Highly oxidized germacrane-type sesquiterpenoid dimers from Elephantopus tomentosus L.: Structural characterization, DFT calculation and anti-hepatoma potential.

Four previously undescribed highly oxidized germacrane-type sesquiterpenoid dimers were isolated from Elephantopus tomentosus. Their planar structures and absolute configurations were unequivocally elucidated through comprehensive spectroscopic analysis, combined with experimental electronic circular dichroism (ECD) and time-dependent density functional theory (TDDFT) calculations. These dimers, characterized by an O-ether linkage, represent the first reported examples of such derivatives from the genus Elephantopus. The structural validity was verified by performing Hartree-Fock energy calculations within the quantum mechanical (QM) framework. All isolated sesquiterpenoid dimers exhibited moderate inhibitory activity against human hepatocellular carcinoma cell lines (HepG2 and Hep3B). Notably, compound 4 demonstrated the most significant cytotoxicity, with IC values of 1.64 μM (HepG2) and 4.85 μM (Hep3B). Furthermore, compound 4 markedly reduced mitochondrial membrane potential (MMP), indicating its role in inducing apoptosis via mitochondrial dysfunction. Network pharmacology and molecular docking further indicated that compound 4 could interact with HSP90AA1 by binding to key amino acid residues, potentially explaining its pharmacological activity.