RESUMO
Marine toxins (MTs) are a group of structurally complex natural products with unique toxicological and pharmacological activities. In the present study, two common shellfish toxins, okadaic acid (OA) (1) and OA methyl ester (2), were isolated from the cultured microalgae strain Prorocentrum lima PL11. OA can significantly activate the latent HIV but has severe toxicity. To obtain more tolerable and potent latency reversing agents (LRAs), we conducted the structural modification of OA by esterification, yielding one known compound (3) and four new derivatives (4-7). Flow cytometry-based HIV latency reversal activity screening showed that compound 7 possessed a stronger activity (EC50 = 46 ± 13.5 nM) but was less cytotoxic than OA. The preliminary structure-activity relationships (SARs) indicated that the carboxyl group in OA was essential for activity, while the esterification of carboxyl or free hydroxyls were beneficial for reducing cytotoxicity. A mechanistic study revealed that compound 7 promotes the dissociation of P-TEFb from the 7SK snRNP complex to reactivate latent HIV-1. Our study provides significant clues for OA-based HIV LRA discovery.
Assuntos
Dinoflagellida , Infecções por HIV , HIV-1 , Humanos , Ácido Okadáico/toxicidade , Latência Viral , Toxinas Marinhas/química , Dinoflagellida/químicaRESUMO
Chromatographic fractionation of the EtOH extracts of the marine-derived fungus Aspergillus versicolor A18 has led to the isolation of 11 homo/hetero-dimers of aromatic bisabolane sesquiterpenoids including eight diphenyl ether-coupled aromatic bisabolanes (1a/1b and 5−10) and three homodimers (2−4), together with their monomers including three aromatic bisabolanes (11−13) and two diphenyl ethers (14 and 15). Their structures and absolute configurations were elucidated by extensive spectroscopic analysis including HRESIMS, 1D/2D NMR, calculated ECD, and the optical rotatory data. Among the four new compounds, (+/−)-asperbisabol A (1a/1b), asperbisabol B (2), and asperbisabol C (3), the enantiomers 1a and 1b represent an unprecedented skeleton of diphenyl ether-coupled aromatic bisabolane sesquiterpenoids with a spiroketal core moiety. The neuroprotective effects of selected compounds against sodium nitroprusside (SNP)-induced injury were evaluated in PC12 cells by the MTT assay. Five compounds (1a, 6, and 8−10) showed remarkable neuroprotective activities at 10 µM, being more active than the positive control edaravone.
Assuntos
Aspergillus , Sesquiterpenos , Aspergillus/química , China , Estrutura Molecular , Sesquiterpenos Monocíclicos , Sesquiterpenos/químicaRESUMO
Three steroidal saponins, including astrogorgiosides A (1) and B (2) bearing acetamido-glucose moieties, and astrogorgioside C (3) with a 19-nor and bearing an aromatized B ring steroid aglycone, together with a known major saponin dimorphoside A (4), were obtained from the gorgonian Astrogorgia dumbea collected near Dongshan Island in East China Sea. Structures of these compounds were elucidated by in-depth spectral and chemical methods, including 2D-NMR, HR-ESI-MS spectra, and acidic hydrolysis. For the first time, acetamido-glucose moiety is being reported from a gorgonian. The B-ring aromatized steroid aglycone of compound 3 is also rare in marine natural products. Compounds 1-3 exhibited moderate cytotoxic activity with IC50 values of 26.8-45.6 µM against human tumor cells Bel-7402 and K562.
Assuntos
Besouros/química , Saponinas/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , China , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Saponinas/química , Saponinas/farmacologiaRESUMO
Ten new prostaglandin derivatives (PGs), sarcoehrendins A-J (1-10), together with five known analogues (11-15) were isolated from the soft coral Sarcophyton ehrenbergi. Compounds 4-8 represented the first examples of PGs featuring an 18-ketone group. The structures including the absolute configurations were elucidated on the basis of spectroscopic analysis and chemical evidence. All of the isolates and six synthetic analogues (3a, 3b, 4a, and 11a-11c) were screened for inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 2, 10, 11a, 11b, and 13-15 exhibited inhibition with IC50 values less than 10 µM, and compound 15 (IC50 = 1.4 µM) showed comparable activity to the positive control rolipram (IC50 = 0.60 µM). The active natural PGs (2, 10, and 13-15) represent the first examples of PDE4 inhibitors without an aromatic moiety, and a preliminary structure-activity relationship is also proposed.
