/química , Movimento Celular , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Estrutura MolecularRESUMO
The chemical examination of two undescribed marine actinobacteria has yielded three rare merosesterterpenoids, marinoterpins A-C (1-3, respectively). These compounds were isolated from the culture broth extracts of two marine-derived actinomycetes associated with the family Streptomycetaceae, (our strains were CNQ-253 and AJS-327). The structures of the new compounds were determined by extensive interpretation of 1D and 2D NMR, MS, and combined spectroscopic data. These compounds represent new chemical motifs, combining quinoline-N-oxides with a linear sesterterpenoid side chain. Additionally, consistent in all three metabolites is the rare occurrence of two five-ring ethers, which were derived from an apparent cyclization of methyl group carbons to adjacent hydroxy-bearing methylene groups in the sesterterpenoid side chain. Genome scanning of AJS-327 allowed for the identification of the marinoterpin (mrt) biosynthetic cluster, which consists of 16 open-reading frames that code for a sesterterpene pyrophosphate synthase, prenyltransferase, type II polyketide synthase, anthranilate:CoA-ligase, and several tailoring enzymes apparently responsible for installing the N-oxide and bis-tetrahydrofuran ring motifs.
Assuntos
Actinobacteria , Streptomycetaceae , CiclizaçãoRESUMO
Acremonamide (1) was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was established using MS, UV, and NMR spectroscopic data analyses. Acremonamide (1) was found to contain N-Me-Phe, N-Me-Ala, Val, Phe, and 2-hydroxyisovaleric acid. The absolute configurations of the four aforementioned amino acids were determined through acid hydrolysis followed by the advanced Marfey's method, whereas the absolute configuration of 2-hydroxyisovaleric acid was determined through GC-MS analysis after formation of the O-pentafluoropropionylated derivative of the (-)-menthyl ester of 2-hydroxyisovaleric acid. As an intrinsic biological activity, acremonamide (1) did not exert cytotoxicity to cancer and noncancer cells and increased the migration and invasion. Based on these activities, the wound healing properties of acremonamide (1) were confirmed in vitro and in vivo.
Assuntos
Acremonium/química , Peptídeos Cíclicos/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Organismos Aquáticos/química , Células CACO-2 , Células HaCaT , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Células NIH 3T3 , Peptídeos Cíclicos/isolamento & purificaçãoRESUMO
Six cytotoxic and antimicrobial metabolites of a new bromo-phenazinone class, the marinocyanins A-F (1-6), were isolated together with the known bacterial metabolites 2-bromo-1-hydroxyphenazine (7), lavanducyanin (8, WS-9659A) and its chlorinated analog WS-9659B (9). These metabolites were purified by bioassay-guided fractionation of the extracts of our MAR4 marine actinomycete strains CNS-284 and CNY-960. The structures of the new compounds were determined by detailed spectroscopic methods and marinocyanin A (1) was confirmed by crystallographic methods. The marinocyanins represent the first bromo-phenazinones with an N-isoprenoid substituent in the skeleton. Marinocyanins A-F show strong to weak cytotoxicity against HCT-116 human colon carcinoma and possess modest antimicrobial activities against Staphylococcus aureus and amphotericin-resistant Candida albicans.
RESUMO
Two new (1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC50 values of 4.1, 24.2, and 16.3 µM, respectively) and LPS-induced nitric oxide production (IC50 values of >48.6, 15.1, and 8.0 µM, respectively). PGE2 production was blocked with greater efficacy (IC50 values of 7.5, 0.89, and 0.63 µM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects.
Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos/isolamento & purificação , Anticarcinógenos/farmacologia , Organismos Aquáticos/metabolismo , Fenazinas/isolamento & purificação , Fenazinas/farmacologia , Streptomyces/metabolismo , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacologia , Anticarcinógenos/química , Anticarcinógenos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Transformada , Descoberta de Drogas , Fermentação , Fase G1/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Concentração Inibidora 50 , Leucemia Promielocítica Aguda/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Fenazinas/química , Fenazinas/metabolismoRESUMO
Spliceostatin C (SPC) is a component of a bioherbicide isolated from the soil bacterium Burkholderia rinojensis. The chemical structure of SPC closely resembles spliceostatin A (SPA) which was characterized as an anticancer agent and splicing inhibitor. SPC inhibited the growth of Arabidopsis thaliana seedlings with an IC50 value of 2.2 µM. The seedlings exposed to SPC displayed a significant response with decreased root length and number and inhibition of gravitropism. Reverse transcriptase semi-quantitative PCR (RT-sqPCR) analyses of 19 selected genes demonstrated the active impact of SPC on the quality and quantity of transcripts that underwent intron rearrangements as well as up or down expression upon exposure to SPC. Qualitative and quantitative proteomic profiles identified 66 proteins that were significantly affected by SPC treatment. Further proteomics data analysis revealed that spliceostatin C induces hormone-related responses in Arabidopsis seedlings. In silico binding studies showed that SPC binds to a pocket between the SF3B3 and PF5A of the spliceosome.
RESUMO
Three new cyclohexadepsipeptides, arenamides A-C (1-3), were isolated from the fermentation broth of a marine bacterial strain identified as Salinispora arenicola. The planar structures of these compounds were assigned by detailed interpretation of NMR and MS/MS spectroscopic data. The absolute configurations of the amino acids, and those of the chiral centers on the side chain, were established by application of the Marfey and modified Mosher methods. The effect of arenamides A and B on NFkappaB activity was studied with stably transfected 293/NFkappaB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor (TNF). Arenamides A (1) and B (2) blocked TNF-induced activation in a dose- and time-dependent manner with IC(50) values of 3.7 and 1.7 microM, respectively. In addition, the compounds inhibited nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production with lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Moderate cytotoxicity was observed with the human colon carcinoma cell line HCT-116, but no cytotoxic effect was noted with cultured RAW cells. Taken together, these data suggest that the chemoprevention and anti-inflammatory characteristics of arenamides A and B warrant further investigation.
Assuntos
Actinobacteria/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Depsipeptídeos/isolamento & purificação , Depsipeptídeos/farmacologia , NF-kappa B/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Anti-Inflamatórios não Esteroides/química , Depsipeptídeos/química , Dinoprostona/antagonistas & inibidores , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Concentração Inibidora 50 , Rim/citologia , Rim/efeitos dos fármacos , Rim/embriologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Biologia Marinha , Camundongos , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Ressonância Magnética Nuclear Biomolecular , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
A new shunt in the phenylalanine biosynthetic pathway to the nonproteinogenic amino acid L-3-cyclohex-2'-enylalanine was exploited in the marine bacterium Salinispora tropica by mutagenesis to allow for the genetic engineering of unnatural derivatives of the potent proteasome inhibitor salinosporamide A (2) such as antiprotealide (1).
Assuntos
Lactamas/química , Lactamas/metabolismo , Lactonas/química , Lactonas/metabolismo , Micromonosporaceae/genética , Inibidores de Proteases/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Engenharia de Proteínas , Pirróis/metabolismo , Estrutura Molecular , Inibidores de Proteases/química , Pirróis/químicaRESUMO
Chemical investigation of the culture broth extracts of the marine-derived fungus Massarina sp. (strain CNT-016) has yielded two secondary metabolites, spiromassaritone (1) and massariphenone (2), as well as the previously reported fungal metabolites 6-epi-5'-hydroxy-mycosporulone (3) and enalin A (4). The structures of these compounds were established by a variety of one- and two-dimensional NMR experiments, while the relative configuration of spiromassaritone (1) was determined by X-ray crystallographic methods. The fungal strain was isolated as a sterile mycelium from an ocean mud sample and identified using ITS sequence analysis.
