RESUMO
In our continuing efforts to describe the biological and chemical diversity of sponges from Kimbe Bay, Papua New Guinea, the known 30-norlanostane saponin sarasinoside C1 (1) was identified along with six new analogues named sarasinosides C4, C5, C6, C7, C8, and C9 (2-7) from the sponge Melophlus sarasinorum. The structures of the new compounds were elucidated by analysis of 1D and 2D NMR and HRMS data, as well as comparison with literature data. All new compounds are characterized by the same tetraose moiety, ß-d-Xylp-(1â6)-ß-d-GlcNAcp-(1â2)-[ß-d-GalNAcp-(1â4)]-ß-d-Xylp, as described previously for sarasinoside C1, but differed in their aglycone moieties. When comparing NMR data of sarasinoside C8 with those of known analogues, a misassignment was identified in the configuration of the C-8/C-9 diol for the previously described sarasinoside R (8), and it has been corrected here using a combination of ROESY analysis and molecular modeling.
Assuntos
Poríferos , Saponinas , Animais , Poríferos/química , Papua Nova Guiné , Estrutura MolecularRESUMO
An abundant sponge of the order Bubarida was selected for further chemical investigation following biological and chemical screening of sponges collected from Futuna Islands in the Indo-Pacific. Ten new nitrogenous bisabolene derivatives were isolated and identified: the monomeric theonellin formamide analogues named bubaridins A-F (1-6) with unusual oxidised linear chains, and the first isocyanide/formamide dimeric and cyclised bisabolenes 7-9. The structure elucidation of these nitrogenous bisabolenes involved HRESIMS, NMR, and ECD analyses, and the chiral compounds were found to be racemates. A biosynthetic hypothesis for the production of these metabolites is proposed and some chemotaxonomic considerations are discussed. Furthermore, the antimicrobial and antitumoral activity were evalutated and the trans-dimer theonellin isocyanide (7) was shown to exhibit potent and selective antifungal activity.
Assuntos
Antifúngicos/farmacologia , Cicloexilaminas/farmacologia , Sesquiterpenos Monocíclicos/farmacologia , Poríferos/química , Animais , Antifúngicos/química , Antifúngicos/isolamento & purificação , Candida/efeitos dos fármacos , Linhagem Celular Tumoral , Cicloexilaminas/síntese química , Cicloexilaminas/isolamento & purificação , Humanos , Ilhas , Testes de Sensibilidade Microbiana , Estrutura Molecular , Sesquiterpenos Monocíclicos/química , Sesquiterpenos Monocíclicos/isolamento & purificação , Oceano PacíficoRESUMO
Using both multi-informative molecular network and score-based approaches as prioritization strategies, the Northeastern Atlantic marine terebellid Eupolymnia nebulosa was selected for in-depth chemical investigation. A family of 16 new metabolites named nebulosins was isolated and structurally characterized from extensive analyses of HRMS/MS and NMR spectroscopic data. Nebulosins feature an unprecedented highly substituted thiolane ring leading to up to four contiguous chiral centers. The relative configurations were assigned through a combination of NOESY analysis, spin-spin coupling constant analysis, and NMR chemical shifts measurements, while the absolute configurations were determined by comparison between experimental and theoretical ECD spectra. This family of natural product exhibits promising antioxidant activities in both ORAC and ROS assays.
Assuntos
Produtos Biológicos , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
The chemical investigation of the sponge Stylissa aff. carteri collected around Futuna Islands in the Pacific Ocean led to the isolation of three new dimeric pyrrole 2-aminoimidazole alkaloids (PIAs). Futunamine (1) features an unprecedented pyrrolo[1,2-c]imidazole core, while two other new dimeric PIAs were identified as analogues of palau'amine. Together with other known PIAs isolated from this species, they were shown to exhibit anti-inflammatory and neuroprotective activities.
