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). Com-pounds
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 hepa-toma
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 μM,
respectively.