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1.
Org Lett ; 22(1): 98-101, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31829608

RESUMO

The recently discovered antibiotic burnettramic acid A (1) and three new congeners, burnettramic acids C-E (2-4), were identified from the co-cultures of two marine Aspergillus strains. The structure of burnettramic acid A was revised on the basis of reinterpretation of the nuclear magnetic resonance (NMR) data and chemical derivatization. The full absolute configurations of burnettramic acids were established using the Mosher ester method and Marfey's analysis, combined with density functional theory calculation of NMR and electric circular dichroism data.

2.
Chem Sci ; 10(32): 7549-7553, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31588306

RESUMO

The photoprotection and isolation of marinomycin A using sporopollenin exine capsules (SpECs) derived from the spores of the plant Lycopodium clavatum is described. The marinomycins have a particularly short half-life in natural light, which severely impacts their potential biological utility given that they display potent antibiotic and anticancer activity. The SpEC encapsulation of the marinomycin A dramatically increases the half-life of the polyene macrodiolide to the direct exposure to UV radiation by several orders of magnitude, thereby making this a potentially useful strategy for other light sensitive bioactive agents. In addition, we report that the SpECs can also be used to selectively extract culture broths that contain the marinomycins, which provides a significantly higher recovery than with conventional XAD resins and provides concomitant photoprotection.

3.
Molecules ; 24(15)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31382398

RESUMO

A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3ß-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 µM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1-16 µg/mL.


Assuntos
Antivirais/farmacologia , Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Penicillium/química , Antivirais/química , Produtos Biológicos/química , Linhagem Celular , HIV/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
4.
J Nat Prod ; 82(5): 1391-1395, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31013089

RESUMO

Raistrickindole A (1), a new indole diketopiperazine alkaloid containing an unusual pyrazino[1',2':2,3][1,2]oxazino[6,5- b]indole tetraheterocyclic ring system, a new benzodiazepine derivative, raistrickin (2), and the known haenamindole (3) and sclerotigenin (4) were isolated from the marine-derived fungus Penicillium raistrickii IMB17-034. Their structures were elucidated by extensive spectroscopic analyses and TDDFT calculations of the NMR and ECD data. Compounds 1 and 2 showed inhibitory activities against the hepatitis C virus.

5.
Org Lett ; 21(5): 1530-1533, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30785290

RESUMO

Isocoumarindole A (1), a novel polyketide synthetase-nonribosomal peptide synthetase (PKS-NRPS) hybrid metabolite, was isolated from the endolichenic fungus Aspergillus sp. CPCC 400810. The structure of isocoumarindole A (1) was featured by an unprecedented skeleton containing chlorinated isocoumarin and indole diketopiperazine alkaloid moieties linked by a carbon-carbon bond, which was determined by a combination of spectroscopic analyses, Marfey's method, and calculations of NMR chemical shifts, ECD spectra, and optical rotation values. Isocoumarindole A showed significant cytotoxicity and mild antifungal activities.


Assuntos
Aspergillus/química , Dicetopiperazinas/química , Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Isocumarinas/química , Isocumarinas/metabolismo , Peptídeo Sintases/metabolismo , Fungos , Halogenação , Alcaloides Indólicos/isolamento & purificação , Isocumarinas/isolamento & purificação , Estrutura Molecular , Peptídeo Sintases/química
6.
Mar Drugs ; 17(1)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669360

