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1.
J Nat Prod ; 82(12): 3469-3476, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31833370

RESUMO

We report the isolation and characterization of three new nybomycins (nybomycins B-D, 1-3) and six known compounds (nybomycin, 4; deoxynyboquinone, 5; α-rubromycin, 6; ß-rubromycin, 7; γ-rubromycin, 8; and [2α(1E,3E),4ß]-2-(1,3-pentadienyl)-4-piperidinol, 9) from the Rock Creek (McCreary County, KY) underground coal mine acid reclamation site isolate Streptomyces sp. AD-3-6. Nybomycin D (3) and deoxynyboquinone (5) displayed moderate (3) to potent (5) cancer cell line cytotoxicity and displayed weak to moderate anti-Gram-(+) bacterial activity, whereas rubromycins 6-8 displayed little to no cancer cell line cytotoxicity but moderate to potent anti-Gram-(+) bacterial and antifungal activity. Assessment of the impact of 3 or 5 cancer cell line treatment on 4E-BP1 phosphorylation, a predictive marker of ROS-mediated control of cap-dependent translation, also revealed deoxynyboquinone (5)-mediated downstream inhibition of 4E-BP1p. Evaluation of 1-9 in a recently established axolotl embryo tail regeneration assay also highlighted the prototypical telomerase inhibitor γ-rubromycin (8) as a new inhibitor of tail regeneration. Cumulatively, this work highlights an alternative nybomycin production strain, a small set of new nybomycin metabolites, and previously unknown functions of rubromycins (antifungal activity and inhibition of tail regeneration) and also provides a basis for revision of the previously proposed nybomycin biosynthetic pathway.


Assuntos
Streptomyces/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Estrutura Molecular , Quinolonas/química , Quinolonas/metabolismo , Quinolonas/farmacologia , Análise Espectral/métodos
2.
Angew Chem Int Ed Engl ; 56(11): 2994-2998, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28140487

RESUMO

Four cyclopentenone-containing ansamycin polyketides (mccrearamycins A-D), and six new geldanamycins (Gdms B-G, including new linear and mycothiol conjugates), were characterized as metabolites of Streptomyces sp. AD-23-14 isolated from the Rock Creek underground coal mine acid drainage site. Biomimetic chemical conversion studies using both simple synthetic models and Gdm D confirmed that the mccrearamycin cyclopentenone derives from benzilic acid rearrangement of 19-hydroxy Gdm, and thereby provides a new synthetic derivatization strategy and implicates a potential unique biocatalyst in mccrearamycin cyclopentenone formation. In addition to standard Hsp90α binding and cell line cytotoxicity assays, this study also highlights the first assessment of Hsp90α modulators in a new axolotl embryo tail regeneration (ETR) assay as a potential new whole animal assay for Hsp90 modulator discovery.


Assuntos
Carvão Mineral/microbiologia , Ciclopentanos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Streptomyces/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Kentucky , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Conformação Molecular , Estereoisomerismo , Streptomyces/metabolismo
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