Synthesis and antihepatoma activity of guaianolide dimers derived from lavandiolide I

[Display omitted] Guaianolide dimers represent a unique class of natural products with anticancer activities, but their low content in plants has limited in-depth pharmacological studies. Lavandiolide I is a guaianolide dimer isolated from Artemisia species, and had been synthesized on a ten-gram scale in four steps with 60 % overall yield, which showed potent antihepatoma activity on the HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values of 12.1, 18.4, and 17.6 µM, respectively. To explore more active dimers, 33 lavandiolide I derivatives were designed, synthesized, and evaluated for their inhibitory activity on human hepatoma cell lines. Among them, 10 derivatives were more active than lavandiolide I and sorafenib on the three cell lines. The primary structure–activity relationship concluded that the introduction of aldehyde, ester, azide, amide, carbamate and urea functional groups at C-14′ of the guaianolide dimer significantly enhanced the antihepatoma activity. Among these compounds, derivatives 25, 27, and 33 enhanced antihepatoma activity more than 1.2–5.8 folds than that of lavandiolide I, and demonstrated low toxicity to the human liver cell lines (THLE-2) and good safety profiles with selective index ranging from 1.3 to 3.4, while lavandiolide I was more toxic to THLE-2 cells. This work provides new insights into enhancing the antihepatoma efficacy and reducing the toxicity of sesquiterpenoid dimers.