RESUMO
Toporosides A-D (1-4), new ω-glycosylated fatty acid amides, were isolated from the sponge Stelodoryx toporoki. The structures of these compounds, including absolute configurations of stereogenic centers, were established using analysis of 1D and 2D NMR, ECD, and HR mass spectra as well as chemical transformations. Toporosides A (1) and B (2) are the first lipids containing a cyclopentenyl α,ß-unsaturated carbonyl moiety in the polymethylene chain. Toporoside C (3) is likely a precursor, which undergoes intramolecular aldol condensation to produce 1 and 2. Toporosides A, C, and D showed protective effects against TNF-α-induced injury in H9c2 cardiomyocytes.
Assuntos
Amidas , Poríferos , Amidas/química , Animais , Ácidos Graxos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Poríferos/químicaRESUMO
Seven new deoxyisoaustamide derivatives (1-7) together with known compounds (8-10) were isolated from the coral-derived fungus Penicillium dimorphosporum KMM 4689. Their structures were established using spectroscopic methods, X-ray diffraction analysis and by comparison with related known compounds. The absolute configurations of some alkaloids were determined based on CD and NOESY data as well as biogenetic considerations. The cytotoxic and neuroprotective activities of some of the isolated compounds were examined and structure-activity relationships were pointed out. New deoxyisoaustamides 4-6 at concentration of 1 µM revealed a statistical increase of PQ(paraquat)-treated Neuro-2a cell viability by 30-39%.
Assuntos
Antozoários , Antineoplásicos/isolamento & purificação , Indóis/isolamento & purificação , Penicillium/isolamento & purificação , Animais , Antozoários/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cristalografia por Raios X/métodos , Humanos , Indóis/química , Indóis/farmacologia , Penicillium/químicaRESUMO
Seven new polyoxygenated steroids belonging to a new structural group of sponge steroids, gracilosulfates A-G (1-7), possessing 3ß-O-sulfonato, 5ß,6ß epoxy (or 5(6)-dehydro), and 4ß,23-dihydroxy substitution patterns as a common structural motif, were isolated from the marine sponge Haliclona gracilis. Their structures were determined by NMR and MS methods. The compounds 1, 2, 4, 6, and 7 inhibited the expression of prostate-specific antigen (PSA) in 22Rv1 tumor cells.
Assuntos
Antineoplásicos/farmacologia , Haliclona/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Esteroides/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Calicreínas/metabolismo , Masculino , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Esteroides/química , Esteroides/isolamento & purificaçãoRESUMO
The phenomenon of high sugar consumption by tumor cells is known as Warburg effect. It results from a high glycolysis rate, used by tumors as preferred metabolic pathway even in aerobic conditions. Targeting the Warburg effect to specifically deliver sugar conjugated cytotoxic compounds into tumor cells is a promising approach to create new selective drugs. We designed, synthesized, and analyzed a library of novel 6-S-(1,4-naphthoquinone-2-yl)-d-glucose chimera molecules (SABs)-novel sugar conjugates of 1,4-naphthoquinone analogs of the sea urchin pigments spinochromes, which have previously shown anticancer properties. A sulfur linker (thioether bond) was used to prevent potential hydrolysis by human glycoside-unspecific enzymes. The synthesized compounds exhibited a Warburg effect mediated selectivity to human prostate cancer cells (including highly drug-resistant cell lines). Mitochondria were identified as a primary cellular target of SABs. The mechanism of action included mitochondria membrane permeabilization, followed by ROS upregulation and release of cytotoxic mitochondrial proteins (AIF and cytochrome C) to the cytoplasm, which led to the consequent caspase-9 and -3 activation, PARP cleavage, and apoptosis-like cell death. These results enable us to further clinically develop these compounds for effective Warburg effect targeting.
Assuntos
Antineoplásicos/farmacologia , Pigmentos Biológicos/química , Neoplasias da Próstata/tratamento farmacológico , Ouriços-do-Mar/química , Efeito Warburg em Oncologia/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glucose/síntese química , Glucose/farmacologia , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Neoplasias da Próstata/patologiaRESUMO
The structural elucidation of primary and secondary peroxidation products, formed from complex lipids, is a challenge in lipid analysis. In the present study, rare minor oxidized cerebrosides, isolated from the extract of a far eastern deep-sea glass sponge, Aulosaccus sp., were analyzed as constituents of a multi-component RP-HPLC (high-performance liquid chromatography on reversed-phase column) fraction using NMR (nuclear magnetic resonance) spectroscopy, mass spectrometry, GC (gas chromatography), and chemical transformations (including hydrogenation or derivatization with dimethyl disulfide before hydrolysis). Eighteen previously unknown ß-D-glucopyranosyl-(1â1)-ceramides (1a-a//, 1b-b//, 2a-a//, 2b-b//, 3c-c//, 3d-d//) were shown to contain phytosphingosine-type backbones (2S,3S,4R,11Z)-2-aminoeicos-11-ene-1,3,4-triol (in 1), (2S,3S,4R,13Z)-2-aminoeicos-13-ene-1,3,4-triol (in 2), and (13S*,14R*)-2-amino-13,14-methylene-eicosane-1,3,4-triol (in 3). These backbones were N-acylated with straight-chain monoenoic (2R)-2-hydroxy acids that had allylic hydroperoxy/hydroxy/keto groups on C-17/ in the 15/E-23:1 chain (a-a//), C-16/ in the 17/E-23:1 (b-b//) and 14/E-22:1 (c-c//) chains, and C-15/ in the 16/E-22:1 chain (d-d//). Utilizing complementary instrumental and chemical methods allowed for the first detailed structural analysis of a complex mixture of glycosphingolipids, containing allylically oxygenated monoenoic acyl chains.
Assuntos
Amidas/química , Cerebrosídeos/química , Ácidos Graxos/química , Oxigênio/química , Poríferos/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Misturas Complexas/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Glicoesfingolipídeos/química , Lipídeos/químicaRESUMO
A series of new tetracyclic oxathiine-fused quinone-thioglycoside conjugates based on biologically active 1,4-naphthoquinones and 1-mercapto derivatives of per-O-acetyl d-glucose, d-galactose, d-xylose, and l-arabinose have been synthesized, characterized, and evaluated for their cytotoxic and antimicrobial activities. Six tetracyclic conjugates bearing a hydroxyl group in naphthoquinone core showed high cytotoxic activity with EC50 values in the range of 0.3 to 0.9 µM for various types of cancer and normal cells and no hemolytic activity up to 25 µM. The antimicrobial activity of conjugates was screened against Gram-positive bacteria (Staphylococcus aureus, Bacillus cereus), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungus Candida albicans by the agar diffusion method. The most effective juglone conjugates with d-xylose or l-arabinose moiety and hydroxyl group at C-7 position of naphthoquinone core at concentration 10 µg/well showed antimicrobial activity comparable with antibiotics vancomicin and gentamicin against Gram-positive bacteria strains. In liquid media, juglone-arabinosidic tetracycles showed highest activity with MIC 6.25 µM. Thus, a positive effect of heterocyclization with mercaptosugars on cytotoxic and antimicrobial activity for group of 1,4-naphthoquinones was shown.
Assuntos
Naftoquinonas/química , Oxati-Inas/química , Quinonas/química , Tioglucosídeos/síntese química , Tioglucosídeos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Técnicas de Química Sintética , Células HeLa , Humanos , Tioglucosídeos/químicaRESUMO
Guitarrins A-E (1-5), the first natural 5-azaindoles, and aluminumguitarrin A (1a), the first aluminum-containing compound from marine invertebrates, were isolated from the sponge Guitarra fimbriata. The structures of these compounds were established using detailed analysis of 1D and 2D NMR data, mass spectra, and X-ray analysis of 1 and 1a. Compound 3 was proved to be a natural inhibitor of alkaline phosphatase.
