RESUMEN
A series of aqueous heterogeneous Suzuki coupling reactions of substrates containing basic nitrogen centers with phenylboronic acid in the absence of added base and ligand is presented. High yields of products were obtained by employing aryl bromides containing aliphatic 1°, 2°, and 3° amine substituents, and good to high yields were obtained by employing a variety of substituted bromopyridines. In the former series, the pH of the aqueous phase changed from basic to acidic during the course of the reaction, while in the latter series the aqueous phase was on the acidic side of the pH scale throughout the entire course of reaction. A mechanistic interpretation for these observations, which generally preserves the oxo palladium catalytic cycle widely accepted in the literature, is presented.
RESUMEN
The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.
Asunto(s)
Imidazolinas/síntesis química , Inhibidores de Proteasoma/síntesis química , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular , Humanos , Imidazolinas/farmacología , FN-kappa B/antagonistas & inhibidores , Inhibidores de Proteasoma/farmacología , Pirazinas/farmacologíaRESUMEN
An efficient synthetic methodology of converting trans-4,5-diaryl-2-imidazolines to the corresponding cis-4,5-diaryl-2-imidazolines has been developed. This methodology features mild reaction conditions and a simple one-pot two-step procedure.
RESUMEN
We herein describe the synthesis and anti-inflammatory properties of a small library of imidazoline-based NF-kappaB inhibitors. The structure-activity relationship of various substituents on an imidazoline core structure was evaluated for the ability to inhibit NF-kappaB mediated IL-6 production. Optimization of the scaffolds was pursued by correlating luciferase-based NF-kappaB reporter assays with inhibition of IL-6 production in IL-1beta stimulated human blood. Several derivatives were found to inhibit NF-kappaB mediated IL-6 production in the nanomolar range in IL-1beta stimulated human blood.
Asunto(s)
Imidazolinas/química , Imidazolinas/farmacología , Interleucina-6/biosíntesis , FN-kappa B/antagonistas & inhibidores , Células Cultivadas , Células HeLa , Humanos , Interleucina-1beta/sangre , Interleucina-1beta/farmacología , Interleucina-6/sangre , FN-kappa B/genética , FN-kappa B/metabolismo , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/farmacología , Relación Estructura-Actividad , Activación Transcripcional/efectos de los fármacosRESUMEN
The mammalian nuclear transcription factor NF-kappaB is responsible for the transcription of multiple cytokines, including the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Elevated levels of pro-inflammatory cytokines play an important role in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Inhibition of the pro-inflammatory transcription factor NF-kappaB has therefore been identified as a possible therapeutic treatment for RA. We describe herein the synthesis and biological activity of a series of imidazoline-based scaffolds as potent inhibitors of NF-kappaB mediated gene transcription in cell culture as well as inhibitors of TNF-alpha and IL-6 production in interleukin 1 beta (IL-1beta) stimulated human blood.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Imidazolinas/síntesis química , Interleucina-6/antagonistas & inhibidores , FN-kappa B/fisiología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Células HeLa , Humanos , Imidazolinas/química , Imidazolinas/farmacología , Técnicas In Vitro , Interleucina-1beta/farmacología , Interleucina-6/biosíntesis , FN-kappa B/genética , Estereoisomerismo , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
tert-Alkyl amino hydroxy carboxylic acids are abundantly present within the structure of many biologically active natural products. We describe herein the synthesis of these substrates using an oxazolone-mediated ene-type reaction with enol ethers followed by NaBH4 reduction of the intermediate oxazolone.
Asunto(s)
Alquinos/síntesis química , Ácidos Carboxílicos/síntesis química , Éteres/química , Cetonas/química , Oxazolona/análogos & derivados , Oxazolona/química , Cristalografía por Rayos X , Ésteres , Conformación Molecular , Estructura MolecularRESUMEN
The assembly of structurally diverse scaffolds via substrate controlled diversity oriented synthesis (DOS) has proven to be an effective tool in the discovery of novel biologically important compounds. This tutorial review aims to summarize some of the more recent applications of oxazolones as a general template for the stereoselective syntheses of amino acids and heterocyclic scaffolds. A brief introduction covers a short history, nomenclature and general reactivity of oxazolones. The main body of this tutorial review highlights several applications of oxazolones as starting blocks for the diverse and stereoselective synthesis of amino acids, oxazoles, beta-lactams, pyrroles, imidazolines, pyrrolines, and imidazoles.