Assuntos
Ascomicetos/metabolismo , Derivados de Benzeno/química , Cicloexanonas/química , Cetonas/química , Fenóis/química , Ascomicetos/classificação , Derivados de Benzeno/isolamento & purificação , Derivados de Benzeno/metabolismo , Cristalografia por Raios X , Cicloexanonas/isolamento & purificação , Cicloexanonas/metabolismo , Cetonas/isolamento & purificação , Cetonas/metabolismo , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Fenóis/isolamento & purificação , Fenóis/metabolismo , Filogenia , Compostos de EspiroRESUMO
Sarmentine, 1-(1-pyrrolidinyl)-(2E,4E)-2,4-decadien-1-one, is a natural amide isolated from the fruits of Piper species. The compound has a number of interesting biological properties, including its broad-spectrum activity on weeds as a contact herbicide. Initial studies highlighted a similarity in response between plants treated with sarmentine and herbicidal soaps such as pelargonic acid (nonanoic acid). However, little was known about the mechanism of action leading to the rapid desiccation of foliage treated by sarmentine. In cucumber cotyledon disc-assays, sarmentine induced rapid light-independent loss of membrane integrity at 100 µM or higher concentration, whereas 3 mM pelargonic acid was required for a similar effect. Sarmentine was between 10 and 30 times more active than pelargonic acid on wild mustard, velvetleaf, redroot pigweed and crabgrass. Additionally, the potency of 30 µM sarmentine was greatly stimulated by light, suggesting that this natural product may also interfere with photosynthetic processes. This was confirmed by observing a complete inhibition of photosynthetic electron transport at that concentration. Sarmentine also acted as an inhibitor of photosystem II (PSII) on isolated thylakoid membranes by competing for the binding site of plastoquinone. This can be attributed in part to structural similarities between herbicides like sarmentine and diuron. While this mechanism of action accounts for the light stimulation of the activity of sarmentine, it does not account for its ability to destabilize membranes in darkness. In this respect, sarmentine has some structural similarity to crotonoyl-CoA, the substrate of enoyl-ACP reductase, a key enzyme in the early steps of fatty acid synthesis. Inhibitors of this enzyme, such as triclosan, cause rapid loss of membrane integrity in the dark. Sarmentine inhibited the activity of enoyl-ACP reductase, with an I 50app of 18.3 µM. Therefore, the herbicidal activity of sarmentine appears to be a complex process associated with multiple mechanisms of action.
RESUMO
In our screening of marine streptomycete isolates for bioactive components, a new macrolide antibiotic designated as chalcomycin B (1b) was isolated from the culture broth of a marine Streptomycete isolate B7064 together with chalcomycin (1a) as the active principles. The structure of the new antibiotic was determined by EI and ESI MS, 1H, 13C and 2D NMR spectroscopy and by comparison of the NMR data with those of chalcomycin.
Assuntos
Antibacterianos/isolamento & purificação , Macrolídeos , Streptomyces , Antibacterianos/química , FermentaçãoRESUMO
N-Phenylethylamides 1a-1f, were isolated from cultures of three limnic strains GW90a, GW102a and GW73a. Strain GW102a delivered additionally the compound cyclo(isoleucyldehydroalanyl) (2). The structure of these compounds were assigned by a detailed spectral analysis. Due to their potential use as herbicides, various related compounds 1a, 3, 4a and 4b were synthesized. The minimum inhibitory concentration (MIC) against Chlorella vulgaris, Chlorella sorokiniana, Chlorella salina and Scenedesmus subspicatus ranged from 100 to 12.5 microg/ml. All these amides were found to be inactive against Mucor miehei, Candida albicans, and some bacteria.