RESUMO

Tetracenomycin X (Tcm X) has been reported to have antitumour activity in various cancers, but there have not been any studies on its activity with respect to lung cancer to date. Therefore, this study aims to investigate the anti-lung cancer activity of Tcm X. In this study, we found that tetracenomycin X showed antitumour activity in vivo and selectively inhibited the proliferation of lung cancer cells without influencing lung fibroblasts. In addition, apoptosis and autophagy did not contribute to the antitumour activity. Tetracenomycin X exerts antitumour activity through cell cycle arrest induced by the downregulation of cyclin D1. To explore the specific mechanism, we found that tetracenomycin X directly induced cyclin D1 proteasomal degradation and indirectly downregulated cyclin D1 via the activation of p38 and c-JUN proteins. All these findings were explored for the first time, which indicated that tetracenomycin X may be a powerful antimitotic class of anticancer drug candidates for the treatment of lung cancer in the future.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Organismos Aquáticos/química , Ciclina D1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Actinobacteria/química , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos , Humanos , Pulmão/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Naftacenos/isolamento & purificação , Naftacenos/farmacologia , Naftacenos/uso terapêutico , Proteólise/efeitos dos fármacos
7.
Mar Drugs ; 16(10)2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30241346

RESUMO

Six new tetracenomycin congeners, saccharothrixones E⁻I (1⁻5) and 13-de-O-methyltetracenomycin X (6), were isolated from the rare marine-derived actinomycete Saccharothrix sp. 10-10. Their structures were elucidated by spectroscopic analysis and time-dependent density functional theory (TDDFT)-electronic circular dichroism (ECD) calculations. Saccharothrixones G (3) and H (4) are the first examples of tetracenomycins featuring a novel ring-A-cleaved chromophore. Saccharothrixone I (5) was determined to be a seco-tetracenomycin derivative with ring-B cleavage. The new structural characteristics, highlighted by different oxidations at C-5 and cleavages in rings A and B, enrich the structural diversity of tetracenomycins and provide evidence for tetracenomycin biosynthesis. Analysis of the structure⁻activity relationship of these compounds confirmed the importance of the planarity of the naphthacenequinone chromophore and the methylation of the polar carboxy groups for tetracenomycin cytotoxicity.


Assuntos
Actinomycetales/química , Antineoplásicos/farmacologia , Organismos Aquáticos/química , Naftacenos/farmacologia , Policetídeos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Dicroísmo Circular , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftacenos/química , Naftacenos/isolamento & purificação , Policetídeos/química , Quinonas/química , Relação Estrutura-Atividade
8.
J Nat Prod ; 81(1): 178-187, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29308897

RESUMO

Analysis of the whole genome sequence of Streptomyces sp. IMB7-145 revealed the presence of seven type I polyketide synthase biosynthetic gene clusters, one of which was highly homologous to the biosynthetic gene cluster of azalomycin F. Detailed bioinformatic analysis of the modular organization of the PKS gene suggested that this gene is responsible for niphimycin biosynthesis. Guided by genomic analysis, a large-scale cultivation ultimately led to the discovery and characterization of four new niphimycin congeners, namely, niphimycins C-E (1-3) and 17-O-methylniphimycin (4). The configurations of most stereocenters of niphimycins have not been determined to date. In the present study, the relative configurations were elucidated by spectroscopic analysis, including J-based analysis and the CNMR database method. Further, the full absolute configurations of niphimycins were completely proposed for the first time based on biosynthetic gene cluster analysis of the ketoreductase and enoylreductase domains for hydroxy- and methyl-bearing stereocenters. Compounds 1, 3, 4, and niphimycin Iα (5) showed antimicrobial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC: 8-64 µg/mL), as well as cytotoxicity against the human HeLa cancer cell line (IC50: 3.0-9.0 µM). In addition, compounds 1 and 5 displayed significant activity against several Mycobacterium tuberculosis clinical isolates (MIC: 4-32 µg/mL).


Assuntos
Organismos Aquáticos/química , Streptomyces/química , Streptomyces/genética , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Genômica/métodos , Guanidinas/química , Guanidinas/farmacologia , Células HeLa , Células Hep G2 , Humanos , Células K562 , Células MCF-7 , Macrolídeos/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Família Multigênica/genética , Policetídeo Sintases/genética
9.
Sci Rep ; 7(1): 3591, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28620204

RESUMO

Neo-actinomycins A and B (1 and 2), two new natural actinomycins featuring an unprecedented tetracyclic 5H-oxazolo[4,5-b]phenoxazine chromophore, were isolated from the marine-derived actinomycete Streptomyces sp. IMB094. Their structures were elucidated by spectroscopic analyses. The presence of this ring system was proposed to originate from a condensation between actinomycin D (3) with α-ketoglutarate and pyruvate, respectively. Compound 1 showed potent cytotoxic activities against human cancer HCT116 and A549 cell lines in the nanomolar range (IC50: 38.7 and 65.8 nM, respectively) and moderate antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) strains.