Assuntos
Antozoários/química , Inibidores da Fosfodiesterase 4/isolamento & purificação , Inibidores da Fosfodiesterase 4/farmacologia , Prostaglandinas/isolamento & purificação , Prostaglandinas/farmacologia , Animais , China , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Inibidores da Fosfodiesterase 4/química , Prostaglandinas/química , Rolipram/farmacologia , Relação Estrutura-AtividadeRESUMO
Six new tetraprenylated alkaloids, designated as malonganenones L-Q (1-6), were isolated from the gorgonian Echinogorgia pseudossapo, collected in Daya Bay of Guangdong Province, China. The structures of 1-6 featuring a methyl group at N-3 and a tetraprenyl chain at N-7 in the hypoxanthine core were established by extensive spectroscopic analyses. Compounds 1-6 were tested for their inhibitory activity against the phosphodiesterases (PDEs)-4D, 5A, and 9A, and compounds 1 and 6 exhibited moderate inhibitory activity against PDE4D with IC50 values of 8.5 and 20.3 µM, respectively.
Assuntos
Alcaloides/farmacologia , Antozoários/química , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Alcaloides/administração & dosagem , Alcaloides/isolamento & purificação , Animais , China , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/efeitos dos fármacos , Concentração Inibidora 50 , Oceanos e Mares , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/isolamento & purificação , Análise EspectralRESUMO
Five purine and carboline alkaloids were isolated from the methanol extract of the ascidian Symplegma oceania. Classic chromatographies including preparative HPLC were used for isolation and purification of the compounds. The structures were established as 6-methoxy-7-methyl-8-oxoguanine (1), 2-methylimino-3-methyl-6-methylamino- 9H-purine (2), 1,2,3,4-tetrahydro-betacarboline (3), 1,2,3,4-tetrahydro-1-methyl-beta-carboline (4) and 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (5) by comparison the spectroscopic data (MS, 1H, 13C-NMR) with those reported in the literatures. Compounds 2-5 were reported from the the genus Symplegma for the first time. The purine and carboline were the major alkaloid types of S. oceania.
Assuntos
Alcaloides/química , Carbolinas/química , Purinas/química , Urocordados/química , Animais , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Microscopic interactions between phycosphere microbiota and host algae play crucial roles in aquatic ecosystems. Despite their significance, there is a scarcity of available genome sequences derived from the phycosphere microbiome. Here, we report the draft genome sequences of nine heterotrophic proteobacterial strains isolated from the toxic dinoflagellate Alexandrium catenella LZT09 during execution of our Phycosphere Microbiome Project. Further exploration of the genomic features of the alga-associated bacterial community will profoundly help in deeply deciphering the processes and mechanisms governing the host-microbe interactome within algal holobionts in the ocean.
Assuntos
Antozoários/química , Diterpenos/química , Diterpenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Peso MolecularRESUMO
Two novel limonoids, chuktabrin A (1), featuring the unique motifs of a 1,3-dioxolan-2-one and a 3,4-dihydro-2 H-pyran, and chuktabrin B (2), possessing an unprecedented polycyclic skeleton, were isolated from Chukrasia tabularis. The structures of 1 and 2 bearing a biosynthetically extended C3 and C2 unit at C-15, respectively, were elucidated on the basis of spectroscopic data, and that of 1 was confirmed by a single-crystal X-ray diffraction.
Assuntos
Limoninas/química , Meliaceae/química , Limoninas/isolamento & purificação , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Caules de Planta/química , Difração de Raios XRESUMO
Six limonoids, trijugins D-H (1-5) and methyl 8alpha-hydroxy-8,30-dihydroangolensate (6), two degraded limonoids, trichiconnarins A and B (7-8), and a pregnane steroid, 3beta,4alpha-dihydroxypregnan-21-one (9), along with the known trijugin C (10) and 3beta,4alpha-dihydroxypregnan-16-one (11) were isolated from twigs and leaves of Trichilia connaroides. Their structures were established on the basis of extensive spectroscopic analysis.