Assuntos
Alcaloides/química , Imidazóis/química , Pirróis/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Linhagem Celular Tumoral , Humanos , Imidazóis/isolamento & purificação , Ilhas , Microglia/citologia , Microglia/efeitos dos fármacos , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Oceano Pacífico , Pirróis/isolamento & purificação , Análise Espectral/métodosRESUMO
This paper reports the isolation and structural characterization of four new ent-kaurane derivatives from the Lamiaceae plant Sideritis hyssopifolia. Planar structures and relative configurations were determined using both mass spectrometry and nuclear magnetic resonance (1D and 2D). Absolute configurations were determined by comparing experimental and theoretical electronic circular dichroism spectra. The cytotoxic and microbial activities of all new compounds were tested. Compounds that were non-cytotoxic were further evaluated for anti-inflammatory activity.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Extratos Vegetais/farmacologia , Sideritis/química , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/isolamento & purificação , Humanos , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Análise EspectralRESUMO
The structures of the commercially available microginins 674 and 690 isolated from a cultured strain of Microcystis aeruginosa and only recently characterized have been revisited. Using NMR and HRMS/MS data, an inversion of two amino acids, N-methylmethionine and tyrosine, in the structure of these metabolites is unambiguously demonstrated. These results highlight the importance of careful examination of spectroscopic data for the proposition of structures of natural products, especially when they are of commercial value.
Assuntos
Proteínas de Bactérias/química , Microcystis/química , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
So far, the Futuna Islands located in the Central Indo-Pacific Ocean have not been inventoried for their diversity in marine sponges and associated chemical diversity. As part of the Tara Pacific expedition, the first chemical investigation of the sponge Narrabeena nigra collected around the Futuna Islands yielded 18 brominated alkaloids: seven new bromotryptamine derivatives 1-7 and one new bromotyramine derivative 8 together with 10 known metabolites of both families 9-18. Their structures were deduced from extensive analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) data. In silico metabolite anticipation using the online tool MetWork revealed the presence of a key and minor biosynthetic intermediates. These 18 compounds showed almost no cytotoxic effect up to 10 µM on human neuroblastoma SH-SY5Y and microglia BV2 cells, and some of them exhibited an interesting neuroprotective activity by reducing oxidative damage.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Poríferos/química , Alcaloides/isolamento & purificação , Alcaloides/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Internet , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Oceano Pacífico , Clima TropicalRESUMO
The first chemical study of the marine sponge Callyspongia cf. californica widely distributed along the coasts of the Tropical Eastern Pacific led to the identification of a new family of amphiphilic derivatives called callyspongidic acids. The four isolated metabolites 1-4 feature a hydrophilic diacid end opposed to both an aromatic moiety and a long alkyl chain. They were evaluated against a panel of pathogenic microbes and seven tumoral cell lines, displaying moderate inhibitory properties against the A2058 melanoma cell line with an IC50 of 3.2 µM for callyspongidic acid C13:0 (2).
Assuntos
Callyspongia/química , Poli-Inos/farmacologia , Animais , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oceano Pacífico , Poli-Inos/isolamento & purificaçãoRESUMO
Despite a large occurrence, especially over the Pacific Ocean, the chemical diversity of marine invertebrates belonging to the order Zoantharia is largely underexplored. For the two species of the genus Antipathozoanthus no chemical study has been reported so far. The first chemical investigation of Antipathozoanthus hickmani collected at the Marine Protected Area "El Pelado", Santa Elena, Ecuador, led to the isolation of four new ecdysteroid derivatives named ecdysonelactones. The structures of ecdysonelactones A-D (1-4) were determined based on their spectroscopy data, including 1D and 2D NMR and HRMS. The four compounds of this family of ecdysteroids feature an unprecedented γ-lactone fused at the C-2/C-3 position of ring A. These derivatives exhibited neither antimicrobial nor cytotoxic activities.
