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

• Published in: Bioorganic chemistry 2021-10, Vol.115, p.105178-105178, Article 105178
• Main Authors: Zhou, Xiao-Qiong, Li, Si-Qi, Liao, Cai-Ceng, Dai, Wei-Feng, Rao, Kai-Rui, Ma, Xiu-Rong, Li, Rong-Tao, Chen, Xuan-Qin
• Format: Article
• Language: English
• Subjects: Abietane diterpenoids; Abietanes - chemistry; Abietanes - pharmacology; Animals; Anti-inflammatory activity; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Diterpenes, Kaurane - chemistry; Diterpenes, Kaurane - pharmacology; Ent-kaurane diterpenoids; Macrophages - drug effects; Macrophages - metabolism; Mice; Nitric Oxide - metabolism; RAW 264.7 Cells; Tripterygium - chemistry; Tripterygium wilfordii; Wilabinoids A−C; Wilkaunoids A−D
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105178

[Display omitted] •Four underscribed ent-kaurane and three undescribed abietane diterpenoids were isolated from T. wilfordii.•Compounds 1 and 2 were a pair of C-19 epimers of ent-kaurane diterpenoids. Compound 3 possessed a rare naturally occurring 1,3-dioxacyclohexane moiety.•Abietane diterpenoids 7–13 showed significant activity to inhibit NO production.•Compounds 7 and 8 significantly suppressed the protein expression of iNOS and COX-2. 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.