Structure-Activity relationship (SAR) of 18-glycyrrhetinic acid derivatives on their antitumor activity through the PPAR receptor and caspase-3 pathway

Licorice is extensively utilized in the food industry, and glycyrrhetinic acid is among the most critical active constituents in licorice. This ingredient has garnered increasing attention in recent years. In a previous study, we identified a new series of Glycyrrhetinic acid derivatives containing piperazine skeleton, using virtual screening techniques based on docking. In this study, we conducted further optimization of the lead compound 4c , with a focus on enhancing the hydrophobic interactions in the binding site to improve agonist efficacy for peroxisome proliferator-activated receptor gamma (PPAR gamma). The obtained compounds were characterized using H-1 NMR, C-13 NMR, HRMS, and HPLC. Furthermore, these compounds were evaluated strong antitumor activity. Some compounds with potent antitumor activities were tested for their PPAR gamma agonist activity. Especially, compound 4f showed the most potent antitumor activity with half maximal inhibitory concentration (IC50) values of 2.382 mu M against the tested tumor cell lines Siha. Docking simulation was performed to position compound 4f into the PPAR gamma active site to determine the probable binding conformation. Consequently, we discovered a novel PPAR gamma agonist 4f that demonstrated high in vitro agonist activity.