Diosgenin Derivatives as Potential Antitumor Agents: Synthesis, Cytotoxicity, and Mechanism of Action.

Thirty-two new diosgenin derivatives were designed, synthesized, and evaluated for their cytotoxic activities in three human cancer cell lines (A549, MCF-7, and HepG2) and normal human liver cells (L02) using an MTT assay in vitro. Most compounds, especially , , , and , were more potent when compared with diosgenin. The structure-activity relationship results suggested that the presence of a succinic acid or glutaric acid linker, a piperazinyl amide terminus, and lipophilic cations are all beneficial for promoting cytotoxic activity. Notably, compound displayed excellent cytotoxic activity against HepG2 cells (IC = 1.9 μM) and showed relatively low toxicity against L02 cells (IC = 18.6 μM), showing some selectivity between normal and tumor cells. Studies on its cellular mechanism of action showed that compound induces G0/G1 cell cycle arrest and apoptosis in HepG2 cells. Predictive studies indicated that p38α mitogen-activated protein kinase (MAPK) is the optimum target of based on its 3D molecular similarity, and docking studies showed that compound fits well into the active site of p38α-MAPK and forms relatively strong interactions with the surrounding amino acid residues. Accordingly, compound may be used as a promising lead compound for the development of new antitumor agents.