Artemidubolides A−T, cytotoxic unreported guaiane-type sesquiterpenoid dimers against three hepatoma cell lines from Artemisia dubia
Zhen Gao, Wenjing Ma, Tian-Ze Li, Yun‐Bao Ma, Jing Hu, Xiaoyan Huang, Chang‐An Geng, Xiao-Feng He, Xue‐Mei Zhang, Ji‐Jun Chen
Abstract
A random bioassay revealed that the EtOH extract and EtOAc fraction of Artemisia dubia Wall. (Asteraceae) exhibited cytotoxic activity against HepG2 cells with inhibitory ratios of 57.1% and 84.2% at a concentration of 100.0 μg/mL. Bio-guided isolation combined by LC-MS-IT-TOF analyses of the active fractions led to the isolation of 20 previously undescribed guaiane-type sesquiterpenoid dimers named artemidubolides A−T ( 1 – 20 ). Their structures and the absolute configurations were determined by comprehensive spectral analyses , comparison of the experimental and calculated ECD spectra, and seven compounds (artemidubolides A, B, D, F, K, O and R) were confirmed unequivocally by single crystal X-ray diffraction analysis. Structurally, artemidubolides A–Q were [4 + 2] Diels–Alder adducts of two monomeric guaianolides, and artemidubolides R–T were linked though an ester bond. All the isolated compounds were evaluated for their hepatomatic cytotoxicity against HepG2, Huh7, and SK-Hep-1 cell lines to demonstrate that 18 compounds exhibited obvious cytotoxicity against three tested hepatoma cell lines with IC 50 values in the range of 5.4–87.6 μM. Importantly, artemidubolides B, D, and M exhibited hepatoma cytotoxicity with IC 50 values of 5.4, 5.7, and 9.7 (HepG2), 8.2, 4.3, and 12.2 (Huh7), and 13.4, 8.4, and 12.9 μM (SK-Hep-1), respectively. Mechanism investigation in HepG2 cells suggested the most active artemidubolide D dose-dependently inhibited cell migration and invasion, induced G1/M cell cycle arrest by down-regulating proteins CDK4, CDK6 and CyclinD1 and up-regulating the level of protein P21 ; and induced apoptosis by down-regulated of PARP-1 and BCL-2 expression and up-regulating Bax and cleaved PARP-1 levels.