sp3‐Rich Glycyrrhetinic Acid Analogues Using Late‐Stage Functionalization as Potential Breast Tumor Regressing Agents

Abstract Late‐stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C−H bonds on pre‐existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A‐ring, expanding the A‐ring and selectively activating one methyl group of the gem ‐dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA‐MB‐231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproliferative and anti‐invasive effects through enhanced mitochondrial superoxide production with parallel depletion of GSH levels. Furthermore, intraperitoneal administration of these two compounds, in comparison with GA, greatly regressed breast tumor growth and metastasis in a SCID mouse model bearing labeled MDA‐MB‐231 cells.