Assuntos
Compostos de Alumínio/farmacologia , Compostos Aza/farmacologia , Indóis/farmacologia , Poríferos/química , Compostos de Alumínio/química , Compostos de Alumínio/isolamento & purificação , Animais , Compostos Aza/química , Compostos Aza/isolamento & purificação , Indóis/química , Indóis/isolamento & purificação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura MolecularRESUMO
Seven new unusual polysulfated steroids-topsentiasterol sulfate G (1), topsentiasterol sulfate I (2), topsentiasterol sulfate H (3), bromotopsentiasterol sulfate D (4), dichlorotopsentiasterol sulfate D (8), bromochlorotopsentiasterol sulfate D (9), and 4ß-hydroxyhalistanol sulfate C (10), as well as three previously described-topsentiasterol sulfate D (7), chlorotopsentiasterol sulfate D (5) and iodotopsentiasterol sulfate D (6) have been isolated from the marine sponge Halichondria vansoesti. Structures of these compounds were determined by detailed analysis of 1D- and 2D-NMR and HRESIMS data, as well as chemical transformations. The effects of the compounds on human prostate cancer cells PC-3 and 22Rv1 were investigated.
Assuntos
Glucose/metabolismo , Poríferos/química , Antígeno Prostático Específico/metabolismo , Esteroides/química , Esteroides/farmacologia , Sulfatos/química , Sulfatos/farmacologia , Animais , Humanos , Espectroscopia de Ressonância Magnética/métodos , Células PC-3 , Esteróis/química , Esteróis/farmacologia , VietnãRESUMO
Ten new diterpene glycosides virescenosides Z9-Z18 (1-10) together with three known analogues (11-13) and aglycon of virescenoside A (14) were isolated from the marine-derived fungus Acremonium striatisporum KMM 4401. These compounds were obtained by cultivating fungus on wort agar medium with the addition of potassium bromide. Structures of the isolated metabolites were established based on spectroscopic methods. The effects of some isolated glycosides and aglycons 15-18 on urease activity and regulation of Reactive Oxygen Species (ROS) and Nitric Oxide (NO) production in macrophages stimulated with lipopolysaccharide (LPC) were evaluated.
Assuntos
Acremonium/química , Diterpenos/química , Glicosídeos/química , Glicosídeos/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Diterpenos/isolamento & purificação , Fungos , Glicosídeos/isolamento & purificação , Holothuria/microbiologia , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Óxido Nítrico , Espécies Reativas de Oxigênio , Urease/efeitos dos fármacosRESUMO
Six new carotane sesquiterpenoids piltunines A-F (1-6) together with known compounds (7-9) were isolated from the marine-derived fungus Penicillium piltunense KMM 4668. Their structures were established using spectroscopic methods. The absolute configurations of 1-7 were determined based on circular dichroism (CD) and nuclear Overhauser spectroscopy (NOESY) data as well as biogenetic considerations. The cytotoxic activity of some of the isolated compounds and their effects on regulation of reactive oxygen species (ROS) and nitric oxide (NO) production in lipopolysaccharide-stimulated macrophages were examined.
Assuntos
Antineoplásicos/farmacologia , Macrófagos/efeitos dos fármacos , Penicillium/química , Sesquiterpenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Células Cultivadas , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificaçãoRESUMO
In our research on biologically active compounds from Vietnamese marine invertebrates, rare melibiose-containing glycosphingolipids were found in a sample of a sponge-coral association (Desmapsamma anchorata/Carijoa riisei). Melibiosylceramides were analyzed as constituents of some multi-component RP-HPLC fractions, and the structures of 14 new (1b, 3b, 4a-4c, 6a-6c, 8b, 9a, 9b, 10b, 11a, 11b) and five known (2b, 5a-5c, 7b) natural compounds were elucidated using NMR, mass spectrometry, optical rotation, and chemical transformations. These α-d-Galp-(1â6)-ß-d-Glcp-(1 â 1)-ceramides (presumably sponge-derived compounds) were shown to contain phytosphingosine-type n-t17:0 (1), (6E)-n-t17:1 (2), i-t17:0 (3), n-t18:0 (4), (6E)-n-t18:1 (5), i-t18:0 (6), (6E)-i-t18:1 (7), i-t19:0 (8), (6E)-i-t19:1 (9), ai-t19:0 (10), and (6E)-ai-t19:1 (11) backbones N-acylated with saturated straight-chain (2R)-2-hydroxy C21 (a), C22 (b), and C23 (c) acids. Characteristic trends in the fragmentations of the terminal parts of tetraacetylated normal-chain and iso- and anteiso-branched sphingoid bases were observed using GC/MS. The total sum of melibiosylceramides and compound 5b caused a reduction in colony formation of human melanoma cells.
Assuntos
Antozoários/química , Produtos Biológicos/química , Glicoesfingolipídeos/análise , Melibiose/análise , Poríferos/química , Animais , Produtos Biológicos/isolamento & purificação , Biomarcadores/análise , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cerebrosídeos/química , Cerebrosídeos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres , Ácidos Graxos não Esterificados/química , Cromatografia Gasosa-Espectrometria de Massas , Glicoesfingolipídeos/química , Glicoesfingolipídeos/farmacologia , Humanos , Melibiose/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Açúcares/análiseRESUMO
The absolute configuration of the cytotoxic guanidine alkaloid monanchocidin A with 11 stereogenic centers from the marine sponge Monanchora pulchra was determined as 5 R, 8 S, 10 S, 13 R, 14 S, 15 R, 19 R, 23 R, 37 S, 42 S, 43 R after extensive reductive degradation and conversion of the resulting alcohols to MTPA derivatives.
Assuntos
Alcaloides/química , Organismos Aquáticos/química , Citotoxinas/química , Guanidina/análogos & derivados , Animais , Guanidina/química , Guanidinas/química , Poríferos/químicaRESUMO
Melonoside B (1) and melonosins B (2) and A (3), new lipids based on polyoxygenated fatty acid amides, and known melonoside A (4) were isolated from two different collections of the marine sponge Melonanchora kobjakovae. The structures of these compounds, including their absolute configurations, were established using detailed analysis of 1D and 2D NMR, ECD, and mass spectra as well as chemical transformations. Melonosins 2 and 3 inhibit AP-1- and NF-kB-dependent transcriptional activities in JB6 Cl41 cells at noncytotoxic concentrations, demonstrating potential cancer preventive activity.
Assuntos
Ácidos Graxos/isolamento & purificação , Poríferos/química , Animais , Linhagem Celular , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , NF-kappa B/antagonistas & inibidoresRESUMO
Twelve new polyketides, zosteropenillines A-L (1-12), together with known polyketide pallidopenilline A (13), were isolated from the ethylacetate extract of the fungus Penicillium thomii associated with the seagrass Zostera marina. Their structures were established based on spectroscopic methods. The absolute configuration of zosteropenilline A (1) as 4R, 5S, 8S, 9R, 10R, and 13S was determined by a combination of the modified Mosher's method, X-ray analysis, and NOESY data. Absolute configurations of zosteropenillines B-D (2-4) were determined by timedependent density functional theory (TD-DFT) calculations of ECD spectra. The effect of compounds 1-3, 7, 8, 10, and 11 on the viability of human drug-resistant prostate cancer cells PC3 as well as on autophagy in these cancer cells and inhibitory effects of compounds 1, 2, and 8-10 on NO production in LPS-induced RAW 264.7 murine macrophages were examined.
Assuntos
Antineoplásicos/farmacologia , Organismos Aquáticos/química , Autofagia/efeitos dos fármacos , Penicillium/química , Policetídeos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Ressonância Magnética Nuclear Biomolecular , Policetídeos/química , Policetídeos/isolamento & purificação , Células RAW 264.7 , Zosteraceae/microbiologiaRESUMO
Eleven new polyketides, pallidopenillines 1-11, were isolated from the alga-derived fungus Penicillium thomii. The structures of these compounds were established based on spectroscopic methods. The absolute configuration of pallidopenilline A (1) as 4R, 5S, 8S, 9R, 10R, 13R was established using a combination of the modified Mosher's method, X-ray analysis, and NOESY data. The absolute configurations of 2-5 were determined by time-dependent density functional theory calculations of the ECD spectra and ECD and NOESY data. It was shown that 1-acetylpallidopenilline A (2) and pallidopenilline G (10) inhibit the growth of colonies of 22Rv1 cells by 40% at 2 and 1 µM, respectively.
