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

  • Bioorg Med Chem Lett. 2026 Jul:136:130591. doi: 10.1016/j.bmcl.2026.130591.
Chenmeng Xu  1 ,  Rui Wang  2 ,  Fuyang Liu  3 ,  Jianjun Huang  4 ,  Yonghao Deng  1 ,  Junhua Li  1 ,  Ying Wang  1 ,  Wim Dehaen  4 ,  Yuyu Fang  5 ,  Qiyong Huai  6
Affiliations
  • 1. Marine College, Shandong University, Weihai 264209, China.
  • 2. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, 11 Yuk Choi Rd, Hung Hom, Hong Kong Special Administrative Region of China. Electronic address: [email protected].
  • 3. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
  • 4. Sustainable Chemistry for Metals and Molecules, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.
  • 5. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. Electronic address: [email protected].
  • 6. Marine College, Shandong University, Weihai 264209, China. Electronic address: [email protected].
PMID: 41702463 DOI: 10.1016/j.bmcl.2026.130591
Abstract

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.

Keywords
Antiproliferative activity; F16; Imaging; Liver cancer; Mitochondria-targeted; Podophyllotoxin.
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