Assuntos
Antozoários/química , Ecdisteroides/química , Animais , Ecdisteroides/farmacologia , Equador , Lactonas/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Oceano PacíficoRESUMO
Two new zoanthamine alkaloids, namely 3-acetoxynorzoanthamine (1) and 3-acetoxyzoanthamine (2), have been isolated from the zoantharian Zoanthus cf. pulchellus collected off the coast of the Santa Elena Peninsula, Ecuador, together with three known derivatives: zoanthamine, norzoanthamine, and 3-hydroxynorzoanthamine. The chemical structures of 1 and 2 were determined by interpretation of their 1D and 2D NMR data and comparison with literature data. This is the first report of zoanthamine-type alkaloids from Zoanthus cf. pulchellus collected in the Tropical Eastern Pacific. The neuroinflammatory activity of all the isolated compounds was evaluated in microglia BV-2 cells and high inhibitory effects were observed in reactive oxygen species (ROS) and nitric oxide (NO) generation.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Antozoários/química , Azepinas/química , Azepinas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamação/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Animais , Espectroscopia de Ressonância Magnética/métodos , Microglia/efeitos dos fármacos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , EstereoisomerismoRESUMO
During investigations on the peroxidase-catalysed oxidation of polyhydroxylated monoaromatic substrates such as 5-methylpyrogallol, we observed a spectacular dimerisation proceeding by dearomatisation in contrast with most common reaction patterns involving phenolics oxidation and dimerization. A tetracyclic fused product featuring an unusual 2-oxatetracyclo [6.3.1.01,6.04,12] dodecan-3-one core was obtained and characterized by combined NMR techniques and high resolution mass spectroscopy (HRMS). This is an example of a spontaneous cascade triggered by a simple enzymatic reaction that could provide new options for biosynthetic hypothesis and a synthetic method to access this complex core in one operation.
Assuntos
Peroxidase do Rábano Silvestre/química , Peróxido de Hidrogênio/química , Compostos Policíclicos/síntese química , Pirogalol/química , Biocatálise , Dimerização , Química Verde , Espectrometria de Massas , Oxirredução , Estresse Oxidativo , Compostos Policíclicos/químicaRESUMO
The first chemical investigation of the Mediterranean deep-sea sponge Poecillastra compressa (Bowerbank, 1866) led to the identification of seven new steroidal saponins named poecillastrosides A-G (1-7). All saponins feature an oxidized methyl at C-18 into a primary alcohol or a carboxylic acid. While poecillastrosides A-D (1-4) all contain an exo double bond at C-24 of the side-chain and two osidic residues connected at O-2', poecillastrosides E-G (5-7) are characterized by a cyclopropane on the side-chain and a connection at O-3' between both sugar units. The chemical structures were elucidated through extensive spectroscopic analysis (High-Resolution Mass Spectrometry (HRESIMS), 1D and 2D NMR) and the absolute configurations of the sugar residues were assigned after acidic hydrolysis and cysteine derivatization followed by LC-HRMS analyses. Poecillastrosides D and E, bearing a carboxylic acid at C-18, were shown to exhibit antifungal activity against Aspergillus fumigatus.
