RESUMO
General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (Danio rerio) of a natural pyrroloformamide (PFD), N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei. The complete structure of PFD was determined by a detailed NMR analysis, including 1H-13C and 1H-15N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (n = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 µL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT1, 5-HT2A/2C and 5-HTR3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.
Pyrroloformamide (PFD), isolated from the marine Streptomyces sp. associated ascidian Eudistoma vannamei, showed no toxicity in adult zebrafish but reduced its locomotor activity.The structural elucidation of PFD was determined by the analysis of 1D and 2D NMR and HRESIMS data.The density functional theory (DFT) study confirmed the existence of two conformers as determined by NMR spectra.The serotonergic system modulated the anxiolytic effect of PFD via the 5-HT receptor in adult zebrafish.Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.
Assuntos
Ansiolíticos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Peixe-Zebra , Serotonina , Flumazenil/farmacologia , Pizotilina , Simulação de Acoplamento Molecular , Granisetron , CiproeptadinaRESUMO
Five unusual kaurane diterpenes, designated as bezerraditerpenes A-E (1-5), along with six known ones (6-11), were isolated from the hexane extract of the stems of Erythroxylum bezerrae. Their structures were elucidated based on the interpretation of the NMR spectroscopy, mass spectrometry, and X-ray diffraction analysis. The anti-inflammatory potential of the diterpenes 1-11 was screened through cellular viability and lipopolysaccharide (LPS)-induced nitric oxide (NO) production on murine macrophage-like cells RAW 264.7. Diterpene 6 (cauren-6ß-ol) showed potent cytotoxicity and increased ability to inhibit NO production. Diterpenes 1 (bezerraditerpene A), 2 (bezerraditerpene B), and 8 (ent-kaur-16-ene-3ß,15ß-diol) exhibited the same significant anti-inflammatory activity with NO CI50 inhibition (3.21-3.76 µM) without cytotoxicity, in addition to decreasing the levels of pro-inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 cells.
Assuntos
Diterpenos do Tipo Caurano , Diterpenos , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Óxido Nítrico , Erythroxylaceae/químicaRESUMO
Benzodiazepines are commonly used to treat disorders of the central nervous system, including anxiety. However, due to their adverse effects, there is a continuing interest in discovering new safe and effective drugs. Marine natural products have emerged as a prolific source of bioactive nitrogenated compounds. Aiming to discover new biologically active natural compounds, the marine sponge Aplysina fulva, a nitrogen-bearing heterocyst producer, was investigated. The main isolated compounds (4, 6, and 9) were evaluated on adult zebrafish (Danio rerio). A group of fishes (n = 6) was preliminarily subjected to acute toxicity, and open field tests using 0.1, 0.5, and 1.0 mg/mL (v. o.) of those compounds was performed. The anxiolytic effect was further investigated in the light/dark assay based on the locomotor response at zebrafish. Interactions through the GABAergic system were investigated using flumazenil, a silent modulator of GABA receptors. To improve the results, a study of molecular docking using the GABAA receptor also was performed. Based on the results, the bromotyrosine derivative compounds 4, 6, and 9 exhibited anxiolytic-like effects mediated by the GABAergic system.
Assuntos
Ansiolíticos/farmacologia , Produtos Biológicos/farmacologia , Brometos/farmacologia , Moduladores GABAérgicos/farmacologia , Receptores de GABA-A/metabolismo , Fatores Etários , Animais , Ansiolíticos/química , Ansiolíticos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Brometos/química , Brometos/isolamento & purificação , Relação Dose-Resposta a Droga , Feminino , Moduladores GABAérgicos/química , Moduladores GABAérgicos/isolamento & purificação , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Poríferos , Estrutura Secundária de Proteína , Receptores de GABA-A/química , Peixe-ZebraRESUMO
Two steroids (1 and 2), two oxepin derivatives (3 and 4) and seven flavonoids (5-11) were isolated from the stems of Bauhinia pentandra. Their structures were elucidated on the basis of NMR spectroscopic data, and by comparison with data previously reported in the literature. The ethanol extract from the stems of B. pentandra and the compounds, 4, 5, 6, 7, 8 and 11 have been evaluated as acetylcholinesterase inhibitors, and among these, the compound 5 exhibited the strongest activity. In addition, all the isolated compounds are reported for the first time as constituents of B. pentandra.
Assuntos
Bauhinia , Acetilcolinesterase , Inibidores da Colinesterase/farmacologia , Flavonoides/farmacologia , Espectroscopia de Ressonância MagnéticaRESUMO
Six previously undescribed tropane alkaloids, designated as erythrobezerrines A-F, were isolated from the EtOH extract from the stem bark of Erythroxylum bezerrae Plowman. Their structures were elucidated based on the interpretation of the NMR and MS data and in some instances, confirmed by X-ray diffraction analysis. The cytotoxicity of the isolated compounds was evaluated against the cancer cell lines L929, PC-3, HCT-116, SNB-19 and NCI-H460, but only erythrobezerrine C showed moderate activity with IC50 values of 3.38 and 5.43⯵M for HCT-116 and NCI-H460, respectively.
