Novel paeonol derivatives: Design, synthesis and anti-inflammatory activity in vitro and in vivo
Novel paeonol derivatives: Design, synthesis and anti-inflammatory activity in vitro and in vivo
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DOI：
10.1016/j.bioorg.2020.103735
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发表时间：
2020-05-01
影响因子：
5.1
通讯作者：
Shi, Jing Bo
中科院分区：
文献类型：
--
作者：
Hu, Yang Sheng;Han, Xu;Shi, Jing Bo
丹皮酚已被证明具有潜在的抗炎活性，但由于其抗炎活性较差(20MU时抑制率为14.74%)，临床应用并不广泛。为了寻找新的具有抗炎活性的先导化合物，设计合成了一系列丹皮酚衍生物，并对其体内外抗炎活性进行了筛选。结果表明，(E)-N-(4-(2-acetyl-5-methoxyphenoxy)phenyl)-3-(3，4，5-trimet-hoxyphenyl)丙烯酰胺(化合物11a)对脂多糖诱导的RAW 264.7巨噬细胞一氧化氮(NO)过表达的抑制率为96.32%，IC50值为6.96mU。初步的机制研究表明，它可以抑制TLR4的表达，从而抑制核因子-kappaB和MAPK通路。进一步研究表明，化合物11a对佐剂诱导的大鼠关节炎模型有明显的治疗作用。
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 mu M). 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 1 la) was found to be the best active compound with low toxicity, which showed 96.32% inhibitory activity at 20 mu M and IC50 value of 6.96 mu M 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-kappa B and MAPK pathways. Further studies have shown that compound 11a has obvious therapeutic effect against the adjuvant-induced rat arthritis model.