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.