2. Academic Validation
  3. Coumarin-Quinazolinone based photosensitizers: Mitochondria and endoplasmic reticulum targeting for enhanced phototherapy via different cell death pathways

Coumarin-Quinazolinone based photosensitizers: Mitochondria and endoplasmic reticulum targeting for enhanced phototherapy via different cell death pathways

  • Eur J Med Chem. 2024 Oct 19:280:116990. doi: 10.1016/j.ejmech.2024.116990.
Xuzi Zhao 1,  Ting Wang 1,  Fucheng Shang 1,  Jiangyu Yan 1,  Mingyan Jiang 2,  Xiaoyan Zou 3,  Guorui Li 4,  Zhibin Song 5,  Jing Huang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemo/Biosensing and Chemometrics, School of Biomedical Sciences, Hunan University, Changsha, 410082, China; Hunan Key Laboratory of Animal Models and Molecular Medicine, Hunan University, Changsha, 410082, Hunan Province, China.
  • 2 Affiliated Hospital of Hunan University/ Xiangtan Central Hospital, Xiangtan, 411100, China.
  • 3 Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, the "Double-First Class" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), Changsha Medical University, Changsha, 410219, China.
  • 4 Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, the "Double-First Class" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), Changsha Medical University, Changsha, 410219, China. Electronic address: liguorui@hnu.edu.cn.
  • 5 Key Laboratory for Green Chemistry of Jiangxi Province, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, China. Electronic address: zbsong@jxnu.edu.cn.
  • 6 State Key Laboratory of Chemo/Biosensing and Chemometrics, School of Biomedical Sciences, Hunan University, Changsha, 410082, China; Hunan Key Laboratory of Animal Models and Molecular Medicine, Hunan University, Changsha, 410082, Hunan Province, China; Affiliated Hospital of Hunan University/ Xiangtan Central Hospital, Xiangtan, 411100, China. Electronic address: huangjing16@hnu.edu.cn.
PMID: 39442335 DOI: 10.1016/j.ejmech.2024.116990
Abstract

Organelle-targeted photosensitizers (PSs) offer valuable tools for improving photodynamic therapy (PDT), yet systematic studies on how different organelles influence phototherapeutic outcomes are limited. In particular, the connection between organelle targeting and various modes of programmed cell death remains unclear. In this study, we developed a series of PSs using the Coumarin-Quinazolinone (CQ) scaffold, each designed to target different organelles, including the mitochondria, endoplasmic reticulum (ER), lysosome, and nucleolus. Our results show that their PDT performance is highly dependent on their localization, with phototoxic index (PI) ranging from 2 to 245. Notably, the mitochondria-targeted CQ-Mito and ER-targeted CQ-ER exhibited profound phototherapeutic performances, with PI of 167 and 245 respectively. Our further study reveals that CQ-Mito causes cell death by both Apoptosis and Ferroptosis, while CQ-ER primarily triggers Ferroptosis. This study not only provides new agents for PDT but also offers insights into how organelle targeting influences cell death mechanisms, which can shed light on the design of PSs for controlled cell death.

Keywords

Cell death modes; Ferroptosis; Organelle targeting; Photodynamic therapy; Photosensitizers.

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