RESUMO
Covering: up to December 2023Decalin-containing tetramic acid derivatives, especially 3-decalinoyltetramic acids (3-DTAs), are commonly found as fungal secondary metabolites. Numerous biological activities of this class of compounds, such as antibiotic, antiviral, antifungal, antiplasmodial, and antiprotozoal properties, have been the subject of ongoing research. For this reason, these molecules have attracted a lot of interest from the scientific community and various efforts including semi-synthesis, co-culturing with bacteria and biosynthetic gene sequencing have been made to obtain more derivatives. In this review, 3-DTAs are classified into four major groups based on the absolute configuration of the bicyclic decalin ring. Their biosynthetic pathways, various biological activities, and structure-activity relationship are then introduced.
Assuntos
Fungos , Pirrolidinonas , Relação Estrutura-Atividade , Fungos/química , Fungos/metabolismo , Pirrolidinonas/farmacologia , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/metabolismo , Estrutura Molecular , Naftalenos/farmacologia , Naftalenos/química , Naftalenos/isolamento & purificação , Naftalenos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/biossíntese , Antibacterianos/isolamento & purificaçãoRESUMO
Bioactivity-based molecular networking-guided fractionation enabled the isolation of three new polycyclic tetramic acids bearing cis-decalin, epicolidines A-C (1-3), along with one known compound, PF 1052 (4), from the endophytic fungus Epicoccum sp. 1-042 collected in Tibet, China. Their structures were assigned on the basis of extensive spectroscopic data, partial hydrolysis, advanced Marfey's method, quantum chemistry calculations, and X-ray diffraction analysis. Compounds 2-4 displayed promising activities against Gram-positive bacteria in vitro. Particularly, compound 4 displayed remarkable potential against vancomycin-resistant Enterococcus faecium (VRE) with an MIC value of 0.25 µg/mL, lower than the MIC (0.5 µg/mL) of the antibiotic combination quinupristin/dalfopristin (Q/D). In a further in vivo study, compound 4 increased the survival rate to 100% in the VRE-G. mellonella infection model at a concentration of 10 mg/kg.
Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Estrutura Molecular , Ascomicetos/química , Tibet , Animais , Enterococcus faecium/efeitos dos fármacos , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Pirrolidinonas/farmacologia , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificaçãoRESUMO
A new tetramic acid glycoside, aurantoside L (1), was isolated from the sponge Siliquariaspongia japonica collected at Tsushima Is., Nagasaki Prefecture, Japan. The structure of aurantoside L (1) composed of a tetramic acid bearing a chlorinated polyene system and a trisaccharide part was elucidated using spectral analysis. Aurantoside L (1) showed anti-parasitic activity against L. amazonensis with an IC50 value of 0.74 µM.
Assuntos
Glicosídeos , Leishmania , Poríferos , Poríferos/química , Animais , Glicosídeos/farmacologia , Glicosídeos/química , Glicosídeos/isolamento & purificação , Leishmania/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Pirrolidinonas/farmacologia , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Japão , Concentração Inibidora 50RESUMO
Aspergillus is well-known as the second-largest contributor of fungal natural products. Based on NMR guided isolation, three nitrogen-containing secondary metabolites, including two new compounds, variotin B (1) and coniosulfide E (2), together with a known compound, unguisin A (3), were isolated from the ethyl acetate (EtOAc) extract of the deep-sea fungus Aspergillus unguis IV17-109. The planar structures of 1 and 2 were elucidated by an extensive analysis of their spectroscopic data (HRESIMS, 1D and 2D NMR). The absolute configuration of 2 was determined by comparison of its optical rotation value with those of the synthesized analogs. Compound 2 is a rare, naturally occurring substance with an unusual cysteinol moiety. Furthermore, 1 showed moderate anti-inflammatory activity with an IC50 value of 20.0 µM. These results revealed that Aspergillus unguis could produce structurally diverse nitrogenous secondary metabolites, which can be used for further studies to find anti-inflammatory leads.
