RESUMO
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.
Assuntos
Imidazolinas/síntese química , Inibidores de Proteassoma/síntese química , Ácidos Borônicos/farmacologia , Bortezomib , Linhagem Celular , Humanos , Imidazolinas/farmacologia , NF-kappa B/antagonistas & inibidores , Inibidores de Proteassoma/farmacologia , Pirazinas/farmacologiaRESUMO
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.
Assuntos
Alcinos/síntese química , Ácidos Carboxílicos/síntese química , Éteres/química , Cetonas/química , Oxazolona/análogos & derivados , Oxazolona/química , Cristalografia por Raios X , Ésteres , Conformação Molecular , Estrutura MolecularRESUMO
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.