Guaiane‐type Sesquiterpenoid Dimers from Artemisia zhongdianensis and Antihepatoma Carcinoma Activity via the p38MAPK Pathway

Comprehensive Summary 17 new guaiane‐type sesquiterpenoid dimers (GSDs), artemzhongdianolides B1—B17 ( 1 — 17 ), were isolated from Artemisia zhongdianensis under the guidance of bioassay, and elucidated by spectral analyses (HRESIMS, 1D and 2D NMR, IR, ECD). The absolute configuration of compounds 1 , 3 , 7 , 9 , 10 , and 13 was determined by single‐crystal X‐ray diffraction analyses. Structurally, artemzhongdianolides B1 ( 1 ) and B2 ( 2 ) were the first example of the GSDs fused via a C‐13/C‐13' single bond, and artemzhongdianolides B3—B17 were [4 + 2] Diels–Alder adducts of two monomeric guaianolides. Most of the compounds showed antihepatoma cytotoxicity with IC 50 values ranging from 9.9 to 170.1 μmol/L. Importantly, artemzhongdianolide B9 ( 9 ) was the most active one against three hepatoma cell lines with IC 50 values of 13.1 μmol/L (HepG2), 19.5 μmol/L (Huh7), and 19.5 μmol/L (SK‐Hep‐1), and dose‐dependently inhibited cell migration and invasion, induced G1 cell cycle arrest and cell apoptosis in HepG2 cells. Compound 9 might suppress HepG2 cells via affecting the p38MAPK signaling pathway suggested by machine learning approach, and significantly upregulated expression of phosphorylated p38 validated by Western blot assay.