Synthesis of mitochondria-targeted podophyllotoxin derivatives for the imaging and antiproliferation of liver cancer.

To address the systemic toxicity of podophyllotoxin (PPT), two series of mitochondria-targeted PPT derivatives were designed and synthesized by conjugating PPT with delocalized lipophilic cations (DLCs) TPP+ and F16 via alkyl linkers. Biological evaluation revealed that the F16-conjugated compound 6d exhibited the most potent antiproliferative activity against HepG2 cells with an IC50 value of 0.66 μM, which was significantly superior to the positive control etoposide with an IC50 of 10.82 μM. Additionally, 6d demonstrated improved selectivity toward normal hepatocytes (QSG-7701) with a selectivity index of 2.29. Colocalization studies confirmed that 6d specifically accumulates in mitochondria, with a Pearson's correlation coefficient of 0.90. Flow cytometry analysis further demonstrated that 6d induces apoptosis in a concentration-dependent manner. These findings highlight compound 6d as a promising mitochondria-targeted lead agent for liver cancer therapy.