Dimeric sesquiterpenoids with anti-inflammatory activities from Inula britannica

As a continuous work focused on discovery of anti-inflammatory agents from natural sesquiterpenoids, we applied an activity-guided fractionation approach based on LPS-mediated RAW264.7 cells to investigate chemical constituents from Inula britannica. Seven new sesquiterpenoid dimers inulabritanoids A−G (1−7) and two new sesquiterpenoid monomers inulabritanoids H (8) and I (9) were separated from I. britannica along with eighteen known compounds (10−27). The elucidation of their structures was achieved through a combination of 1D and 2D NMR, HRMS, and electronic circular dichroism (ECD) spectra, as well as quantum chemical calculations. Compounds 1, 2, 12, 16, 19, and 26 showed inhibitory effects on NO production, and their IC₅₀ values were 3.65, 5.48, 3.29, 6.91, 3.12, and 5.67 μM, respectively. Further investigation on mechanism of action demonstrated that compound 1 inhibited the IKKβ phosphorylation to block the nuclear translocation of NF-κB, and activated the Keap1/Nrf2 signal pathway, resulting in the decrease of NOX-2, iNOS, TNF-α, IL-6, MCP-1, IL-1β, and IL-1α and the increase of NQO-1 and HO-1 to exert its anti-inflammatory effect in vitro. These findings suggested that dimeric sesquiterpenoids could serve as candidates for developing anti-inflammatory drugs.