Synthesis, biological evaluation and mechanism study based on network pharmacology of amino acids esters of 20(S)-protopanaxadiol as novel anticancer agents.

As one of the metabolites of ginseng, 20(S)-protopanaxadiol (PPD) is a compound with dammarane-type tetracyclic triterpene, which performs a wide range of anticancer activities. In this study, PPD was used as a lead. A series of compounds were synthesized respectively with 11 amino acids through esterification and were evaluated for their cytotoxicity against several cancer cell lines. One of the synthetic products (PL) exhibited potent inhibitory effect on Huh-7 cells relative to that of PPD in vitro. Subsequently, the Annexin V-FITC /PI staining assay was used to verify that PL induced apoptosis of Huh-7 cells in a dose-dependent manner. A UPLC-Q/TOF-MS analysis method was established and validated for assessing pharmacokinetic properties after the administration of PPD and PL in rats. The results showed that compared with PPD, T_1/2of PL in rats was prolonged, and the peak time was delayed, resulting in broader tissue distribution of the compound in the body. In addition, the targets of PL against several cancers were predicted and analyzed via network pharmacology. Molecular docking simulations demonstrated that PL interacted with the active sites of the above targets. In conclusion, this study provided a theoretical basis for the development and clinical application of anti-tumor activity of PPD.