Diterpenoids from Euphorbia peplus possessing cytotoxic and anti-inflammatory activities

Phytochemical investigation into the medium polar fraction of the ethanol extract of Euphorbia peplus led to the identification of 32 diterpenoids with five structural types. Compounds 1–5 and 7–11 are reported for the first time, while the configuration of 6,7-epoxy group of 6 was revised to be β-oriented. Compounds 1–5 feature a rare structural variation of the double bond at Δ1 migrating to Δ1(10) in the tigliane-type diterpenoid family. Biologically, compound 21 was found to be the only one to show moderate cytotoxic activity, associated with the presence of a benzoyloxy residue at C-16. Besides, compounds 4, 8, 12, 13, 16, and 19 show significant inhibitory activities against NO production induced by LPS in RAW264.7 macrophage cells, with IC50 values within 2–5 μM. Structure-activity relationship (SAR) analysis revealed that the ingenane-type diterpenoids have the best anti-inflammatory activity, and the esterification at 3-OH or 5-OH is crucial. Further biological researches demonstrated that 13, the predominant metabolite in this plant, exerts anti-inflammatory effects by blocking the activation of NF-κB and MAPK signaling pathways.