Assuntos
Limoninas/química , Meliaceae/química , Esteroides/química , Estrutura MolecularRESUMO
Eucalyptals A-C (1-3) with a new skeleton of 3,5-diformyl-isopentyl phloroglucinol-coupled cadinane were isolated from the fruits of Eucalyptus globulus. Their structures were elucidated by spectroscopic analysis, and that of 1 was confirmed by single-crystal X-ray diffraction. The biosynthetic pathway of 1-3 was also postulated. Compounds 1-3 exhibited selective cytotoxicity against the HL-60 cell line.
Assuntos
Eucalyptus/química , Extratos Vegetais/química , Terpenos/química , Espectroscopia de Ressonância Magnética , Modelos MolecularesRESUMO
Walsuronoid A (1), a limonoid featuring an unprecedented 3,4-peroxide-bridged A-seco skeleton, together with walsuronoids B (2) and C (3) possessing a rare 18(13-->14)-abeo-limonoid skeleton, was isolated from Walsura robusta. The structures were elucidated by spectroscopic analysis and chemical correlation, and that of 1 was confirmed by single-crystal X-ray diffraction. Biosynthetic pathway of 2 and 3 was proposed and was chemically mimicked. Compounds 1 and 2 showed weak antimalarial activity.
Assuntos
Antimaláricos/química , Hidrocarbonetos Aromáticos com Pontes/química , Limoninas/química , Meliaceae/química , Peróxidos/química , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Cristalografia por Raios X , Limoninas/isolamento & purificação , Limoninas/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/normas , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Testes de Sensibilidade Parasitária , Peróxidos/isolamento & purificação , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Padrões de Referência , Sensibilidade e Especificidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Chuktabularins A-D (1-4), four novel 16-norphragmalin-type limonoids that feature unprecedented skeletons with a biosynthetically extended C2 or C3 unit at C-15 forming a unique 2,7-dioxabicyclo[2.2.1]heptane moiety, were isolated from the stem bark of Chukrasia tabularis. Their structures were elucidated by spectroscopic analysis and computer modeling. The biosynthetic pathway of 1-4 was postulated.
Assuntos
Limoninas/química , Casca de Planta/química , Vias Biossintéticas , Limoninas/biossíntese , Limoninas/isolamento & purificação , Estrutura MolecularRESUMO
[reaction: see text] Four novel tetranortriterpenoids, xylogranatins A-D (1-4), with an unusual 9,10-seco skeleton were isolated from the seeds of a Chinese marine mangrove Xylocarpus granatum. Their structures were determined by spectroscopic and chemical means. Xylogranatin A (1) featured by a unique 1,9-oxygen bridge was confirmed by single-crystal X-ray diffraction, and xylogranatin D (4) with an unprecedented skeleton of C-30-C-9 linkage was postulated biogenetically from 3 via an alpha-hydroxyl ketone rearrangement and was chemically mimicked.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Limoninas/química , Limoninas/isolamento & purificação , Meliaceae/química , Plantas Medicinais/química , Animais , Antineoplásicos Fitogênicos/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Leucemia P388 , Limoninas/farmacologia , Camundongos , Conformação Molecular , Estrutura MolecularRESUMO
[structure: see text] Two novel tetranortriterpenoids, turrapubesins A (1) and B (2), representing the first examples of halogenated and maleimide-bearing limonoids, were isolated from the twigs and leaves of Turraea pubescens. The structures of 1 and 2 were elucidated by extensive spectroscopic analysis. Their absolute configurations were determined by X-ray crystallography of 1 and by CD analysis of a dihydrogenated derivative of 2. Turrapubesin A (1) exhibited weak cytotoxicity against the P-388 tumor cell line.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Limoninas/isolamento & purificação , Meliaceae/química , Plantas Medicinais/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Leucemia P388 , Limoninas/química , Limoninas/farmacologia , Camundongos , Estrutura Molecular , Folhas de PlantaRESUMO
[structure: see text] Two unprecedented C,C-linked dimeric indolizidine alkaloids, flueggenines A (1) and B (2), as well as their biosynthetic precursor (-)-norsecurinine, were isolated from the roots of Flueggea virosa. Their structures and absolute configurations were elucidated by spectroscopic methods, especially 2D NMR and CD spectral analyses, and supported by their unique biosynthetic pathway as proposed. Both 1 and 2 were tested against two tumor cell lines, and alkaloid 1 showed weak activity against the P-388 cell line.
Assuntos
Alcaloides/química , Alcaloides/isolamento & purificação , Euphorbiaceae/química , Indolizinas/química , Indolizinas/isolamento & purificação , Plantas Medicinais/química , Alcaloides/farmacologia , Animais , Azepinas/química , Azepinas/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indolizinas/farmacologia , Leucemia P388 , Camundongos , Estrutura Molecular , Piperidinas/química , Piperidinas/isolamento & purificação , Raízes de Plantas/químicaRESUMO
Three new pregnane steroids, 2beta,3beta,5beta-trihydroxy-pregn-20-en-6-one (1), 3beta-hydroxy-5alpha-pregn-7,20-dien-6-one (2), and 3beta-acetoxy-5alpha-pregn-7,20-dien-6-one (3) were isolated from the twigs and leaves of Turraea pubescens, and were structurally elucidated on the basis of spectroscopic data and chemical method.
Assuntos
Meliaceae/química , Pregnanos/química , Pregnanos/isolamento & purificação , Esteroides/química , Esteroides/isolamento & purificação , Modelos Biológicos , Conformação Molecular , Estrutura Molecular , Componentes Aéreos da Planta/químicaRESUMO
Two novel labdane-type diterpenoids, butanedioic acid mono[(13S)-13-hydroxylabda-8(17),14-dien-19-yl] ester (1) and butanedioic acid bis[(13S)-13-hydroxylabda-8(17),14-dien-19-yl] ester (2), along with the eleven known diterpenoids 3-13 and three other known compounds, were isolated from the bark of Larix chinensis. Their structures were elucidated both spectroscopically and chemically. The major diterpenoids 1-9, 11, and 13, as well as the very abundant phenolic compound 16, were subjected to antibacterial and cytotoxic bioassays. Compounds 7 and 9 showed remarkable in vitro inhibition of Staphylococcus aureus and S. epidermidis (MIC = 37-73 microM).
Assuntos
Antibacterianos/isolamento & purificação , Diterpenos/isolamento & purificação , Larix , Antibacterianos/química , Diterpenos/química , Drogas em Investigação/química , Drogas em Investigação/isolamento & purificação , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Casca de Planta , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificaçãoRESUMO
Four new polyhydroxylated sterols, named halicrasterols A-D (1-4), together with six known analogs (5-10) were isolated from the marine sponge Haliclona crassiloba. Compounds 1 and 2 represented rare examples of steroids featuring 17(20)E-double bonds. The structures of 1-10 were elucidated by spectroscopic analysis and comparison with reported data. This is the first report of a steroid profile for this species. The antimicrobial activities of 1-10 were evaluated against a panel of bacterial and fungal strains in vitro, and compounds 4 and 9 showed moderate activity against some of the Gram-positive strains with MICs ranging from 4 to 32 µg/mL.
Assuntos
Anti-Infecciosos/química , Haliclona/química , Esteróis/química , Animais , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Bacillus/efeitos dos fármacos , Bacillus/crescimento & desenvolvimento , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/crescimento & desenvolvimento , Candida/efeitos dos fármacos , Candida/crescimento & desenvolvimento , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/crescimento & desenvolvimento , Haliclona/metabolismo , Hidroxilação , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Esteróis/isolamento & purificação , Esteróis/farmacologiaRESUMO
Two new alkaloids, angustimine (1) featuring an unprecedented skeleton, and angustifolimine (2) being a rare diamino Daphniphyllum alkaloid, were isolated from Daphniphyllum angustifolium. Their structures were elucidated by extensive spectroscopic analysis. The biosynthetic origin of 1 was postulated. Cytotoxic activities of 1 and 2 were tested, and all of them were inactive.