New guaiane-type sesquiterpenoid dimers from Artemisia atrovirens and their antihepatoma activity

Leading by cytotoxicity against HepG2 cells,bioactivity-guided fractionation of the EtOAc fraction from Artemisia atrovirens led to the isolation of 18 new guaianolide dimers,artematrolides A-R and lavandiolides A,B,C,H,and J.Eight compounds(1,4,10,12,13,and 19-21) were unambiguously confirmed by the single-crystal X-ray diffraction analyses,and the others were elucidated based on IR,UV,HRESIMS,1 D and 2 D NMR experiments,and comparison of the experimental and calculated ECD data.Structurally,all of them were [4+2] Diels-Alder adducts of two monomeric guaianolides.The isolates were evaluated for their cytotoxicity against three human hepatoma cell lines,and 19 compounds demonstrated cytotoxicity against HepG2,SMMC-7721,and Huh7 cell lines.Especially,compounds 1,12,14,and 15 exhibited cytotoxicity with IC50 values of 4.4,3.8,7.6,and 6.7 μmol/L(HepG2),9.6,4.6,6.6,and 6.0 μmol/L(SMMC-7721),and 7.6,4.5,6.9,and 5.6 μmol/L(Huh7),respectively.Notably,compound 12 showed the most promising activity against three human hepatoma cell lines and dose-dependently inhibited cell migration and invasion,induced G2/M cell cycle arrest and cell apoptosis in HepG2 cells,down-regulated the expression of BCL-2 and PARP-1,and activated PARP-1 to up-regulate the expression of cleaved-PARP-1.