Artemdubinoids A–N: novel sesquiterpenoids with antihepatoma cytotoxicity from Artemisia dubia

Abstract

In pursuit of effective agents for hepatocellular carcinoma derived from the Artemisia species, this study built upon initial findings that an ethanol (EtOH) extract and ethyl acetate (EtOAc) fraction of the aerial parts of Artemisia dubia Wall. ex Bess. exhibited cytotoxicity against HepG2 cells with inhibitory rates of 57.1% and 84.2% (100 μg·mL⁻¹), respectively. Guided by bioactivity, fourteen previously unidentified sesquiterpenes, artemdubinoids A–N (1–14), were isolated from the EtOAc fraction. Their structural elucidation was achieved through comprehensive spectroscopic analyses and corroborated by the comparison between the experimental and calculated ECD spectra. Single crystal X-ray diffraction provided definitive structure confirmation for artemdubinoids A, D, F, and H. Artemdubinoids A and B (1–2) represented unique sesquiterpenes featuring a 6/5-fused bicyclic carbon scaffold, and their putative biosynthetic pathways were discussed; artemdubinoid C (3) was a novel guaianolide derivative that might be formed by the [4 + 2] Diels–Alder reaction; artemdubinoids D and E (4–5) were rare 1,10-seco-guaianolides; artemdubinoids F–K (6–11) were chlorine-containing guaianolides. Eleven compounds exhibited cytotoxicity against three human hepatoma cell lines (HepG2, Huh7, and SK-Hep-1) with half-maximal inhibitory concentration (IC₅₀) values spanning 7.5−82.5 μmol·L⁻¹. Artemdubinoid M (13) exhibited the most active cytotoxicity with IC₅₀ values of 14.5, 7.5 and 8.9 μmol·L⁻¹ against the HepG2, Huh7, and SK-Hep-1 cell lines, respectively, which were equivalent to the positive control, sorafenib.