Highly oxygenated ent-abietane diterpenoid lactones from Euphorbia peplus and their anti-inflammatory activity

Eleven new ent-abietane diterpenoid lactones, designated euphjatrophanes H-R (1-11), were isolated from the whole plants of Euphorbia peplus, along with nine previously identified congeners (12-20). Their structures, including absolute configurations, were elucidated through a combination of NMR, HRESIMS, single-crystal X-ray diffraction, and calculations of ECD and DP4 + technologies. Notably, the absolute configurations of six compounds 1, 2, 4, 5, 6, and 7 were unambiguously determined by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation. The anti-inflammatory potential of all ent-abietane diterpenoid lactones was evaluated on macrophages. Compounds 6-9, 12-16 and 19 significantly suppressed nitric oxide production, while 10 μM of compounds 6, 9, 11 and 16 remarkably suppressed the mRNA expression of IL-6, IL-1β, and TNFα in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Notably, compound 6 demonstrated a dose-dependent inhibition of the levels of inflammatory mediators (IL-6, IL-1β, and TNFα). Furthermore, compound 6 effectively suppressed FOXO1 expression and reduced the phosphorylation level of NF-κB p65. These findings suggest that compound 6 might be a promising candidate for treating inflammation-related diseases.