Ailancoumaquinone A and ailancoumarins M-T, undescribed terpenylated coumarins from Ailanthus altissima and their anti-inflammatory activity

Abstract

Nine previously undescribed coumarin congeners, including ailancoumaquinone A (1) and ailancoumarins M-T (2−9), were isolated from the root bark of Ailanthus altissima (Mill.) Swingle. Their structures were confirmed through spectral analyses, computational approaches, and the Mosher's method. Among these compounds, ailancoumaquinone A (1) was identified as a rare hybrid of a coumarin and a naphthoquinone, featuring an unprecedented carbon skeleton in its naphthoquinone moiety. Furthermore, 1 demonstrated significant anti-inflammatory potential, as it not only inhibits pro-inflammatory factors, including nitric oxide (NO) and reactive oxygen species (ROS) in LPS-induced RAW 264.7 macrophages at a concentration of 7.5 μM but also suppresses ROS secretion in the gastrointestinal tract of LPS-treated zebrafish embryos at a concentration of 3.75 μM. Subsequent pharmacological investigations revealed that 1 inhibits the phosphorylation of Janus kinase 2 (P-JAK2), thereby affecting the phosphorylation of nodal proteins in the downstream signaling pathways that are closely associated with inflammation. Molecular docking analysis indicated that 1 occupies the core ATP-binding pocket within the kinase domain of JAK2 (docking score: −8.214 kcal/mol), suggesting that it may function as a competitive inhibitor of JAK2 kinase activity.