Assuntos
Erythroxylaceae , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Casca de Planta , TropanosRESUMO
Melanoma is a type of skin cancer with an elevated incidence of metastasis and chemoresistance. Such features hamper treatment success of these neoplasms, demanding the search for new therapeutic options. Using a two-step resin-based approach, we recently demonstrated that cytotoxic prodiginines bind to the inhibitor of apoptosis protein, survivin. Herein, we explore the role of survivin in melanoma and whether its modulation is related to the antimelanoma properties of three cytotoxic prodiginines (prodigiosin, cyclononylprodigiosin, and nonylprodigiosin) isolated from marine bacteria. In melanoma patients and cell lines, survivin is overexpressed, and higher levels negatively impact survival. All three prodiginines caused a decrease in cell growth with reduced cytotoxicity after 24 h compared to 72 h treatment, suggesting that low concentrations promote cytostatic effects in SK-Mel-19 (BRAF mutant) and SK-Mel-28 (BRAF mutant), but not in SK-Mel-147 (NRAS mutant). An increase in G1 population was observed after 24 h treatment with prodigiosin and cyclononylprodigiosin in SK-Mel-19. Further studies indicate that prodigiosin induced apoptosis and DNA damage, as detected by increased caspase-3 cleavage and histone H2AX phosphorylation, further arguing for the downregulation of survivin. Computer simulations suggest that prodigiosin and cyclononylprodigiosin bind to the BIR domain of survivin. Moreover, knockdown of survivin increased long-term toxicity of prodigiosin, as observed by reduced clonogenic capacity, but did not alter short-term cytotoxicity. In summary, prodiginine treatment provoked cytostatic rather than cytotoxic effects, cell cycle arrest at G0/G1 phase, induction of apoptosis and DNA damage, downregulation of survivin, and decreased clonogenic capacity in survivin knockdown cells.
Assuntos
Melanoma/metabolismo , Prodigiosina/análogos & derivados , Prodigiosina/farmacologia , Survivina/antagonistas & inibidores , Survivina/biossíntese , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/fisiologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Humanos , Melanoma/tratamento farmacológico , Prodigiosina/uso terapêutico , Survivina/genéticaRESUMO
The new glucosyl sarpagan alkaloid designated as 21(R*)-(O-ß-glucosyl)-hydroxy-sarpagan-17-oic acid, along with eleven known alkaloids were isolated from a soluble alkaloidal fraction from the ethanol extract of Rauvolfia ligustrina. Their structures were elucidated by interpretation of spectroscopic data (1D and 2D NMR), HRESIMS experiment, GIAO 13C NMR calculations, and comparison with literature data. All the isolated alkaloids were screened by their neuroinhibitory effects using the electrically stimulated mice vas deferens bioassay. Compounds 1, 2 and 9 presented a potent inhibitory effect in the neurotransmission while 3 and 11 showed an acute neuroexcitatory effect. Compound 10 exhibited a very effective post-synaptic inhibitory activity.
Assuntos
Alcaloides Indólicos/farmacologia , Raízes de Plantas/química , Rauwolfia/química , Transmissão Sináptica/efeitos dos fármacos , Animais , Brasil , Estimulação Elétrica , Técnicas In Vitro , Alcaloides Indólicos/química , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Ducto Deferente/efeitos dos fármacosRESUMO
Three new 3-hydroxy-N-methyl-2-oxindole (1 and 2) and 4-hydroxy-pyran-2-one (3) derivatives, along with the known 3-hydroxy-N-methyl-2-oxindole (4) and 6-methoxy-N-methylisatin (5) were isolated from a marine Salinispora arenicola strain from sediments of the St. Peter and St. Paul Archipelago, Brazil. The structures of the new compounds were elucidated by a combination of spectroscopic (1D and 2D NMR and HR-ESIMS) data, including single-crystal X-ray diffraction analysis for 2 and 3. Compounds 1 to 5 were assayed for their antimicrobial properties, but only 4 and 5 were active against Enterococcus faecalis with MIC value of 15.6⯵g/mL.
Assuntos
Antibacterianos/farmacologia , Sedimentos Geológicos/microbiologia , Micromonosporaceae/química , Oxindóis/farmacologia , Antibacterianos/isolamento & purificação , Brasil , Enterococcus faecalis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxindóis/isolamento & purificação , Água do Mar/microbiologiaRESUMO
Salinaphthoquinones A-E (1-5) were isolated from a marine Salininispora arenicola strain, recovered from sediments of the St. Peter and St. Paul Archipelago, Brazil. The structures of the compounds were elucidated using a combination of spectroscopic (NMR, IR, HRESIMS) data, including single-crystal X-ray diffraction analysis. A plausible biosynthetic pathway for 1-5 is proposed. Compounds 1 to 4 displayed moderate activity against Staphylococcus aureus and Enterococcus faecalis with MIC values of 125 to 16 µg/mL.
Assuntos
Antibacterianos/farmacologia , Sedimentos Geológicos/química , Micromonosporaceae/química , Naftoquinonas/farmacologia , Água do Mar/química , Antibacterianos/química , Brasil , Sedimentos Geológicos/microbiologia , Estrutura Molecular , Naftoquinonas/química , Água do Mar/microbiologiaRESUMO
The chemical study of the Brazilian brittle star Ophionereis reticulata led to the isolation of three chamigrene sesquiterpenes, including the partially characterized isoobtusadiene (1), its unreported acetyl derivative (2), and the known (+)-elatol (3). The complete elucidation of the structures 1 and 2 was accomplished by 1D and 2D NMR spectroscopy. The first assignment of the absolute configuration of the isoobtusadiene skeleton is suggested as 6S,9R,10S on the basis of the NMR analysis of the Mosher's ester derivatives of 1 and the ECD study of the acetyl derivative 2. Chamigrenes are typical constituents of Laurencia red algae. O. reticulata is a predator with a preference for algae. Thus, the origin of these metabolites can be likely ascribed to diet.