Assuntos
Antibacterianos/isolamento & purificação , Antibióticos Antineoplásicos/isolamento & purificação , Organismos Aquáticos/química , Produtos Biológicos/isolamento & purificação , Dactinomicina/isolamento & purificação , Streptomyces/química , Antibacterianos/química , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Organismos Aquáticos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dactinomicina/química , Dactinomicina/farmacologia , Enterococcus/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Análise Espectral , Staphylococcus aureus/efeitos dos fármacos , Streptomyces/isolamento & purificação
10.
Zhongguo Zhong Yao Za Zhi ; 40(13): 2602-11, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26697686

RESUMO

Using a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, macroporous adsorbent resin, and reversed-phase HPLC, 115 compounds including diterpenes, sesquiterpenes, treterpenes, coumarins, lignans, fatty acid derivatives, and simple aromatic derivatives were isolated from an ethanol extract of branch of Fraxinus sieboldiana (Oleaceaue), and their structures of the compounds were elucidated by spectroscopic methods including 1 D, 2D NMR and MS techniques. Among them, 41 compounds were new. In previous reports, we have been described the isolation, structure elucidation, and bioactivities of the 41 new compounds and 22 known orii including 8 coumarins, 4 phenolic and 12 phenylethanoidal glycosides. As a consequence, we herein reported the isolation and structure elucidation of the remaining 50 known compounds including 8- hydroxy-12-oxoabieta-9(11),13-dien-20-oic 8, 20-lactone(1), 6beta-hydroxyfcrruginol(2),(+)-pisiferic acid(3), (+)-pisiferal(4),(+)-7-dehydroabiet6none(5), 1-oxomiltirone(6), subdigitatone(7), linarionoside B(8), (9S)-linarionoside B(9), (3R,9R)-3-hydroxy-7,8-dihydro-beta-ionol 9-O-beta-D-apiofuranosyl-(1-->6)-beta-D-glucopyranoside(10), ursolic acid(11), betulinic acid(12), euscaphic acid(13), (+)-syringaresinol(14), (+)-fraxiresinol(15), (+)-1-hydroxysyringaresinol(16), pinoresinol(17), medioresinol(18), 8-acetoxypinoresinol(19), epipinoresinol(20), (-)-olivil(21), (+)-cyclo-olivil(22), 3,3'-dimethoxy-4,4',9-trihydroxy-7,9'-epoxylignan-7'-one(23),(+)-1-hydroxypinoresinol 4'-O-beta-D-glucopyranoside (24), (+)-1-hydroxypinoresinol 4"-O-beta-D-glucopyranoside(25),(+)-syringaresinol O-beta-D-glucopyranoside (26), liriodendrin (27), ehletianol D(28), icariside E5(29) (-)-(7R, 8R)-threo-1-C-syringylglycerol(30),(-)-(7R, 8S)-erythro-guaiacylglycerol (31),(-)-(7R, 8R)-threo-guaiacylglycerol(32), 3-(4-beta-D-glucopyranosyloxy-3-methoxy)-phenyl-2E-propenol(33),2,3-dihydroxy-l-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone(34), 2,3-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)-1-propanone (35), 3-hydroxy-l-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone(36), omega-hydroxypropioguaiacone(37), sinapyladehyde(38), trans-p-hydroxycinnamaldehyde(39), syringic acid(40), vanilic acid(41), vanillin(42), 4-hydroxy-benzaldehyde (43), (24R)-24-ethyl-5alpha-cholestane-3beta,5,6beta-triol(44), beta-sitosterol(45), daucosterol(46), 2,6-dimethoxy-I,4-benzoquinone(47), 2,6-dimethoxy-pyran-4-one(48), 1-(beta-D-ribofuranosyl)uracil(49), and mannitol(50). Compouds 1-7,12,18,28-37,44 and 48 were obtained from the genus Fraxinus for the first time.