Assuntos
Bacillus/química , Eucariotos/efeitos dos fármacos , Herbicidas/química , Herbicidas/farmacologia , Amidas/química , Bacillus/classificação , Bacillus/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fermentação , Herbicidas/metabolismo , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The ethyl acetate extract of cultures of Janibacter limosus showed a high biological activity against bacteria, and fungi and delivered two new natural products, a tetrahydroquinoline derivative designated as helquinoline (1), and the N-acetylkynuramine (3a), along with other known secondary metabolites. The structure of 1 has been elucidated as 4-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline-8-carboxylic acid on the basis of 1D and 2D NMR and mass spectra. The relative stereochemistry of the compound 1 was assigned as 2R*,4R* with the aid of coupling constants, NOESY correlation and by comparison with a related compound.
Assuntos
Actinomycetales/metabolismo , Antibacterianos/isolamento & purificação , Cinuramina/análogos & derivados , Quinolinas/isolamento & purificação , Actinomycetales/química , Antibacterianos/biossíntese , Antibacterianos/química , Antibacterianos/farmacologia , Fermentação , Cinuramina/química , Cinuramina/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Quinolinas/química , Quinolinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
A new antibiotic, named seitomycin (1c), and the known microbial metabolite tetrangulol methyl ether (2) were found in the ethyl acetate extract of two terrestrial Streptomyces sp. isolates. The structure of the new antibiotic was elucidated by spectroscopic studies and by comparison of the NMR data with the structurally related hatomarubigin C (1a) and SM-196 B (1b). Seitomycin (1c) showed moderate antimicrobial and weak phytotoxic activity, similar to tetrangulol methyl ether (2).
Assuntos
Antibacterianos , Benzo(a)Antracenos , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Benzo(a)Antracenos/química , Benzo(a)Antracenos/isolamento & purificação , Benzo(a)Antracenos/farmacologia , Fermentação , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Chemical investigation of a soft coral of the genus Lobophytum of the Andaman and Nicobar coasts resulted in the isolation of a new marine sterol acetate, (24S)-ergostane-3beta,5alpha,6beta,25-tetraol-3,6,25-triacetate (1) and of two known sterol glycosides 3beta,4alpha-dihydroxypregn-20-ene-4-O-beta-D-arabinopyranoside and 24-methylenecholest-5-ene-3beta,7beta, 16beta-triol-3-O-alpha-L-fucopyranoside-7beta-acetate. The structures of the compounds were elucidated based on spectral studies and chemical conversions.
Assuntos
Antozoários , Ergosterol/química , Fitoterapia , Animais , Espectroscopia de Ressonância Magnética , Extratos Vegetais/químicaRESUMO
Discovery of novel natural herbicides has become crucial to overcome increasing weed resistance and environmental issues. In this article, we describe the finding that a methanol extract of dry long pepper (Piper longum L.) fruits is phytotoxic to lettuce (Lactuca sativa L.) seedlings. The bioassay-guided fractionation and purification of the crude extract led to isolation of sarmentine (1), a known compound, as the active principle. Phytotoxicity of 1 was examined with a variety of seedlings of field crops and weeds. Results indicated that 1 was a contact herbicide and possessed broad-spectrum herbicidal activity. Moreover, a series of sarmentine analogues were then synthesized to study the structure-activity relationship (SAR). SAR studies suggested that phytotoxicity of sarmentine and its analogues was specific due to chemical structures, i.e., the analogues of the acid moiety of 1 were active, but the amine and its analogues were inactive; the ester analogues and amide analogues with a primary amine of 1 were also inactive. In addition, quantification of 1 from different resources of the dry P. longum fruits using liquid chromatography-mass spectrometry showed a wide variation, ranging from almost zero to 0.57%. This study suggests that 1 has potential as an active lead molecule for synthesized herbicides as well as for bioherbicides derived from natural resources.
Assuntos
Frutas/química , Herbicidas , Piper/química , Polienos , Herbicidas/análise , Herbicidas/química , Herbicidas/isolamento & purificação , Polienos/análise , Polienos/química , Polienos/isolamento & purificação , PlântulaRESUMO
The isolation of 2-bromo-1-hydroxyphenazine from a marine Streptomyces species, strain CNS284, and its activity against NF-κB, suggested that a short and flexible route for the synthesis of this metabolite and a variety of phenazine analogues should be developed. Numerous phenazines were subsequently prepared and evaluated as inducers of quinone reductase 1 (QR1) and inhibitors of quinone reductase 2 (QR2), NF-κB, and inducible nitric oxide synthase (iNOS). Several of the active phenazine derivatives displayed IC50 values vs QR1 induction and QR2 inhibition in the nanomolar range, suggesting that they may find utility as cancer chemopreventive agents.
Assuntos
Anticarcinógenos/síntese química , Fenazinas/síntese química , Streptomyces/química , Animais , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Organismos Aquáticos , Linhagem Celular , Linhagem Celular Tumoral , Indução Enzimática , Humanos , Camundongos , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Fenazinas/química , Fenazinas/farmacologia , Quinona Redutases/antagonistas & inibidores , Quinona Redutases/biossíntese , Relação Estrutura-AtividadeRESUMO
Chemical evaluation of the saline fermentation broth of several strains of the obligate marine actinomycete Salinispora arenicola has led to the identification of three new macrolide polyketides designated arenicolides A-C (1-3). The planar structures, elucidated via spectroscopic and chemical methods, consist of 26-membered polyunsaturated macrolactones containing repeating vicinal hydroxyl methoxyl moieties. The relative and absolute stereochemistries of 1-3 were assigned by a combination of J-based configurational analyses and chemical derivatization.
Assuntos
Actinobacteria/química , Macrolídeos/química , Acetona/química , Alcenos , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oceanos e Mares , EstereoisomerismoRESUMO
An extensive study of the secondary metabolites produced by several strains of the marine actinomycete Salinispora arenicola has led to the isolation of two unusual bicyclic polyketides, saliniketals A and B (1, 2). The structures, which contain a new 1,4-dimethyl-2,8-dioxabicyclo[3.2.1]octan-3-yl ring, were assigned mainly by 2D NMR spectroscopic methods. Unexpectedly, chemical derivatization of saliniketal A with Mosher's acid chloride resulted in a functional group interconversion of an unsaturated primary amide to the corresponding nitrile in a quantitative yield under unusually mild conditions. Saliniketals A and B were found to inhibit ornithine decarboxylase induction, an important target for the chemoprevention of cancer, with IC50 values of 1.95 +/- 0.37 and 7.83 +/- 1.2 microg/mL, respectively.
Assuntos
Actinomyces/química , Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Ornitina Descarboxilase/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Guam , Concentração Inibidora 50 , Biologia Marinha , Estrutura Molecular , Inibidores da Ornitina DescarboxilaseRESUMO
Recent fermentation studies have identified actinomycetes of the marine-dwelling genus Salinispora as prolific natural product producers. To further evaluate their biosynthetic potential, we sequenced the 5,183,331-bp S. tropica CNB-440 circular genome and analyzed all identifiable secondary natural product gene clusters. Our analysis shows that S. tropica dedicates a large percentage of its genome ( approximately 9.9%) to natural product assembly, which is greater than previous Streptomyces genome sequences as well as other natural product-producing actinomycetes. The S. tropica genome features polyketide synthase systems of every known formally classified family, nonribosomal peptide synthetases, and several hybrid clusters. Although a few clusters appear to encode molecules previously identified in Streptomyces species, the majority of the 17 biosynthetic loci are novel. Specific chemical information about putative and observed natural product molecules is presented and discussed. In addition, our bioinformatic analysis not only was critical for the structure elucidation of the polyene macrolactam salinilactam A, but its structural analysis aided the genome assembly of the highly repetitive slm loci. This study firmly establishes the genus Salinispora as a rich source of drug-like molecules and importantly reveals the powerful interplay between genomic analysis and traditional natural product isolation studies.