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

Hong-Yan Guo; Yue Xing; Yu-Qiao Sun; Can Liu; Qian Xu; Fan-Fan Shang; Run-Hui Zhang; Xue-Jun Jin; Fener Chen; Jung Joon Lee; Dongzhou Kang; Qing-Kun Shen; Zhe-Shan Quan

doi:10.1016/j.jgr.2022.03.001

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

J Ginseng Res. 2022 Nov;46(6):738-749. doi: 10.1016/j.jgr.2022.03.001. Epub 2022 Mar 10.

Authors

Affiliations

¹ Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, China.
² Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, China.

Abstract

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(R)-panaxotriol is an important sapogenin of ginsenosides. We aimed to synthesize a new ginsengenin derivative from 20(R)-panaxotriol and investigate its antitumor activity in vivo and in vitro.

Methods: Here, 20(R)-panaxotriol was selected as a precursor and was modified into its derivatives. The new products were characterized by ¹H-NMR, ¹³C-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 in vivo 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-2H-pyran-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(tert-butoxycarbonyl)glycinate (A11). The focus of this research was on the antitumor activity of the derivatives. The efficacy of the derivative A11 (IC₅₀ < 0.3 μM) was more than 100 times higher than that of 20(R)- panaxotriol (IC₅₀ > 30 μM). In addition, A11 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, A11 dose-dependently inhibited the proliferation, migration, and invasion of HeLa cells, while promoting their apoptosis. Notably, the inhibition by A11 was more significant than that by 20(R)-panaxotriol (p < 0.01) in vivo.

Conclusion: To our knowledge, this is the first study to report the production of derivative A11 from 20(R)-panaxotriol and its superior antitumor activity compared to its precursor. Moreover, derivative A11 can be used to further study and develop novel antitumor drugs.

Keywords: 20(R)-Panaxotriol; Antitumor; Bax, Bcl-2-associated X; Bcl-2, B cell lymphoma-2; DMEM, Dulbecco's modified Eagle's medium; Derivatives; EdU, 5-ethynyl-2’-deoxyuridine; FBS, fetal bovine serum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HIF-1, hypoxia-inducible factor-1; HIF-1α; HR-MS, high-resolution mass spectra; MMP, matrix metalloproteinase; OD, optical density; PBS, phosphate-buffered saline; TLC, thin-layer chromatography; Topo, topoisomerase; VEGF, vascular endothelial growth factor.