Assuntos
Poríferos/metabolismo , Saponinas/química , Animais , Estrutura Molecular , Poríferos/química , Saponinas/metabolismoRESUMO
Fungal paracyclophane-decahydrofluorene-containing natural products are complex polycyclic metabolites derived from similar hybrid PKS-NRPS pathways. Herein we studied the biosynthesis of pyrrocidines, one representative of this family, by gene inactivation in the producer Sarocladium zeae coupled to thorough metabolic analysis and molecular modeling of key enzymes. We characterized nine pyrrocidines and analogues as well as in mutants a variety of accumulating metabolites with new structures including rare cis-decalin, cytochalasan, and fused 6/15/5 macrocycles. This diversity highlights the extraordinary plasticity of the pyrrocidine biosynthetic gene cluster. From accumulating metabolites, we delineated the scenario of pyrrocidine biosynthesis. The ring A of the decahydrofluorene is installed by PrcB, a membrane-bound cyclizing isomerase, on a PKS-NRPS-derived pyrrolidone precursor. Docking experiments in PrcB allowed us to characterize the active site suggesting a mechanism triggered by arginine-mediated deprotonation at the terminal methyl of the substrate. Next, two integral membrane proteins, PrcD and PrcE, each predicted as a four-helix bundle, perform hydroxylation of the pyrrolidone ring and paracyclophane formation, respectively. Modelization of PrcE highlights a topological homology with vitamin K oxido-reductase and the presence of a disulfide bond. Our results suggest a previously unsuspected coupling mechanism via a transient loss of aromaticity of tyrosine residue to form the strained paracyclophane motif. Finally, the lipocalin-like protein PrcX drives the exo-cycloaddition yielding ring B and C of the decahydrofluorene to afford pyrrocidine A, which is transformed by a reductase PrcI to form pyrrocidine B. These insights will greatly facilitate the microbial production of pyrrocidine analogues by synthetic biology.
Assuntos
Racionalização , Tirosina , Modelos Moleculares , Oxirredutases , Pirrolidinonas/química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Simulação de Acoplamento Molecular , Hypocreales/químicaRESUMO
Seed germination is a major determinant of plant development and final yield establishment but strongly reliant on the plant's abiotic and biotic environment. In the context of global climate change, classical approaches to improve seed germination under challenging environments through selection and use of synthetic pesticides reached their limits. A currently underexplored way is to exploit the beneficial impact of the microorganisms associated with plants. Among plant microbiota, endophytes, which are micro-organisms living inside host plant tissues without causing any visible symptoms, are promising candidates for improving plant fitness. They possibly establish a mutualistic relationship with their host, leading to enhanced plant yield and improved tolerance to abiotic threats and pathogen attacks. The current view is that such beneficial association relies on chemical mediations using the large variety of molecules produced by endophytes. In contrast to leaf and root endophytes, seed-borne fungal endophytes have been poorly studied although they constitute the early-life plant microbiota. Moreover, seed-borne fungal microbiota and its metabolites appear as a pertinent lever for seed quality improvement. This review summarizes the recent advances in the identification of seed fungal endophytes and metabolites and their benefits for seed biology, especially under stress. It also addresses the mechanisms underlying fungal effects on seed physiology and their potential use to improve crop seed performance.'
RESUMO
Gambierdiscus species are the producers of the marine toxins ciguatoxins and maitotoxins which cause worldwide human intoxications recognized as Ciguatera Fish Poisoning. A deep chemical investigation of a cultured strain of G. belizeanus, collected in the Caribbean Sea, led to the identification of a structural homologue of the recently described gambierone isolated from the same strain. The structure was elucidated mainly by comparison of NMR and MS data with those of gambierone and ascertained by 2D NMR data analyses. Gratifyingly, a close inspection of the MS data of the new 44-methylgambierone suggests that this toxin would actually correspond to the structure of maitotoxin-3 (MTX3, m/z 1039.4957 for the protonated adduct) detected in 1994 in a Pacific strain of Gambierdiscus and recently shown in routine monitoring programs. Therefore, this work provides for the first time the chemical identification of the MTX3 molecule by NMR. Furthermore, biological data confirmed the similar activities of both gambierone and 44-methylgambierone. Both gambierone and MTX3 induced a small increase in the cytosolic calcium concentration but only MTX3 caused cell cytotoxicity at micromolar concentrations. Moreover, chronic exposure of human cortical neurons to either gambierone or MTX3 altered the expression of ionotropic glutamate receptors, an effect already described before for the synthetic ciguatoxin CTX3C. However, even when gambierone and MTX3 affected glutamate receptor expression in a similar manner their effect on receptor expression differed from that of CTX3C, since both toxins decreased AMPA receptor levels while increasing N-methyl-d-aspartate (NMDA) receptor protein. Thus, further studies should be pursued to clarify the similarities and differences in the biological activity between the known ciguatoxins and the new identified molecule as well as its contribution to the neurological symptoms of ciguatera.
