RESUMEN
Four new indolosesquiterpenes, lecanindoles A-D (1-4), were isolated from fermentations of the terrestrial fungus Verticillium lecanii 6144. The structures of compounds 1-4 were elucidated from analysis of spectroscopic data. Compound 2 was reduced to give 4 and its isomer 5. Compound 4 was found to be a potent and selective progesterone receptor agonist with an EC50 of 1.1 +/- 0.4 nM in a cell-based luciferase reporter assay.
Asunto(s)
Hypocreales/química , Indoles/aislamiento & purificación , Progestinas/aislamiento & purificación , Receptores de Progesterona/agonistas , Sesquiterpenos/aislamiento & purificación , Animales , Chlorocebus aethiops , Femenino , Humanos , Indoles/química , Indoles/farmacología , Luciferasas/metabolismo , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Progestinas/química , Progestinas/farmacología , Sesquiterpenos/química , Sesquiterpenos/farmacologíaRESUMEN
A microbroth chemiluminometric version of the biochemical induction assay (BIA) was developed using a chemiluminescent substrate widely used to detect beta-galactosidase in high-throughput screening (HTS) laboratories. The assay was run in both 96-well and 384-well plate formats using the Zymark RapidPlate liquid handling system to transfer samples and reagents. Chemiluminescence was read using the Victor-2 multilabel counter. The new microbroth chemiluminometric method, the CBIA, allowed rapid screening of samples, crude extracts, and pure compounds for their DNA-damaging effects in bacteria. In screening a small subset of our natural products library samples by the agar plate BIA and the CBIA, the latter yielded a higher hit rate, suggesting it is more sensitive than the agar plate assay. The CBIA was unaffected by the colored samples often encountered during screening of crude natural products extracts.
Asunto(s)
Antibacterianos/farmacología , Daño del ADN , ADN Bacteriano/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Mediciones Luminiscentes/métodos , Escherichia coli/genética , Escherichia coli/metabolismo , beta-Galactosidasa/análisisRESUMEN
Presentamos nuestra experiencia en 5 casos clínicos: 3 ATLL (todos fallecidos) y 2 HAM/TSP. Incluímos ell ° caso de ATLL sometido a TAMO alogénico en el país. Presentamos nuestra experiencia en 5 casos clínicos: 3 ATLL (todos fallecidos) y 2 HAM/TSP. Incluímos ell ° caso de ATLL sometido a TAMO alogénico en el país. indeterminados". Palabras clave: Leucemia/Linfoma T del Adulto (ATLL); Mielopatía asociada a HTLV-I (HAM/TSP) trasplante alogénico; donantes de sangre; HGIP
Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , TrasplantesRESUMEN
Presentamos nuestra experiencia en 5 casos clínicos: 3 ATLL (todos fallecidos) y 2 HAM/TSP. Incluímos ell º caso de ATLL sometido a TAMO alogénico en el país. Presentamos nuestra experiencia en 5 casos clínicos: 3 ATLL (todos fallecidos) y 2 HAM/TSP. Incluímos ell º caso de ATLL sometido a TAMO alogénico en el país. indeterminados". Palabras clave: Leucemia/Li
Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , TrasplantesRESUMEN
Inhibitors of the enzymes involved in fatty acid biosynthesis (FAB) have been reported as antibacterial agents. These include thiolactomycin, cerulenin, triclosan, diazoborine, naphthyridinones, aminopyridines and pyridoindoles. Our search for new FAB inhibitors, using a lacZ reporter cell-based screen, led to several confirmed hits. Culture F92S91, later identified as a Pseudomonas sp. based on 16S profiling, was found to produce two alpha-pyrones (I and II) and three high molecular weight peptides. The pyrones were unstable under acidic conditions, and they were rearranged into a furanone derivative (III). Of these compounds, pyrone I was the most active with MICs (microg/ml) against B. subtilis (1 to approximately 2), MRSA (2 to approximately 4), M. catarrhalis (4) and VRE (2 to approximately 64). Effects on macromolecular synthesis and membrane functions were tested in B. subtilis. Pyrone I nonspecifically inhibited incorporation of radiolabeled precursors into DNA, RNA and protein within 5 minutes of drug exposure, similar to that of triclosan. Both compounds also inhibited the cellular uptake of these precursors. Cerulenin did not have an effect until 30 minutes of drug treatment. Pyrone I and triclosan were membrane-active (BacLight test); however, pyrone I (at < or = 128 microg/ml concentration) was not hemolytic to human RBCs in contrast to triclosan, which was hemolytic at 16 microg/ml. These data suggest that pyrone-I, unlike triclosan, selectively affects bacterial membrane function.