Assuntos
Fraxinus/química , Extratos Vegetais/análise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
11.
J Nat Prod ; 78(9): 2260-5, 2015 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-26317881

RESUMO

Saccharothrixones A-C (1-3), three new aromatic polyketide seco-tetracenomycins, and saccharothrixone D (4), a new tetracenomycin analogue possessing opposite configurations at all of the stereogenic centers, were isolated from the marine-derived actinomycete Saccharothrix sp. 10-10. Compounds 1-3 represent the first examples of seco-tetracenomycins where the quinone ring B is cleaved and re-formed into a furanone ring. Their structures were elucidated by spectroscopic analyses and ECD calculations. The absolute configuration of 4 was confirmed by single-crystal X-ray diffraction analysis. Saccharothrixone D (4) showed in vitro cytotoxic activity against the HepG2 cancer cell line with an IC50 value of 7.5 µM.


Assuntos
Actinomycetales/química , Policetídeos/isolamento & purificação , Humanos , Estrutura Molecular , Naftacenos , Policetídeos/química
12.
Yao Xue Xue Bao ; 49(2): 230-6, 2014 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-24761614

RESUMO

The crude extracts of the fermentation broth from a marine sediment-derived actinomycete strain, Saccharothrix sp. 10-10, showed significant antibacterial activities against drug-resistant pathogens. A genome-mining PCR-based experiment targeting the genes encoding key enzymes involved in the biosynthesis of secondary metabolites indicated that the strain 10-10 showed the potential to produce tetracenomycin-like compounds. Further chemical investigation of the cultures of this strain led to the identification of two antibiotics, including a tetracenomycin (Tcm) analogs, Tcm X (1), and a tomaymycin derivative, oxotomaymycin (2). Their structures were identified by spectroscopic data analysis, including UV, 1D-NMR, 2D-NMR and MS spectra. Tcm X (1) showed moderate antibacterial activities against a number of drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) pathogens, with the MIC values in the range of 32-64 microg x mL(-1). In addition, 1 also displayed significant cytotoxic activities against human cancer cell lines, including HL60 (leukemia), HepG2 (liver), and MCF-7 (breast) with the IC 50 values of 5.1, 9.7 and 18.0 micromol x L(-1), respectively. Guided by the PCR-based gene sequence analysis, Tcm X (1) and oxotomaymycin (2) were identified from the genus of Saccharothrix and their 13C NMR data were correctly assigned on the basis of 2D NMR spectroscopic data analysis for the first time.


Assuntos
Actinomycetales/química , Antibacterianos/isolamento & purificação , Antineoplásicos/isolamento & purificação , Actinomycetales/genética , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzodiazepinonas/química , Benzodiazepinonas/isolamento & purificação , Benzodiazepinonas/farmacologia , Linhagem Celular Tumoral , Mineração de Dados/métodos , Farmacorresistência Bacteriana , Enterococcus faecalis/efeitos dos fármacos , Fermentação , Genômica , Humanos , Concentração Inibidora 50 , Biologia Marinha , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Naftacenos/química , Naftacenos/isolamento & purificação , Naftacenos/farmacologia , Filogenia , Staphylococcus epidermidis/efeitos dos fármacos
13.
Yao Xue Xue Bao ; 48(9): 1369-75, 2013 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-24358768

RESUMO

In the last decade, along with the development of taxonomy research in marine-derived actinobacteria, more and more halogenated natural products were discovered from marine actinobacteria. Most of them showed good biological activity and unique structure compared to those from land. The special halogenation mechanism in some compounds' biosynthesis has drawn great attention. So in this review, we focus on the halogenated natural products from marine actinobacteria and their halogenation mechanisms.


