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白介素-6(IL-6)/转录激活因子(STAT)信号通路的活化与动脉粥样硬化(AS)的发生发展密切相关。本研究以我国天然产物单体盐酸小檗碱(BBR)为先导物,通过在其3-位或/和9-位引入不同类型的侧链基团,设计合成了一系列全新结构BBR衍生物,并对其抑制IL-6诱导的STAT1/3的磷酸化进行了评价。构效关系表明,3-位或9-位引入刚性结构有利于活性提高,其中,化合物2b和9显示出最优的抑制活性。进一步研究提示,化合物2b和9通过激活HUVEC细胞中AMPK活性,抑制IL-6诱导的STAT1和STAT3磷酸化。研究结果显示,BBR衍生物通过AMPK途径抑制IL-6/STAT信号通路介导的炎症反应,为此类化合物发展成为抗AS候选物提供了有益的科学数据。
The activation of interleukin-6 (IL-6) / activator of transcription (STAT) signaling pathway is closely related to the development of atherosclerosis (AS). In this study, a series of new BBR derivatives were designed and synthesized with the introduction of different types of side chain groups at their 3-position or / and 9-position by taking the natural product monomer, berberine hydrochloride (BBR) , And its inhibition of IL-6-induced phosphorylation of STAT1 / 3 was evaluated. The structure-activity relationship shows that introduction of a rigid structure at the 3-position or the 9-position facilitates the enhancement of activity, and compounds 2b and 9 show the best inhibitory activity. Further studies suggest that compounds 2b and 9 inhibit IL-6-induced STAT1 and STAT3 phosphorylation by activating AMPK activity in HUVEC cells. The results show that BBR derivatives inhibit IL-6 / STAT signaling pathway-mediated inflammatory responses through the AMPK pathway and provide useful scientific data for the development of these compounds as anti-AS candidates.