Ginsengenin derivatives synthesized from 20()-panaxotriol: Synthesis, characterization, and antitumor activity targeting HIF-1 pathway.

BACKGROUND

Ginseng possesses antitumor effects, and ginsenosides are considered to be one of its main active chemical components. Ginsenosides can further be hydrolyzed to generate secondary saponins, and 20()-panaxotriol is an important sapogenin of ginsenosides. We aimed to synthesize a new ginsengenin derivative from 20()-panaxotriol and investigate its antitumor activity and .

METHODS

Here, 20()-panaxotriol was selected as a precursor and was modified into its derivatives. The new products were characterized by H-NMR, C-NMR and HR-MS and evaluated by molecular docking, MTT, luciferase reporter assay, western blotting, immunofluorescent staining, colony formation assay, EdU labeling and immunofluorescence, apoptosis assay, cells migration assay, transwell assay and antitumor activity assay.

RESULTS

The derivative with the best antitumor activity was identified as 6,12-dihydroxy-4,4,8,10,14-pentamethyl-17-(2,6,6-trimethyltetrahydro-2-pyran-2-yl)hexadecahydro-1-cyclopenta[a]phenanthren-3-yl(-butoxycarbonyl)glycinate (). The focus of this research was on the antitumor activity of the derivatives. The efficacy of the derivative (IC < 0.3 μM) was more than 100 times higher than that of 20()- panaxotriol (IC > 30 μM). In addition, inhibited the protein expression and nuclear accumulation of the hypoxia-inducible factor HIF-1α in HeLa cells under hypoxic conditions in a dose-dependent manner. Moreover, dose-dependently inhibited the proliferation, migration, and invasion of HeLa cells, while promoting their apoptosis. Notably, the inhibition by was more significant than that by 20()-panaxotriol ( < 0.01) .

CONCLUSION

To our knowledge, this is the first study to report the production of derivative from 20()-panaxotriol and its superior antitumor activity compared to its precursor. Moreover, derivative can be used to further study and develop novel antitumor drugs.