Assuntos
Anti-Inflamatórios , Aspergillus/química , Produtos Biológicos , Peptídeos Cíclicos , Sulfetos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/metabolismo , Organismos Aquáticos , Aspergillus/metabolismo , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Nitrogênio/química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/metabolismo , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/metabolismo , Células RAW 264.7 , Metabolismo Secundário , Sulfetos/química , Sulfetos/isolamento & purificação , Sulfetos/metabolismoRESUMO
Liver cancer is a leading cause of cancer death globally. Marine mollusc-derived drugs have gained attention as potential natural-based anti-cancer agents to overcome the side effects caused by conventional chemotherapeutic drugs during cancer therapy. Using liquid chromatography-mass spectrometry, the main biomolecules in the purple ink secretion released by the sea hare, named Bursatella leachii (B. leachii), were identified as hectochlorin, malyngamide X, malyngolide S, bursatellin and lyngbyatoxin A. The cytotoxic effects of B. leachii ink concentrate against human hepatocarcinoma (HepG2) cells were determined to be dose- and time-dependent, and further exploration of the underlying mechanisms causing the programmed cell death (apoptosis) were performed. The expression of cleaved-caspase-8 and cleaved-caspase-3, key cysteine-aspartic proteases involved in the initiation and completion of the apoptosis process, appeared after HepG2 cell exposure to the B. leachii ink concentrate. The gene expression levels of pro-apoptotic BAX, TP53 and Cyclin D1 were increased after treatment with the B. leachii ink concentrate. Applying in silico approaches, the high scores predicted that bioactivities for the five compounds were protease and kinase inhibitors. The ADME and cytochrome profiles for the compounds were also predicted. Altogether, the B. leachii ink concentrate has high pro-apoptotic potentials, suggesting it as a promising safe natural product-based drug for the treatment of liver cancer.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Gastrópodes/química , Neoplasias Hepáticas/tratamento farmacológico , Amidas/química , Amidas/isolamento & purificação , Amidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Células Hep G2 , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Toxinas de Lyngbya/química , Toxinas de Lyngbya/isolamento & purificação , Toxinas de Lyngbya/farmacologia , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Tiazóis/química , Tiazóis/isolamento & purificação , Tiazóis/farmacologiaRESUMO
N-Ethyl-2-pyrrolidinone-substituted flavanols (EPSF) are marker compounds for long-term stored white teas. However, due to their low contents and diasteromeric configuration, EPSF compounds are challenging to isolate. In this study, two representative epimeric EPSF compounds, 5'''R- and 5'''S-epigallocatechin gallate-8-C N-ethyl-2-pyrrolidinone (R-EGCG-cThea and S-EGCG-cThea), were isolated from white tea using centrifugal partition chromatography (CPC). Two different biphasic solvent systems composed of 1. N-hexane-ethyl acetate-methanol-water (1:5:1:5, v/v/v/v) and 2. N-hexane-ethyl acetate-acetonitrile-water (0.7:3.0:1.3:5.0, v/v/v/v) were used for independent pre-fractionation experiments; 500 mg in each separation of white tea ethyl acetate partition were fractionated. The suitability of the two solvent systems was pre-evaluated by electrospray mass-spectrometry (ESI-MS/MS) analysis for metabolite distribution and compared to the results of the CPC experimental data using specific metabolite partition ratio KD values, selectivity factors α, and resolution factors RS. After size-exclusion and semi-preparative reversed-phase liquid chromatography, 6.4 mg of R-EGCG-cThea and 2.9 mg of S-EGCG-cThea were recovered with purities over 95%. Further bioactivity evaluation showed that R- and S-EGCG-cThea possessed in vitro inhibition effects on α-glucosidase with IC50 of 70.3 and 161.7 µM, respectively.
Assuntos
Flavonóis/isolamento & purificação , Pirrolidinonas/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray , Chá/química , Catequina/análogos & derivados , Catequina/farmacologia , Centrifugação , Cromatografia Líquida , Distribuição Contracorrente , Glutamatos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Metaboloma , Extratos Vegetais/química , Polifenóis/análise , Polifenóis/química , alfa-Glucosidases/metabolismoRESUMO
Submerged mycelial cultures of the ascomycete Colpoma quercinum CCTU A372 were found to produce five previously undescribed tetramic acids, for which we propose the trivial names colposetins A-C (1-3) and colpomenoic acids A and B (4 and 5), along with the known compounds penicillide (6) and monodictyphenone (7). The planar structures of 1-5 were determined by high-resolution electrospray ionization mass spectrometry (HR-ESIMS) and extensive 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. Their absolute configurations were determined by the combination of electronic circular dischroism (ECD) analysis, J-based configurational analysis, and a rotating-frame Overhauser effect spectroscopy (ROESY) experiment. Colposetin B displayed weak antimicrobial activity against Bacillus subtilis and Mucor hiemalis (MIC 67 µg/mL).
