Synthesis and biological evaluation of diosgenin derivatives as potential anti-breast cancer agents.

Diosgenin (DSG) can function as a promising anti-tumor lead compound. However, its moderate anti-tumor efficacy limits its clinical applications. Herein, we report the design, synthesis, and evaluation of 24 DSG derivatives for their anti-breast cancer activities in vitro. Their inhibitory activities against three different human breast cancer cell lines (MDA-MB-231, MDA-MB-468, and MCF-7) and one normal human breast cell line (MCF-10A) were screened. The results indicated that compound 6j featuring 4-bromobenzyl exhibited remarkable inhibitory effects against MCF-7 cells (IC50 = 6.2 μM), with an IC50 value 7.95-fold lower than that of DSG (IC50 = 49.3 μM). Moreover, 6j exhibited relatively low toxicity against MCF-10A cells, indicating good selectivity. The mechanistic studies revealed that 6j significantly arrested MCF-7 cells in the G2/M phase, increased reactive oxygen species accumulation, induced mitochondrial membrane potential depolarization, and triggered apoptosis through the mitochondrial pathway. Therefore, 6j represents a promising anti-breast cancer lead compound and warrants further investigation.