Assuntos
Toxinas Marinhas/química , Toxinas Marinhas/farmacologia , Oxocinas/química , Oxocinas/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciguatoxinas/farmacologia , Dinoflagellida , Éteres/química , Éteres/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de Glutamato/metabolismoRESUMO
The chemical investigation of marine invertebrates from the deep Northeastern Atlantic revealed new lipoglycotripeptides named characellides isolated from the tetractinellid sponge Characella pachastrelloides. This new family of natural products features a central tripeptide linked to a rare sugar unit and a long alkyl chain ending with a 2,3-dimethyltetrahydropyran. The configurations of all 13 chiral centers were determined by extensive use of NMR data and circular dichroism spectra combined with calculations.
Assuntos
Anti-Inflamatórios não Esteroides/química , Lipoglicopeptídeos/química , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Lipoglicopeptídeos/isolamento & purificação , Lipoglicopeptídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Conformação Molecular , Poríferos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
The isolation and structure elucidation of puna'auic acid, an allenic fatty acid isolated from a marine cyanobacterium, is described. All configurations were first assessed through molecular modeling of NMR and ECD spectra and then confirmed through a straightforward enantioselective total synthesis of puna'auic acid featuring a key reductive opening of a propargylic epoxide.
Assuntos
Cianobactérias , Ácidos Graxos , Estrutura Molecular , EstereoisomerismoRESUMO
A new natural product named gambierone (1) was isolated from the cultured dinoflagellate Gambierdiscus belizeanus. The structure of this compound features an unprecedented polyether skeleton and an unusual right-hand side chain. Its relative configuration was fully determined by interpretation of ROESY experiment and comparison between experimental and theoretical NMR data. Although the succession of cycles has no chemical similarity with ciguatoxins, 1 has a molecular formula and biological activity similar to those of CTX-3C, although much lower in intensity.
Assuntos
Dinoflagellida/química , Éteres/química , Éteres/isolamento & purificação , Espectroscopia de Ressonância Magnética , Conformação MolecularRESUMO
The toxic dinoflagellate Karenia brevis, responsible for early harmful algal blooms in the Gulf of Mexico, produces many secondary metabolites, including potent neurotoxins called brevetoxins (PbTx). These compounds have been identified as toxic agents for humans, and they are also responsible for the deaths of several marine organisms. The overall biosynthesis of these highly complex metabolites has not been fully ascertained, even if there is little doubt on a polyketide origin. In addition to gaining some insights into the metabolic events involved in the biosynthesis of these compounds, feeding studies with labeled precursors helps to discriminate between the de novo biosynthesis of toxins and conversion of stored intermediates into final toxic products in the response to environmental stresses. In this context, the use of radiolabeled precursors is well suited as it allows working with the highest sensitive techniques and consequently with a minor amount of cultured dinoflagellates. We were then able to incorporate [U-¹4C]-acetate, the renowned precursor of the polyketide pathway, in several PbTx produced by K. brevis. The specific activities of PbTx-1, -2, -3, and -7, identified by High-Resolution Electrospray Ionization Mass Spectrometer (HRESIMS), were assessed by HPLC-UV and highly sensitive Radio-TLC counting. We demonstrated that working at close to natural concentrations of acetate is a requirement for biosynthetic studies, highlighting the importance of highly sensitive radiolabeling feeding experiments. Quantification of the specific activity of the four, targeted toxins led us to propose that PbTx-1 and PbTx-2 aldehydes originate from oxidation of the primary alcohols of PbTx-7 and PbTx-3, respectively. This approach will open the way for a better comprehension of the metabolic pathways leading to PbTx but also to a better understanding of their regulation by environmental factors.