Assuntos
Ascomicetos/química , Bacillus subtilis/crescimento & desenvolvimento , Mucor/crescimento & desenvolvimento , Micélio/química , Pirrolidinonas , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Irã (Geográfico) , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologiaRESUMO
During the course of our chemical analysis of the hydrophilic fractions from marine cyanobacterium Moorena producens, we have isolated natural dolapyrrolidone (Dpy, 1), a natural pyrrolidone derived from phenylalanine, for the first time as a single compound. Compound 1, with an (S)-l absolute stereochemistry, was previously identified as a substructure that is common among several bioactive natural peptides. Surprisingly, the absolute stereochemistry of the isolated natural 1, determined through total synthesis, was (R)-d. This result was unambiguously determined by HPLC analysis using a chiral stationary column by comparing the retention times of the natural 1 and authentic samples of synthetic enantiomers. To verify the unexpected result, the absolute stereochemistry of the natural 1 was confirmed by X-ray crystallographic analysis of Pt-complex derivative using the synthetic enantiomer.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Peptídeos/química , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , EstereoisomerismoRESUMO
The chromatographic properties of a new coated amylose tris(3-chloro-5-methylphenylcarbamate) were evaluated in supercritical fluid chromatography for the separation of enantiomers of chiral 1-aryl-5-aryl-pyrrolidin-2-one derivatives, potential anticancer agents, and some commercial drugs. The mobile phase consisted of CO2-modifier mixtures with 30% of either methanol or ethanol, the flow rate was 3 mL/min. The column oven temperature was 40 °C and the outlet pressure was 15 MPa, in order to limit the compressibility of the CO2, thus limiting density variation along the column. The obtained results were then compared to those observed toward 3 other stationary phases: the coated amylose tris(3,5-dimethylphenylcarbamate), the immobilized amylose tris(3,5-dimethylphenylcarbamate) and the coated amylose tris(5-chloro-2-methylphenylcarbamate). It was shown that the new coated amylose tris(3-chloro-5-methylphenylcarbamate) was the most retentive column whatever the studied compounds, particularly for thalidomide and omeprazole with retention factors up to 73.3 and 29.5for the second enantiomer, respectively. Concerning the enantioselectivity, even most of the compounds are separated on all the four columns, the coated amylose tris(3-chloro-5-methylphenylcarbamate) allows the best resolution for most of the ten studied analytes (except omeprazole for which the resolution values are equal to 7.8 and 9.7 on the coated amylose tris(3-chloro-5-methylphenylcarbamate) and amylose tris(3,5-dimethylphenylcarbamate), respectively). Acting in complementary ways, the two chlorinated stationary phases permitted the complete separation of enantiomers of nine compounds out of the ten.
Assuntos
Amilose/análogos & derivados , Cromatografia com Fluido Supercrítico/métodos , Amilose/química , Antineoplásicos/análise , Antineoplásicos/isolamento & purificação , Carbamatos/química , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/isolamento & purificação , Fenilcarbamatos/química , Pirrolidinonas/análise , Pirrolidinonas/isolamento & purificação , Dióxido de Silício/química , EstereoisomerismoRESUMO
Aloe vera, a succulent herb, has a long history of use in traditional medicine, including diabetes. Earlier studies from our laboratory demonstrated that the Aloe vera extract has the ability to inhibit the diabetic drug target dipeptidyl peptidase (DPP) IV in vitro. This current study focuses on the isolation of small water soluble active molecule(s) involved in DPP-IV inhibition from Aloe vera extract, and further to characterize its structure and to elucidate the mode of inhibition of the DPP-IV enzyme. Aloe vera gel ethanolic extract was subjected to preparative reverse-phase high-pressure liquid chromatography (RP-HPLC), LH-20 Sephadex gel filtration chromatography, followed by analytical RP-HPLC, to isolate the active molecule involved in DPP-IV inhibition. Based on the spectroscopic studies, the structure of the isolated DPP-IV inhibitor was predicted to be 3, 6-dioxo-3, 3a, 6, 6 a-tetrahydropyrrolo [3, 4-c] pyrrole-1, 4-dicarboxamide with the chemical formula C8H6N4O4, having the molecular weight of 225.175 Da. This molecule inhibited the DPP-IV enzyme in a noncompetitive manner with an IC50 value of 8.59 ± 2.61 µM, with a Ki of 4.7 ± 0.038 µM. Thus, the mechanism of DPP-IV inhibition and the inhibitory constants were determined. The results of our studies suggested that the inhibition of the DPP-IV enzyme as one of the pathways by which the Aloe vera extract may restore the pancreatic islets cell mass in diabetic animal model.
