RESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Imidazolinas/síntese química , Interleucina-6/antagonistas & inibidores , NF-kappa B/fisiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Células HeLa , Humanos , Imidazolinas/química , Imidazolinas/farmacologia , Técnicas In Vitro , Interleucina-1beta/farmacologia , Interleucina-6/biossíntese , NF-kappa B/genética , Estereoisomerismo , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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.
