RESUMEN
The thiopeptide antibiotic baringolin has been synthesized, and its structure and stereochemistry have been confirmed. The use of a strategy based on palladium-catalyzed cross-couplings permitted a modular construction of this natural product.
Asunto(s)
Antibacterianos/síntesis química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Fragmentos de Péptidos/síntesis química , Péptidos Cíclicos/síntesis química , Piridinas/química , Infecciones Estafilocócicas/tratamiento farmacológico , Compuestos de Sulfhidrilo/síntesis química , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Fragmentos de Péptidos/farmacología , Péptidos Cíclicos/farmacología , Infecciones Estafilocócicas/microbiología , Estereoisomerismo , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
An efficient and versatile solid-phase route for the preparation of aryl-alkyl ethers is described. Regioselective ring opening of a resin-bound chiral aziridine with phenolic nucleophiles constitutes the key feature of the present protocol that allows incorporation of fluorescent moieties and subsequent on-resin protecting group interconversion. Initial experiments demonstrated that a competing oligomerization may occur by concomitant attacks of transient nosylamide anions on neighboring aziridines, resulting in formation of dimeric and trimeric byproduct. Expectedly, the significance of this alternative reaction pathway was strongly dependent on resin loading, and a low loading (<0.4 mmol g(-1)) was required for obtaining high yields of the desired aryl-alkyl ethers. The developed methodology allowed preparation of novel N-Fmoc-protected coumaryl amino acid building blocks, which were incorporated into peptides by solid-phase peptide synthesis.
Asunto(s)
Aziridinas/química , Fenoles/química , Cromatografía Líquida de Alta Presión , Ciclización , Colorantes Fluorescentes/química , Espectroscopía de Resonancia Magnética , EstereoisomerismoRESUMEN
A novel class of CB1 inverse agonists was discovered. To efficiently establish structure-activity relationships (SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were evaluated in a mammalian cell-based functional assay and in radioligand binding assays expressing recombinant human cannabinoid receptors (CB1 and CB2). In general, all of the compounds exhibited high binding selectivity at CB1 vs CB2 and the general SAR revealed a lead compound 11-(4-chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12e) which showed excellent in vivo activity in pharmacodynamic models related to CB1 receptor activity. The low solubility that hampered the development of 12e was solved leading to a potential preclinical candidate 11-(3-chloro-4-fluorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12h).
Asunto(s)
Dibenzotiazepinas/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tiazepinas/síntesis química , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Depresores del Apetito/síntesis química , Depresores del Apetito/química , Depresores del Apetito/farmacología , Línea Celular , Técnicas Químicas Combinatorias , Dibenzotiazepinas/química , Dibenzotiazepinas/farmacología , Agonismo Inverso de Drogas , Ingestión de Alimentos/efectos de los fármacos , Humanos , Hipotermia/inducido químicamente , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Solubilidad , Relación Estructura-Actividad , Tiazepinas/química , Tiazepinas/farmacologíaRESUMEN
An efficient solid-phase route to ring-substituted piperazines from O-linked resin-bound (S)-aziridine-2-methanol is described. Regioselective microwave-assisted aminolysis followed by intramolecular Fukuyama-Mitsunobu cyclization constitute the key features of the protocol. Simple piperazines and diazepanes were readily obtained without preceding N-protection of the acyclic intermediate, whereas attempts to extend this protocol to chiral 2,5-disubstituted piperazines failed. Modifications encompassing N-carbamoylation prior to ring-closure were therefore investigated. However, standard carbamoylating agents, for example, Fmoc-Cl and Alloc-Cl tended to give bis-protected by-products. Thus, novel microwave-assisted solid-phase N-protection procedures were developed for efficient introduction of Fmoc, Boc and Alloc groups. The subsequent cyclization proceeded in moderate to excellent yields depending on the bulk of the side chain and type of N-protecting group. This protocol readily provided novel cis- and trans-2,5-disubstituted piperazines displaying a variety of N-protecting group patterns after further on-resin manipulations. Also, unexpected by-products obtained during these optimization studies were identified and characterized. This includes nosylated ureas arising from an alternative cyclization pathway. Finally, post-cleavage oxidation gave access to the Fmoc/Boc-protected alpha-amino acid as well as the corresponding aldehyde. The chiral piperazines described in this work will enable construction of combinatorial libraries with a higher chemical diversity compared to those containing simple N,N'-difunctionalized piperazines, often present in drug-like compounds.
Asunto(s)
Aziridinas/química , Técnicas Químicas Combinatorias , Piperazinas/química , Piperazinas/síntesis química , Ciclización , Microondas , Estructura Molecular , EstereoisomerismoRESUMEN
[reaction: see text] A general, high yielding rapid iron-catalyzed cross-coupling reaction between Grignard reagents and imidoyl chlorides is described. These reactions are typically completed within 5 min, resulting in high yields of 71-96% using 5% iron catalyst in a THF-NMP solvent mixture. Functionalized imidoyl chlorides (e.g., R = CO(2)Me) gave excellent yields (89%).