RESUMEN
In this article, we describe the discovery of an aryl ether series of potent and selective Nav1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Nav channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Nav1.3 as a target for pain.
RESUMEN
[reaction: see text] The 3-alkoxy-4-arylpiperidine inhibitors of aspartic peptidases are shown to be a new type of non-peptide peptidomimetic inhibitor. These piperidines can be designed from peptide-derived inhibitors by use of a structure-generating program but only after the enzyme active site conformation has been modified in a mechanistically related fashion. New enantioselective syntheses of 3-alkoxy-4-arylpiperidine analogues are described.
Asunto(s)
Pepsina A/antagonistas & inhibidores , Piperidinas/química , Piperidinas/síntesis química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/química , Sitios de Unión , Pepsina A/química , Piperidinas/farmacología , Inhibidores de Proteasas/farmacología , Estructura Secundaria de Proteína , Renina/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-Actividad , PorcinosRESUMEN
We evaluated the effectiveness of Ambersorb, a carbonaceous resin, in reducing bioavailability of polycyclic aromatic hydrocarbons (PAHs) in contaminated sediments collected from the field. In laboratory studies, sediment pore-water concentrations of eight unsubstituted PAHs were significantly decreased after resin addition. Reduced PAH concentrations in oligochaete tissues from a laboratory bioaccumulation test, along with increased survival/reproduction and reduced photo-enhanced toxicity and sediment avoidance, also resulted from sediment treatment with Ambersorb. Resin amendment also decreased pore-water PAH concentrations in field deployed sediments but did not improve benthic invertebrate colonization. Prediction of partitioning of PAHs between solid and aqueous phases in the test sediments was complicated by the presence of coal and soot. However, accurate predictions of bioavailability were achieved based on pore-water chemistry. Overall, these studies show that the addition of high affinity sorbents effectively reduces pore-water PAH concentrations and bioavailability and suggests that sorbent addition may serve as an option for in situ remediation of some contaminated sediments.
Asunto(s)
Carbono/química , Sedimentos Geológicos/química , Compuestos Policíclicos/farmacocinética , Animales , Disponibilidad Biológica , OligoquetosRESUMEN
[reaction: see text]. Cysteine sulfhydryl protection with either the Fmoc or the Fm group was accomplished in one step and in high yield using commercially available FmocCl or FmocOSu, respectively. Mechanisms for the Fmoc to Fm transformations are discussed. Additionally, Fmoc-Cys(Fmoc)-OH (7) was synthesized and used in amide bond forming reactions. The S-Fmoc group is cleaved selectively from peptides containing the N-Fmoc group.
Asunto(s)
Química Orgánica/métodos , Cisteína/química , Modelos Químicos , Péptidos/química , Compuestos de Sulfhidrilo/químicaRESUMEN
[formula: see text] Chlorophenylalanines eta 6-complexed to ruthenium undergo SNAr reactions with a variety of nucleophiles to form substituted phenylalanines exemplified by 4b. Extension of these reactions to intramolecular ruthenium-activated SNAr cyclizations led to three novel cyclic tripeptide systems (exemplified by 17 and 20).
Asunto(s)
Aminoácidos/síntesis química , Péptidos Cíclicos/síntesis química , Rutenio , Conformación Molecular , Fenilalanina/químicaRESUMEN
Four sites from a stream system near Huntsville, Alabama, contaminated with DDT and its metabolites, were sampled using a coring device. Grab samples were also collected at these and five other sites. Analytical and toxicological evaluations were made on both sets of samples. Core samples provided vertical delineation of toxicity and contamination in sediments, and documented periods of sedimentation with clean material, which appears to be isolating the contaminated sediments from benthic communities. Grab samples yielded less information about the sites. Relationships between DDT concentration and sediment toxicity to Chironomus tentans were similar regardless of the sampling method. Substantial increases in toxicity occurred in most samples when concentrations exceeded 3000 micrograms of DDT residue/g organic carbon.