RESUMEN
Total syntheses of the morphine alkaloids are described that use a direct stereoselective formation of the phenanthrofuran system via an intramolecular 4 + 2 cycloaddition of a diene tethered to the 4-position of a 7-methoxybenzofuran-3-carboxylic acid ester.
Asunto(s)
Codeína/síntesis química , Morfina/síntesis química , Tebaína/síntesis química , Estructura Molecular , EstereoisomerismoRESUMEN
From a series of 4'-[(trifluoromethyl)pyrazol-1-yl]carboxanilides derived from 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1,2,3-thiadiazole-5-carboxanilide, one inhibited thapsigargin-induced Ca2+ influx in Jurkat T cells (IC(50)=77 nM) and exhibited high selectivity for the CRAC channel over the VOC channel (index: >130). Another acted as an inhibitor for both T lymphocyte activation-induced diseases and ovalbumin-induced airway eosinophilia in rats (ED(50)=1.3 mg/kg) p.o.
Asunto(s)
Anilidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Calcio/metabolismo , Pirazoles/farmacología , Anilidas/síntesis química , Anilidas/química , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Señalización del Calcio/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Hipersensibilidad/tratamiento farmacológico , Interleucina-2/metabolismo , Células Jurkat , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Eosinofilia Pulmonar/inducido químicamente , Eosinofilia Pulmonar/tratamiento farmacológico , Pirazoles/síntesis química , Pirazoles/química , Ratas , Ratas Endogámicas BN , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Tapsigargina/farmacologíaRESUMEN
We performed a large-scale random screening of an in-house chemical library based on the inhibition of respiratory syncytial virus (RSV)-induced cytopathic effect on HeLa (human cervical carcinoma) cells, and found a novel and specific anti-RSV agent, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403). YM-53403 potently inhibited the replication of RSV strains belonging to both A and B subgroups, but not influenza A virus, measles virus, or herpes simplex virus type 1. A plaque reduction assay was used to determine the 50% effective concentration (EC(50)) value for YM-53403. The value, 0.20 microM, was about 100-fold more potent than ribavirin. The result of a time-dependent drug addition test showed that YM-53403 inhibited the life cycle of RSV at around 8h post-infection, suggesting an inhibitory effect on early transcription and/or replication of the RSV genome. Consistent with this result, two YM-53403-resistant viruses have a single point mutation (Y1631H) in the L protein which is a RNA polymerase for both the transcription and replication of the RSV genome. YM-53403 is an attractive compound for the treatment of RSV infection because of its highly potent anti-RSV activity and the new mode of action, which differs from that of currently reported antiviral agents.
Asunto(s)
Antivirales/farmacología , Benzazepinas/farmacología , Ciclopropanos/farmacología , Virus Sincitiales Respiratorios/efectos de los fármacos , Animales , Antivirales/química , Benzazepinas/química , Línea Celular , Chlorocebus aethiops , Ciclopropanos/química , Perros , Farmacorresistencia Viral/genética , Genes Virales , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Mutación Puntual , Virus Sincitiales Respiratorios/genética , Virus Sincitiales Respiratorios/patogenicidad , Virus Sincitiales Respiratorios/fisiología , Células Vero , Proteínas Virales/genética , Replicación Viral/efectos de los fármacosAsunto(s)
Técnicas Químicas Combinatorias , Oro/química , Indoles/síntesis química , Compuestos Organometálicos/química , Poliestirenos/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Catálisis , Indoles/química , Estructura Molecular , Compuestos Organometálicos/síntesis química , Dióxido de Silicio/química , EstereoisomerismoRESUMEN
Polymer incarcerated platinum catalysts (PI Pt) were conveniently prepared from PtCl(2)(COD) or H(2)PtCl(6).6H(2)O and styrene copolymers via reduction of the Pt sources with triethylamine, coacervation, and cross-linking. The Pt catalysts have been successfully applied to catalytic hydrogenation including saturation of heterocyclic compounds.