Unexpected Discovery of a Novel Triphenylphosphonium Alkylalcohol That Triggers Cancer Cell Death via Mitophagy and Ferroptosis

  • J Med Chem. 2025 Jun 12;68(11):11852-11874. doi: 10.1021/acs.jmedchem.5c00701.
Ding Huang  1  2 ,  Maojie Zhang  1  3 ,  Haibo Yan  1 ,  Ligang Mei  4 ,  Aiming Yang  4 ,  Yun He  1  5 ,  Kin Yip Tam  2 ,  Shao-Lin Zhang  1
Affiliations
  • 1. School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 401331, PR China.
  • 2. Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR 999078, PR China.
  • 3. Zunyi Medical and Pharmaceutical College, Zunyi 563006, PR China.
  • 4. School of Life Sciences, Chongqing University, Chongqing 401331, PR China.
  • 5. Therapeutic Innovation Center, Shenzhen Bay Laboratory, Shenzhen 518132, P. R. China.
PMID: 40393945 DOI: 10.1021/acs.jmedchem.5c00701
Abstract

Mitochondria-targeted delivery is a promising strategy in Anticancer drug development. Triphenylphosphine cation (TPP+) is the most widely used mitochondrial-targeting carrier due to the elevated mitochondrial membrane potential (MMP) in Cancer cells. Here, we report the serendipitous discovery of a mitochondrial-targeting carrier, compound 23, which exhibited potent Anticancer activity (IC50 = 70 nM, HCC827) with minimal toxicity to normal cells. Compound 23 selectively accumulates in Cancer cell mitochondria, induces MMP depolarization, and activates Mitophagy via PINK1-Parkin pathway. It also disruptes mitochondrial functions, elevates ROS levels, and inhibits the xCT-GSH-GPX4 axis, leading to lipid peroxidation and ferroptotic cell death. In vivo, 23 significantly suppressed the growth of HCC827 xenograft tumors at 10 mg/kg. These findings support compound 23 as a highly selective and effective mitochondrial-targeting Anticancer agent for further investigation.

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