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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 8, 18, 26, and 30, 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 8 displayed excellent cytotoxic activity against HepG2 cells (IC 50 = 1.9 μM) and showed relatively low toxicity against L02 cells (IC 50 = 18.6 μM), showing some selectivity between normal and tumor cells. Studies on its cellular mechanism of action showed that compound 8 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 8 based on its 3D molecular similarity, and docking studies showed that compound 8 fits well into the active site of p38α-MAPK and forms relatively strong interactions with the surrounding amino acid residues. Accordingly, compound 8 may be used as a promising lead compound for the development of new antitumor agents.

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Steroidal saponins, a class of natural products formed by the combination of spirosteranes with sugars, are widely distributed in plants and have various biological activities, such as anti-tumor, anti-inflammatory, anti-bacterial, anti-Alzheimer's, anti-oxidation, etc. Particularly, extensive researches on the antitumor property of steroidal saponins have been received. Steroidal sapogenins, the aglycones of steroidal saponins, also have attracted much attention due to a vast range of pharmacological activities similar to steroidal saponins. In the past few years, structural modifications on the aglycones and sugar chains of steroidal saponins have been carried out and some achievements have been made. In this mini-review, the antitumor activity, action mechanisms, and structural modifications along with the structure-activity relationships of steroidal saponins and their derivatives are summarized.