Assuntos
Actinobacteria/química , Antibacterianos/isolamento & purificação , Antineoplásicos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Halogenação , Biologia Marinha , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular
14.
J Nat Prod ; 76(11): 2153-7, 2013 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-24164206

RESUMO

A PCR-based genetic screening experiment targeting the dTDP-glucose-4,6-dehydratase gene revealed that a marine sediment-derived strain, Streptomyces sp. 7-145, had the potential to produce glycosidic antibiotics. Chemical investigation of culture extracts of this strain yielded two new 6-deoxyhexose-containing antibiotics, 11',12'-dehydroelaiophylin (1) and 11,11'-O-dimethyl-14'-deethyl-14'-methylelaiophylin (2), together with four known elaiophylin analogues (3-6). Their structures were determined by extensive NMR, MS, and CD analyses. Compounds 1, 3, 4, and 6 showed good antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci pathogens.


Assuntos
Antibacterianos/isolamento & purificação , Macrolídeos/isolamento & purificação , Streptomyces/química , Antibacterianos/química , Antibacterianos/farmacologia , Macrolídeos/química , Macrolídeos/farmacologia , Biologia Marinha , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Reação em Cadeia da Polimerase , Vancomicina/farmacologia
15.
J Nat Prod ; 76(9): 1535-40, 2013 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-23972215

RESUMO

Three new polyketide compounds (1-3), a new quinolone alkaloid (4), and seven known polyketide derivatives were identified from the cultures of Penicillium sp. I09F 484, a strain isolated from the rhizosphere soil of the plant Picea asperata from Kanas Lake, Xinjiang, China. Their structures were elucidated by extensive spectroscopic data analysis. The absolute configurations of 1 and 4 were established by quantum chemical time-dependent density functional theory electronic circular dichroism calculation and Marfey's method, respectively. Compounds 1 and 2 displayed inhibitory activity against New Delhi metallo-ß-lactamase 1 with IC50 values of 94.9 and 87.9 µM, respectively.


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Penicillium/química , Policetídeos/isolamento & purificação , Policetídeos/farmacologia , Quinolonas/isolamento & purificação , Inibidores de beta-Lactamases , Alcaloides/química , China , Dicroísmo Circular , Cristalografia por Raios X , Concentração Inibidora 50 , Estrutura Molecular , Policetídeos/química , Quinolonas/química , Quinolonas/farmacologia , Rizosfera , beta-Lactamases
16.
J Nat Prod ; 76(5): 969-73, 2013 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-23656556

RESUMO

A novel natural geldanamycin analogue was discovered in Streptomyces hygroscopicus 17997. Its 4,5-dihydro form was also identified in the gdmP gene disruption mutant of Streptomyces hygroscopicus 17997. The structures of the two compounds were determined to be 19-[(1'S,4'R)-4'-hydroxy-1'-methoxy-2'-oxopentyl]geldanamycin (1) and 19-[(1'S,4'R)-4'-hydroxy-1'-methoxy-2'-oxopentyl]-4,5-dihydrogeldanamycin (2), respectively, by extensive spectroscopic data analysis, including 2D NMR, modified Mosher's method, and electronic circular dichroism. Compared to geldanamycin, 1 and 2 showed increased water solubility and decreased cytotoxicity against HepG2 cells.


Assuntos
Antineoplásicos/isolamento & purificação , Benzoquinonas/isolamento & purificação , Lactamas Macrocíclicas/isolamento & purificação , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoquinonas/química , Benzoquinonas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Solubilidade , Estereoisomerismo , Streptomyces/genética , Água
17.
Molecules ; 18(1): 236-43, 2012 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-23271463

RESUMO

We have isolated an extraordinary pentapeptide, called 4862F, from the culture broth of Streptomyces albosporus I03A-04862 by Diaion HP-20 macroporous adsorbent resin column, ODS-A and Sephadex LH-20 chromatography, followed by preparative HPLC. This peptide shows inhibitory activity against HIV-1 protease. The structure was elucidated by spectroscopic approaches, including ESI-MS and various NMR methods. Absolute configuration of the amino acid residues in 4862F was defined using Marfey's method, and the structure was identified as N,N,N-(trimethylated)-Tyr-L-Leu-L-Val-L-Leu-(dehydrated)-His. The peptide 4862F displays inhibitory activity against HIV-1 protease, with IC50 values of 15.26 nM, using a fluorescence-based assay.


Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Streptomyces/metabolismo , Aminoácidos/análise , Cromatografia Líquida de Alta Pressão , Fermentação , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular
18.
Bioorg Med Chem Lett ; 22(19): 6151-4, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22939698

RESUMO

Two new streptothricins (1 and 2) and a new streptothricin acid derivative (3), all with the carbamoyl group substituted at C-12 of the gulosamine moiety, together with the known N(ß)-acetylstreptothricin D acid (4), have been isolated from the culture broth of Streptomyces sp. I08A 1776. The structures of the new compounds were determined by MS, CD, and 1D and 2D NMR spectroscopic data analysis. The isolated compounds were evaluated for antibacterial and antifungal activities. Streptothricin E (6) showed potent activity against the clinically isolated extensively drug-resistant Mycobacterium tuberculosis with MIC values of 0.25-0.5µg/mL.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Streptomyces/química , Estreptotricinas/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antifúngicos/química , Antifúngicos/isolamento & purificação , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Estereoisomerismo , Estreptotricinas/química , Estreptotricinas/isolamento & purificação
19.
Eur J Pharmacol ; 694(1-3): 45-52, 2012 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-22975264

RESUMO

Tuberculosis is a serious threat to world-wide public health usually caused in humans by Mycobacterium tuberculosis (M. tuberculosis). It exclusively utilizes the methylerythritol phosphate (MEP) pathway for biosynthesis of isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), the precursors of all isoprenoid compounds. The 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (IspD; EC 2.7.7.60) is the key enzyme of the MEP pathway. It is also of interest as a new chemotherapeutic target, as the enzyme is absent in mammals and ispD is an essential gene for growth. A high-throughput screening method was therefore developed to identify compounds that inhibit IspD. This process was applied to identify a lead compound, domiphen bromide (DMB), that may effectively inhibit IspD. The inhibitory action of DMB was confirmed by over-expressing or down-regulating IspD in Mycobacterium smegmatis (M. smegmatis), demonstrating that DMB inhibit M. smegmatis growth additionally through an IspD-independent pathway. This also led to higher levels of growth inhibition when combined with IspD knockdown. This novel IspD inhibitor was also reported to exhibit antimycobacterial activity in vitro, an effect that likely occurs as a result of perturbation of cell wall biosynthesis.


Assuntos
Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Oxirredutases/antagonistas & inibidores , Compostos de Amônio Quaternário/farmacologia , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Cinética , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/enzimologia , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/genética , Oxirredutases/isolamento & purificação , Reprodutibilidade dos Testes
20.
J Nat Prod ; 75(8): 1480-4, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22849774

RESUMO

Two new geldanamycin (GDM) analogues, (4S)-4,5-dihydro-4-hydroxygeldanamycin (1) and (4R)-4,5-dihydro-4-hydroxygeldanamycin (2), were identified from Streptomyces hygroscopicus 17997. Compounds 1 and 2 were not normal intermediates of GDM biosynthesis but shunt products of C-4,5 oxidation catalyzed by GdmP, a cytochrome P450 oxidase acting as a desaturase in GDM biosynthesis. Preliminary assays implied that, compared with GDM, 1 and 2 exhibited decreased cytotoxicity.


Assuntos
Benzoquinonas , Lactamas Macrocíclicas , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Streptomyces/química , Benzoquinonas/química , Benzoquinonas/metabolismo , Benzoquinonas/farmacologia , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/metabolismo , Lactamas Macrocíclicas/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oxirredução , Streptomyces/genética , Streptomyces/metabolismo
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