Bisfischoids A and B, dimeric ent-abietane-type diterpenoids with anti-inflammatory potential from Euphorbia fischeriana Steud

• Published in: Bioorganic chemistry 2021-11, Vol.116, p.105356-105356, Article 105356
• Main Authors: Sun, Cheng-Peng, Chang, Yi-Bo, Wang, Chao, Lv, Xia, Zhou, Wei-Yu, Tian, Xiang-Ge, Zhao, Wen-Yu, Ma, Xiao-Chi
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - isolation & purification; Anti-Inflammatory Agents - pharmacology; Diterpenoid dimer; Dose-Response Relationship, Drug; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - isolation & purification; Drugs, Chinese Herbal - pharmacology; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - metabolism; Euphorbia - chemistry; Euphorbia fischeriana Steud; Humans; Medicine, Chinese Traditional; Molecular dynamics; Molecular Structure; Soluble epoxide hydrolase; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105356

[Display omitted] •Rare diterpenoid dimers with nonacyclic skeleton were obtained from E. fischeriana.•Novel dimers 1 and 2 exhibited inhibitory activities against soluble epoxide hydrolase.•The inhibition kinetics and molecular dynamics of 1 and 2 with sEH were studied. Two undescribed ent-abietane-type diterpenoid dimers with nonacyclic backbone formed by intermolecular [4 + 2] cycloaddition into a spirocyclic skeleton, bisfischoids A (1) and B (2), along with a known one fischdiabietane A (3), were identified from Euphorbia fischeriana Steud. Their structures were elucidated by extensive spectroscopic analysis, ECD and NMR calculation combined with DP4+ probability analysis, as well as X-ray diffraction. The anti-inflammatory potential of dimers 1–3 were examined using their inhibitory effects on soluble epoxide hydrolase (sEH), which revealed that 1 and 2 exhibited promising activities with inhibition constant (Ki) of 3.20 and 1.95 μM, respectively. Further studies of molecular docking and molecular dynamics indicated that amino acid residue Tyr343 in the catalytic cavity of sEH was the key site for their inhibitory function.