RESUMEN
Some important pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-α and nitric oxide are thought to play key roles in the destruction of cartilage and bone tissue in joints affected by rheumatoid arthritis. In the present study, a series of new myricetin-pentadienone hybrids were designed and synthesized. Majority of them effectively inhibited the expressions liposaccharide-induced secretion of IL-6, TNF-α and NO in RAW264.7. The most prominent compound 5o could significantly decrease production of above inflammatory factors with IC50 values of 5.22 µM, 8.22 µM and 9.31 µM, respectively. Preliminary mechanism studies indicated that it could inhibit the expression of thioredoxin reductase, resulting in inhibiting of cell signaling pathway nuclear factor (N-κB) and mitogen-activated protein kinases. Significantly, compound 5o was found to effectively inhibit Freund's complete adjuvant induced rat adjuvant arthritis in vivo.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Flavonoides/química , Flavonoides/farmacología , Alcadienos/síntesis química , Alcadienos/química , Alcadienos/farmacología , Animales , Antiinflamatorios/síntesis química , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Técnicas de Química Sintética , Flavonoides/síntesis química , Interleucina-6/antagonistas & inhibidores , Interleucina-6/metabolismo , Masculino , Ratones , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Células RAW 264.7 , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Paeonol has been proved to have potential anti-inflammatory activity, but its clinical application is not extensive due to the poor anti-inflammatory activity (14.74% inhibitory activity at 20 µM). In order to discover novel lead compound with high anti-inflammatory activity, series of paeonol derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. Structure-activity relationships (SARs) have been fully concluded, and finally (E)-N-(4-(2-acetyl-5-methoxyphenoxy)phenyl)-3-(3,4,5-trimet-hoxyphenyl)acrylamide (compound 11a) was found to be the best active compound with low toxicity, which showed 96.32% inhibitory activity at 20 µM and IC50 value of 6.96 µM against LPS-induced over expression of nitric oxide (NO) in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4, resulting in inhibiting of NF-κB and MAPK pathways. Further studies have shown that compound 11a has obvious therapeutic effect against the adjuvant-induced rat arthritis model.