Assuntos
Aloe/química , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Hipoglicemiantes/química , Pirrolidinonas/química , Inibidores da Dipeptidil Peptidase IV/isolamento & purificação , Ensaios Enzimáticos , Humanos , Hipoglicemiantes/isolamento & purificação , Cinética , Pirrolidinonas/isolamento & purificaçãoRESUMO
It is estimated that Trichomonas vaginalis affects an astonishing 3.9% of the world's population, and while many of those infected are asymptomatic, progression of the disease can lead to serious health problems. Currently, the nitroimidazoles constitute the only drug class approved to treat trichomoniasis in the United States, which makes the spread of drug resistance a realistic concern. We developed a new image-based, high-throughput, and high-content assay for testing natural products (purified compounds and extracts) for antitrichomonal activity. Applying this assay system to a library of fungal natural product extracts led to the identification of three general classes of natural product inhibitors that exhibited moderate to strong activities against T. vaginalis: anthraquinones, xanthone-anthraquinone heterodimers, and decalin-linked tetramic-acid-containing metabolites. The tetramate natural products emerged as the most promising candidate molecules with pyrrolocin A (51) exhibiting potent activity against the parasite (EC50 = 60 nM), yet this metabolite showed limited toxicity to mammalian cell lines (selectivity index values of 100 and 167 versus 3T3 fibroblast and Ect1 normal cervical cells, respectively). The imaging-based assay system is a powerful tool for the bioassay-guided purification of single-component antitrichomonal biomolecules from complex natural product mixtures.
Assuntos
Antiprotozoários/farmacologia , Produtos Biológicos/farmacologia , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Processamento de Imagem Assistida por Computador/métodos , Trichomonas vaginalis/efeitos dos fármacos , Antiprotozoários/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Linhagem Celular , Feminino , Fibroblastos/efeitos dos fármacos , Fungos/química , Humanos , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Quinonas/isolamento & purificação , Quinonas/farmacologia , Sensibilidade e Especificidade , Vaginite por Trichomonas/tratamento farmacológicoRESUMO
Fusarium solani H915 is a fungus derived from mangrove sediments. From its ethyl acetate extract, a new alkenoic acid, fusaridioic acid A (1), three new bis-alkenoic acid esters, namely, fusariumester A1 (2), A2 (3) and B (4), together with three known compounds (5â»7), were isolated. The structures of the new compounds were comprehensively characterized by high resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). Additionally, the antifungal activities against tea pathogenic fungi Pestalotiopsis theae and Colletotrichum gloeosporioides were studied. The new compound, 4, containing a ß-lactone ring, exhibited moderate inhibitory activity against P. theae, with an MIC of 50 µg/disc. Hymeglusin (6), a typical ß-lactone antibiotic and a terpenoid alkaloid, equisetin (7), exhibited potent inhibitory activities against both fungal species. The isolated compounds were evaluated for their effects on zebrafish embryo development. Equisetin clearly imparted toxic effect on zebrafish even at low concentrations. However, none of the alkenoic acid derivatives exhibited significant toxicity to zebrafish eggs, embryos, or larvae. Thus, the ß-lactone containing alkenoic acid derivatives from F. solani H915 are low in toxicity and are potent antifungal agents against tea pathogenic fungi.
Assuntos
Alcenos/farmacologia , Antifúngicos/farmacologia , Camellia sinensis/microbiologia , Fusarium/química , Doenças das Plantas/prevenção & controle , Alcenos/química , Alcenos/isolamento & purificação , Animais , Antifúngicos/química , Antifúngicos/isolamento & purificação , Colletotrichum/efeitos dos fármacos , Embrião não Mamífero , Sedimentos Geológicos/microbiologia , Testes de Sensibilidade Microbiana , Doenças das Plantas/microbiologia , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/isolamento & purificação , Tetra-Hidronaftalenos/farmacologia , Testes de Toxicidade , Áreas Alagadas , Peixe-ZebraRESUMO
Seven new unstable tetramic acid derivatives, cladosporiumins I-O (1â»7), together with the known analogue cladodionen (8) were isolated from the extract of the deep-sea-derived fungus Cladosporium sphaerospermum EIODSF 008. Their structures were elucidated by spectroscopic analysis, quantum chemical calculations and ECD spectra. Compound 4 was a Mg complex of tetramic acid derivative. In acidic solvent, 4 could change to 1 and 6, and 7 could change to 5. In addition, 1, 5 and 8 existed as two exchangeable isomers, respectively. The structures of cladosporiumins E-H were reassigned as their Na complexes. The antibacterial and cytotoxic activities of 1â»8 were also evaluated. However, because of their instability, all of the isolated compounds did not show significant antibacterial activity as the preliminary EtOAc extracts of the fungal strain.
