Three Types of Isocoumarins with Unusual Carbon Skeletons from Artemisia dubia var. subdigitata and Their Antihepatoma Activity

Abstract

Ten novel isocoumarins, including four pairs of enantiomers, were isolated from Artemisia dubia var. subdigitata (Asteraceae). Compounds 1, 2 and 3a/ 3b possessed a unique 6/6/6-tricyclic system comprising an unusual 1-(2-methylcyclohexyl) propan-1-one moiety fused with isocoumarin core skeleton. Compounds 4a/ 4b were characterized as an unexpected 2, 5-dimethylcyclohexan-1-one scaffold, and compounds 5a/ 5b and 6a/ 6b were rare 1, 2- seco-isocoumarin. Their structures and absolute configurations were elucidated through spectroscopic data, X-ray crystallography, ECD and NMR calculations with DP4+ analyses. Plausible biosynthetic pathways were proposed from the naturally occurring isocoumarin. Network pharmacological analysis suggested that the targets of compound 1 were significantly enriched in the cell cycle and PI3K-Akt signaling pathway. The molecular docking revealed that compound 1 had high binding affinity with CDK2 (total score: 6.8717). Furthermore, compounds 1 and 2 exhibited inhibitory activity on three human hepatoma cell lines, with inhibitory ratios of 85.1% and 84.5% (HepG2), 88.2% and 87.3% (Huh7), and 69.2% and 69.1% (SK-Hep-1) at 200 µmol·L ^–1, respectively.

Keywords

Artemisia dubia var. subdigitata / Isocoumarins / Antihepatoma activity / Cancer / Natural products / X-ray diffraction

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