RESUMO
The rph gene cluster for prodigiosin biosynthesis has been identified in Streptomyces griseoviridis 2464-S5, which produces cyclic prodigiosin derivatives including roseophilin (2), prodigiosin R1 (3) and prodigiosin R2 (4). A new cyclic prodigiosin, prodigiosin R3 (1), was produced by the redG redP double disruptant of Streptomyces coelicolor M511 expressing four cyclization gene candidates (rphG, rphG2, rphG3 and rphG4) in the rph cluster. The same compound was isolated from Streptomyces griseoviridis 2464-S5. The molecular formula of 1 was established as C27H33N3O by ESI and FAB mass spectrometry. The structure was determined to be a multicyclic prodigiosin with three alkyl linkages by NMR spectroscopic analysis. Prodigiosin R3 (1) showed cytotoxicity against HeLa human cervical carcinoma cells and HT1080 human fibrosarcoma cells with IC50s of 2.1 µM and 3.2 µM, respectively.
Assuntos
Streptomyces coelicolor , Streptomyces , Humanos , Ciclização , Família Multigênica , Prodigiosina , Streptomyces/metabolismo , Streptomyces coelicolor/genética , Streptomyces coelicolor/metabolismoRESUMO
A neuroprotective compound (2) was isolated from the culture broth of the dutomycin (1) producer Streptomyces sp. RAP78. The molecular formula of 2 was established as C44H55NO16 by high-resolution FAB-MS. The structure was determined to be a new dutomycin derivative possessing an acetimidoyl group in place of an acetyl group by NMR spectroscopic analysis. 13-Deoxo-13-iminodutomycin (2) but not dutomycin (1) protected C6 rat glioma cells and N18-RE-105 rat primary retina-mouse neuroblastoma hybrid cells from glutamate-induced toxicity with EC50s of 0.12 µM and 0.72 µM, respectively.
Assuntos
Fármacos Neuroprotetores/farmacologia , Streptomyces/química , Animais , Antraciclinas , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Descoberta de Drogas , Ácido Glutâmico/toxicidade , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Ratos , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
A new member of the dunaimycin family, dunaimycin C3 (2), was isolated from a fermented broth of Streptomyces sp. RAN389. The molecular formula of 2 was established as C42H70O10 by high-resolution FAB-MS, and the structure was elucidated by NMR spectroscopic analyses. Dunaimycin C3 inhibited the expression of the molecular chaperone GRP78 in HT1080 G-L cells in the presence of 10 mM of 2-deoxyglucose with an IC50 of 8.4 nM.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Choque Térmico/metabolismo , Streptomyces/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Humanos , Concentração Inibidora 50 , Estrutura MolecularRESUMO
A new curromycin-related compound, neocurromycin A (2), was isolated from the fermented broth of Streptomyces sp. RAI364. The molecular formula of 2 was established as C35H44N4O7 by ESI-MS and the structure was elucidated by NMR spectroscopic analyses. Neocurromycin A showed selective cytotoxicity against MKN45 human gastric cancer cells in a nutrient-deprived medium with an IC50 of 380 nM and inhibited the expression of the molecular chaperone GRP78 in HT1080 G-L cells in the presence of 10 mM of 2-deoxyglucose with an IC50 of 1.7 µM.
Assuntos
Antineoplásicos/isolamento & purificação , Proteínas de Choque Térmico/antagonistas & inibidores , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Chaperona BiP do Retículo Endoplasmático , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Neoplasias Gástricas/tratamento farmacológicoRESUMO
A neuroprotective compound designated pyroxazone (1) was isolated from the culture broth of Streptomyces sp. RAN54. The molecular formula of 1 was established as C18H14N2O5 by high-resolution FAB-MS. The structure was determined to be a new 2-amino-3H-phenoxazin-3-one derivative by NMR spectroscopic analysis. Pyroxazone (1) protected C6 rat glioma cells and N18-RE-105 rat primary retina-mouse neuroblastoma hybrid cells from glutamate-induced toxicity with EC50s of 8.2 µM and 1.7 µM, respectively.
Assuntos
Ácido Glutâmico/toxicidade , Fármacos Neuroprotetores/farmacologia , Ftalazinas/farmacologia , Streptomyces/metabolismo , Animais , Linhagem Celular Tumoral , Glioma , Camundongos , Estrutura Molecular , Neuroblastoma , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Ftalazinas/química , Ftalazinas/metabolismo , Ratos , RetinaRESUMO
Two new cytotoxic antibiotics designated quinomycins H1 (2) and H2 (3) were isolated from the culture broth of Streptomyces sp. RAL404. The molecular formula of both compounds was established as C52H65N11O13S2 by electrospray ionization mass spectrometry (ESI-MS). Their structures were determined as echinomycin (1) derivatives containing a 3-hydoxyquinaldic acid molecule in place of one of the two quinoxaline-2-carboxylic acid chromophores. Quinomycins H1 (2) and H2 (3) showed selective cytotoxicity against RG-E1-4 cells bearing the adenovirus oncogenes with IC50s of 11 nM and 12 nM, respectively.
Assuntos
Equinomicina/análogos & derivados , Streptomyces/metabolismo , Animais , Linhagem Celular , Equinomicina/química , Equinomicina/metabolismo , Equinomicina/farmacologia , Fibroblastos/efeitos dos fármacos , Estrutura Molecular , Neuroglia/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Roseophilin (2) is a unique prodigiosin-related compound produced by Streptomyces griseoviridis 2464-S5, and is characterized by a central furan ring and a bicyclic alkyl chain. During a search for biosynthetic intermediates of 2, a new metabolite designated prodigiosin R2 (1) was isolated from the culture of the roseophilin producer. The molecular formula of 1 was established as C27H35N3O by high-resolution FAB-MS. The structure of 1 was determined by NMR spectroscopic analyses as a prodigiosin derivative with the same bicyclic alkyl chain as 2. Prodigiosin R2 (1) showed potent cytotoxicity against HeLa human cervical carcinoma cells and HT1080 human fibrosarcoma cells with IC50s of 0.41 and 0.82 µM, respectively.
Assuntos
Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/farmacologia , Prodigiosina/isolamento & purificação , Prodigiosina/farmacologia , Streptomyces/metabolismo , Antibióticos Antineoplásicos/biossíntese , Linhagem Celular Tumoral , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Prodigiosina/biossíntese , Espectrofotometria Ultravioleta , Streptomyces/químicaAssuntos
Antineoplásicos/química , Prodigiosina/análogos & derivados , Streptomyces coelicolor/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/fisiologia , Compostos Heterocíclicos com 3 Anéis/metabolismo , Humanos , Estrutura Molecular , Família Multigênica , Prodigiosina/química , Prodigiosina/metabolismo , Prodigiosina/farmacologia , Pirróis/metabolismoRESUMO
The function of hatomarubigin biosynthesis genes was analyzed by heterologous expression of the hrb gene cluster. Streptomyces lividans carrying a gene cluster consisting of 25 genes (hrbR1-hrbX) with hrbY was found to produce all the known hatomarubigins including hatomarubigin D, which has a unique dimeric angucycline with a methylene linkage. Gene disruption was used in this heterologous expression system to analyze the function of hrbF, a gene with no homology to any known angucycline biosynthesis genes. A new metabolite was detected in the fermented broth of S. lividans expressing the hrb genes lacking hrbF and was designated hatomarubigin F. This compound was identified as 5-hydroxyhatomarubigin E by NMR spectroscopic analysis, suggesting that HrbF regulates the regiospecificity of oxygenation enzymes.