Assuntos
Organismos Aquáticos/química , Cladosporium/química , Pirrolidinonas/química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Estabilidade de Medicamentos , Células HL-60 , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Solventes/químicaRESUMO
Four new tetramic acids, cladosins H-K (1-4), and a related known compound, cladodionen (5), were isolated from the culture of the Mariana Trench (depth 6562 m) sediment-derived fungus Cladosporium sphaerospermum L3P3 treated with the histone deacetylase inhibitor SAHA (suberanilohydroxamic acid). Interestingly, compounds 1-5 existed as equilibrium E/ Z mixtures and 1-4 were the first cases of tetramic acids containing aniline moieties. Their structures including absolute configurations were elucidated through a combination of NMR, MS, and Mosher's method, together with the consideration of biogenetic origins. Incubation experiments of exogenous aniline and N-phenyloctanamide revealed that the aniline moiety in cladosins H-K (1-4) is probably derived from the degradation of SAHA, indicating that the well-known histone deacetylase inhibitor SAHA could be metabolized by L3P3 and provide aniline as a precursor for biotransformation of chemically reactive polyketides. The cytotoxicity of 1-5 was evaluated against the PC-3, MGC-803, SH-SY5Y, HCT-116, K562, and HL-60 cell lines, and compound 2 showed promising cytotoxicity against the HL-60 cell line with an IC50 value of 2.8 µM.
Assuntos
Compostos de Anilina/isolamento & purificação , Cladosporium/química , Policetídeos/isolamento & purificação , Pirrolidinonas/isolamento & purificação , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Estrutura Molecular , Policetídeos/química , Policetídeos/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Vorinostat/química , Vorinostat/farmacologiaRESUMO
Brivaracetam (BRV) is a new high affinity synaptic vesicle protein 2A ligand recently approved for adults with partial-onset seizures. As a support to in vitro metabolism assays, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method coupled to off-line solid phase extraction (SPE) was developed to quantify BRV acid metabolites, that is, BRV-AC (carboxylic derivative derived from BRV hydrolysis) and BRV-OHAC (corresponding to hydroxylated BRV-AC). The method was validated for various incubates (liver and kidney tissue homogenates and blood, all from humans) and applied to in vitro metabolism assays. The analytes were isolated from buffered samples using ISOLUTE C8 96-well SPE plates. Chromatographic separation was achieved on a Waters Atlantis T3 C18 analytical column (2.1â¯mmâ¯×â¯50â¯mm, 5⯵m) with detection accomplished using a Waters Premier tandem mass spectrometer in positive ion electrospray and multiple reaction monitoring (MRM) mode. The standard curves, which ranged from 1.00 to 200â¯ng/mL for BRV-AC, BRV-OHAC, were fitted to a 1/x2 weighted linear regression model. The intra-assay precision and inter-assay precision (expressed as coefficient of variation -%CV) were <8.5%, and the assay accuracy (deviation - %Dev) was within ±7.1% for the different matrices. This accurate, precise, and selective SPE/LC-MS/MS method has been successfully applied to in vitro assays aimed at characterizing the kinetics of BRV hydrolysis. BRV was found to be a better substrate for hydrolysis than its hydroxylated metabolite BRV-OH. BRV hydrolysis was detected in blood, liver and kidneys, demonstrating the broad distribution of the enzyme catalyzing the reaction.
