Synthesis and antihepatoma activity of dimeric 1-O-acetylbritannilactone derivatives.

1-O-Acetylbritannilactone (ABL), a natural 1,10-seco-eudesmane sesquiterpenoid, exhibited moderate antihepatoma activity on HepG2, Huh7, and SK-Hep-1cells with IC50 values of 50.7, 60.7, and 62.4 μM, respectively. Given that sesquiterpenoid dimers often exhibit stronger antitumor activity than their monomeric counterparts, a strategy of dimerization was employed to improve the activity of ABL. A total of 49 dimeric derivatives of ABL linked via ester bonds or carbamate bonds were synthesized and evaluated for their inhibitory activity against human hepatoma cell lines. As a result, all dimeric derivatives significantly enhanced the antihepatoma activity against the three cell line with IC50 values ranging from 0.5 μM-20.2 μM. Among them, 43 derivatives were more active than sorafenib with IC50 values below 7.0 μM. In particular, eight compounds (17, 21, 23, 24, 25, 30, 38 and 47) displayed IC50 values at or below approximately 1.0 μM, indicating a 27.2- to 123.2-fold enhancement in potency over the parent ABL. These results highlighted their potential as promising novel antihepatoma candidates worthy of further investigation.