Assuntos
Antineoplásicos/isolamento & purificação , Penicillium/química , Policetídeos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Policetídeos/química , Policetídeos/farmacologia , Sargassum/microbiologiaRESUMO
Neopetrosides A (1) and B (2), new naturally occurring ribosides of nicotinic acid with extremely rare α-N-glycoside linkages and residues of p-hydroxybenzoic and pyrrole-2-carboxylic acids attached to C-5', were isolated from a marine Neopetrosia sp. sponge. Structures 1 and 2 were determined by NMR and MS methods and confirmed by the synthesis of 1 and its ß-riboside analogue (3). Neopetroside A (1) upregulates mitochondrial functions in cardiomyocytes.
Assuntos
Nucleosídeos/química , Nucleosídeos/isolamento & purificação , Poríferos/química , Piridinas/química , Piridinas/isolamento & purificação , Trifosfato de Adenosina/análise , Animais , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Nucleosídeos/síntese química , Piridinas/síntese químicaRESUMO
Several classes of glycerolipids were isolated from the total lipids of the algae Saccharina cichorioides, Eualaria fistulosa, Fucus evanescens, Sargassum pallidum, Silvetia babingtonii (Ochrophyta, Phaeophyceae), Tichocarpus crinitus, and Neorhodomela larix (Rhodophyta, Florideophyceae). The structures of these lipids were examined by nuclear magnetic resonance (NMR) spectroscopy, including 1D ((1) H and (13) C) and 2D (COSY, HSQC and HMBC) experiments. All of the investigated algae included common galactolipids and sulfonoglycolipids as the major glycolipids. Minor glycolipids isolated from S. cichorioides, T. crinitus, and N. laris were identified as lyso-galactolipids with a polar group consisted of the galactose. Comparison of the (1) H NMR data of minor nonpolar lipids isolated from the extracts of the brown algae S. pallidum and F. evanescens with the (1) H NMR data of other lipids allowed them to be identified as diacylglycerols. The structures of betaine lipids isolated from brown algae were confirmed by NMR for the first time. The fatty acid compositions of the isolated lipids were determined by gas chromatography-mass spectrometry.
RESUMO
Ten new austalide meroterpenoids (1-10) were isolated from the alga-derived fungi Penicillium thomii KMM 4645 and Penicillium lividum KMM 4663. Their structures were elucidated by extensive spectroscopic analysis and by comparison with related known compounds. The absolute configurations of some of the metabolites were assigned by the modified Mosher's method and CD data. Compounds 1, 2, 8, and 9 were able to inhibit AP-1-dependent transcriptional activity in JB6 Cl41 cell lines at noncytotoxic concentrations. Austalides 1-5, 8, and 9 exhibited significant inhibitory activity against endo-1,3-ß-D-glucanase from a crystalline stalk of the marine mollusk Pseudocardium sachalinensis.
Assuntos
Penicillium/química , Terpenos/isolamento & purificação , Animais , Aspergillus/química , Ensaios de Seleção de Medicamentos Antitumorais , Japão , Camundongos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oceanos e Mares , Sargassum/microbiologia , Terpenos/química , Terpenos/farmacologia , Fator de Transcrição AP-1/efeitos dos fármacosRESUMO
Seven new 6,6-spiroketals, sargassopenillines A-G (1-7) were isolated from the alga-derived fungi Penicillium thomii KMM 4645 and Penicillium lividum KMM 4663. The structures of these metabolites were determined by HR-MS and 1D and 2D NMR. The absolute configurations of compounds 1, 5 and 6 were assigned by the modified Mosher's method and by CD data. Sargassopenilline C (3) inhibited the transcriptional activity of the oncogenic nuclear factor AP-1 with an IC50 value of 15 µM.
Assuntos
Fungos/química , Furanos/química , Furanos/farmacologia , Penicillium/química , Phaeophyceae/microbiologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Animais , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Fator de Transcrição AP-1/metabolismoRESUMO
The bacterium Streptomyces sp. KMM 9044 from a sample of marine sediment collected in the northwestern part of the Sea of Japan produces highly chlorinated depsiheptapeptides streptocinnamides A (1) and B (2), representatives of a new structural group of antibiotics. The structures of 1 and 2 were determined using nuclear magnetic resonance and mass spectrometry studies and confirmed by a series of chemical transformations. Streptocinnamide A potently inhibits Micrococcus sp. KMM 1467, Arthrobacter sp. ATCC 21022, and Mycobacterium smegmatis MC2 155.