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In this study, a series of new indole derivatives of ursolic acid bearing different N -(aminoalkyl)carboxamide side chains were designed, synthesized, and evaluated for their in vitro cytotoxic activities against two human hepatocarcinoma cell lines (SMMC-7721 and HepG2) and normal hepatocyte cell line (LO2) via MTT assay. Among them, compound 5f exhibited the most potent activity against SMMC-7721 and HepG2 cells with IC 50 values of 0.56 ± 0.08 μM and 0.91 ± 0.13 μM, respectively, and substantially lower cytotoxicity to LO2 cells. A follow-up enzyme inhibition assay and molecular docking study indicated that compound 5f can significantly inhibit the activity of Topoisomerase IIα. Further mechanistic studies performed in SMMC-7721 cells revealed that compound 5f can elevate the intracellular ROS levels, decrease mitochondrial membrane potential, and finally lead to the apoptosis of SMMC-7721 cells. Collectively, compound 5f is a promising Topoisomerase II (Topo II) inhibitor, which exhibited the potential as a lead compound for the discovery of novel anticancer agents.

Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors