Structurally diversified ent-kaurane and abietane diterpenoids from the stems of Tripterygium wilfordii and their anti-inflammatory activity

Four undescribed ent-kaurane Diterpenoids, wilkaunoids A - D (1-4), and three undescribed abietane Diterpenoids, wilabinoids A - C (13-15), along with thirteen known ones (5-12 and 16-20), were isolated from Tripterygium wilfordii. Their structures were elucidated by extensive spectroscopic methods, electroniccirculardichroism calculation, and X-ray diffraction analysis. Compounds 1 and 2 were a pair of C-19 epimers of ent-kaurane Diterpenoids, featuring a rare 19,20-epoxy-19,20-dimethoxy-kaurane fragment. Compound 3 possessed a rare naturally occurring 1,3-dioxacyclohexane moiety. Compounds 13 and 15 represented the first example of abietane Diterpenoids with an isovalerate substitution from the genus of Tripterygium. The possible biosynthetic pathways of 1-3 were postulated. The effect of 1-20 on nitric oxide production was examined in lipopolysaccharide-stimulated RAW 264.7 cells. Abietane diterpenoid Quinones 7-13 (IC₅₀: 1.9-10.2 μM) exhibited the significant activity to inhibit nitric oxide production versus positive control (NG-monomethyl-l-arginine acetate salt, IC₅₀ = 24.9 μM). The structure activity relationship of 7-13 in inhibiting nitric oxide production was then discussed. The most potent 7 and 8 were found to significantly suppress the expression of cyclooxygenase-2 and inducible nitric oxide synthase proteins, showing a good anti-inflammatory potential. The findings provided some valuable insights for the discovery and structural modification of abietane Diterpenoids towards anti-inflammatory lead compounds.

Abietane diterpenoids; Anti-inflammatory activity; Ent-kaurane diterpenoids; Tripterygium wilfordii; Wilabinoids A−C; Wilkaunoids A−D.