Artematrovirenolides A—D and Artematrolides S—Z, Sesquiterpenoid Dimers with Cytotoxicity against Three Hepatoma Cell Lines from Artemisia atrovirens

Comprehensive Summary Inspired by the intriguing structures and remarkable activities of sesquiterpenoid dimers, 12 new sesquiterpenoid dimers, artematrovirenolides A—D (1—4) and artematrolides S—Z (8—12), were isolated from the EtOAc fraction of Artemisia atrovirens through a bioactivity‐guided approach. Their structures were elucidated by comprehensive spectroscopic data and absolute configuration was assigned based on single crystal X‐ray diffraction data and ECD calculations. Structurally, all compounds are presumably formed via [4+2] cycloaddition involving three connecting model. Compounds 1—4 are four novel hetero‐dimeric [4+2] Diels–Alder adducts dimerized from a rotundane‐type unit and a guaiane‐type monomer, and compounds 5—12 are eight new homo‐dimeric [4+2] adducts derived from two guaianolide moieties. A putative biosynthetic pathway for compounds 1—4 was also proposed. Compounds 4, 6, 7, and 10 demonstrated moderate cytotoxicity against HepG2, SMMC‐7721, and Huh7 cell lines with IC 50 values ranging from 9.3 to 62.3 μmol/L. Interestingly, compounds 5 and 11 manifested cytotoxicity with IC 50 values of 13.6 and 12.8 (HepG2), 18.5 and 13.1 (SMMC‐7721), and 16.5 and 19.4 μmol/L (Huh7), respectively, which were equivalent to the positive control, sorafenib. This investigation suggests that compounds 5 and 11 might be considered as potent antihepatoma candidates and deserve further structural modification and mechanism study.