Design, synthesis and antitumor activity evaluation of novel modified 18(3-glycyrrhetinate derivatives as PPARγ agonists

18(3-Glycyrrhetinic acid (18(3-GA) is the main active component of licorice and one of the most promising lead compounds in traditional Chinese herbal medicine. Previous studies have shown that 18(3-GA can act as a PPAR gamma agonist to exert antitumor activity. However, the number of reported 18(3-GA derivatives as PPAR gamma agonists is limited and they have significant toxic side effects, which greatly restricts their application and development. To obtain highly effective and low-toxic PPAR gamma agonists, through structure-activity relationship (SAR) analysis, we constructed a molecular library of 18(3-GA derivatives containing 13,440 compounds and screened out 14 novel 18(3-GA ester derivatives. The selected compounds were evaluated for their antitumor activity in vitro. The results showed that most of the compounds exhibited strong anti-proliferative activity against five human cancer cell lines, especially the human colon cancer cell line HT-29, without significant toxicity to normal cell lines. Among them, C1 had the strongest anti-proliferative activity against HT-29, with an IC50 value of 12.25 mu M, which was 12 times higher than that of its parent nucleus 18(3-GA. C1 can block the cell cycle of HT-29 cells in G2/M phase, significantly inhibit their migration and induce their apoptosis. Molecular docking and dynamics simulation results suggested that C1 could stably bind to the active pocket of PPAR gamma. Further PPAR gamma activity analysis and drug-likeness prediction results indicated that C1 could act as a PPAR gamma agonist to exert antitumor effects and had certain drug-likeness, which is worthy of further study.