Assuntos
Cromatografia Líquida/métodos , Pirrolidinonas/análise , Pirrolidinonas/metabolismo , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Humanos , Hidrólise , Rim/citologia , Rim/metabolismo , Limite de Detecção , Modelos Lineares , Microssomos Hepáticos/metabolismo , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Reprodutibilidade dos TestesRESUMO
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-ZebraRESUMO
Malaria is one of the major infectious diseases and foremost cause of mortality and morbidity in many subtropical and tropical regions. In the last years, the situation has become worst in many ways, due to increase in the parasites resistance to various available antimalarial agents. Furthermore, malaria`s control is beginning to be more sophisticated by the parallel spread of mosquito vector`s resistance to the available insecticides. Recently, there is a wide consensus to seek for target specific, safe, affordable, and effective new antimalarial agents, which can compete with synthetic ones. Endophytic fungi are of a growing interest as prominent sources of structurally unique bioactive natural products. The bio-metabolites isolated from endophytic fungi, possessing antimalarial potential may compose the base for the synthesis of novel drugs that might be utilized to withstand malaria and its resistance. For getting information on the various studies, PubMed, Google Scholar, ScienceDirect, SpringerLink, Scopus, and Wiley search was done using keywords (malaria, endophytic fungi, and antimalarial activity). The present review covers the literature published from 1996 to 2017 and highlights the metabolites for which antimalarial activities have been reported. Overall, 135 fungal metabolites and 72 references are cited. In addition, their structure, chemical class, fungal source, host, and activity have been presented. This review shows the significance of endophytic fungi as a wealthy pool of antimalarial agents.
Assuntos
Antimaláricos/química , Produtos Biológicos/química , Endófitos/química , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Cromonas/química , Cromonas/isolamento & purificação , Cromonas/farmacologia , Depsipeptídeos/química , Depsipeptídeos/isolamento & purificação , Depsipeptídeos/farmacologia , Endófitos/metabolismo , Humanos , Malária/tratamento farmacológico , Malária/transmissão , Plasmodium/efeitos dos fármacos , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologiaRESUMO
OBJECTIVE: To screen for the quorum-sensing (QS) inhibitors from marine-derived fungi and evaluate their anti-QS properties in Pseudomonas aeruginosa. RESULTS: QS inhibitory activity was found in secondary metabolites of a marine fungus Fusarium sp. Z10 using P. aeruginosa QSIS-lasI biosensor. The major active compound of this fungus was isolated by HPLC and identified as equisetin. Subinhibitory concentration of equisetin could inhibit the formation of biofilm, swarming motility, and the production of virulence factors in P. aeruginosa. The inhibition of las, PQS, and rhl system by equisetin were determined using Escherichia coli MG4/pKDT17, E.coli pEAL08-2, and E.coli pDSY, respectively. Real-time RT-PCR assays showed that equisetin could downregulate the mRNA expression of QS-related genes. CONCLUSIONS: Equisetin proved its potential as an inhibitor against P. aeruginosa QS system and might also serve as precursor compound in development of novel therapeutics for infectious diseases by optimal design of structures.
Assuntos
Fusarium/química , Pseudomonas aeruginosa/fisiologia , Pirrolidinonas/farmacologia , Percepção de Quorum/efeitos dos fármacos , Tetra-Hidronaftalenos/farmacologia , Biofilmes/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Pirrolidinonas/isolamento & purificação , Metabolismo Secundário , Tetra-Hidronaftalenos/isolamento & purificaçãoRESUMO
A new pyrrolidinone derivative named nigrosporamide A (1), and a new acetophenone derivative, 4-prenyloxyclavatol (2), were isolated from an endophytic fungus Nigrospora sphaerica (collection No. ZMT05) isolated from Oxya chinensis Thunberg. Their chemical structures were established on the basis of the interpretation of spectroscopic data. In primary in vitro bioassay, nigrosporamide A (1) exhibited strong antifungal activity against Colletotrichum gloeosporioides and high inhibitory activity towards α-glucosidase.
Assuntos
Acetofenonas/farmacologia , Ascomicetos/química , Colletotrichum/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Gafanhotos/microbiologia , Pirrolidinonas/farmacologia , Acetofenonas/isolamento & purificação , Animais , China , Fungicidas Industriais/isolamento & purificação , Estrutura Molecular , Pirrolidinonas/isolamento & purificaçãoRESUMO
Pseurotin A was isolated from a culture of marine Bacillus sp. FS8D and showed to be active against the proliferation of four different glioma cells with IC50 values of 0.51-29.3 µM. It has been found that pseurotin A downregulated the expression of tumour glycolytic enzymes pyruvate kinase M2 (PKM2) and lactate dehydrogenase 5 (LDH5) and upregulated the expression of pyruvate dehydrogenase beta (PDHB), adenosine triphosphate synthase beta (ATPB) and cytochrome C (Cyto-C), the important regulators for tricarboxylic acid cycle and oxidative phosphorylation. The data suggested that targeting multiple metabolic enzymes might be one of the antiglioma mechanisms of pseurotin A.