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  3. Triphenylphosphine-modified cyclometalated iridiumIII complexes as mitochondria-targeting anticancer agents with enhanced selectivity

Triphenylphosphine-modified cyclometalated iridiumIII complexes as mitochondria-targeting anticancer agents with enhanced selectivity

  • Bioorg Chem. 2025 Feb:155:108148. doi: 10.1016/j.bioorg.2025.108148.
Hanxiu Fu 1,  Shuli Wang 1,  Yuwen Gong 1,  Heqian Dong 1,  Kangning Lai 1,  Zhihao Yang 1,  Chunyan Fan 1,  Zhe Liu 2,  Lihua Guo 3
Affiliations

Affiliations

  • 1 Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165 PR China.
  • 2 Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165 PR China. Electronic address: liuzheqd@163.com.
  • 3 Key Laboratory of Life-Organic Analysis of Shandong Province, Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165 PR China. Electronic address: guolihua@qfnu.edu.cn.
PMID: 39799728 DOI: 10.1016/j.bioorg.2025.108148
Abstract

This study presents the development and evaluation of triphenylphosphine-modified cyclometalated iridiumIII complexes as selective Anticancer agents targeting mitochondria. By leveraging the mitochondrial localization capability of the triphenylphosphine group, these complexes displayed promising cytotoxicity in the micromolar range (3.12-7.24 μM) against A549 and HeLa Cancer cells, these complexes exhibit significantly higher activity compared to their unmodified counterparts lacking the triphenylphosphine moiety. Moreover, they demonstrate improved specificity for Cancer cells over normal cells, achieving selectivity index in the range of 5.46-14.83. Mechanistic studies confirmed that these complexes selectively target mitochondria rather than DNA, as shown by confocal microscopy and flow cytometry, where they accumulate to induce mitochondrial dysfunction. This disruption leads to mitochondrial membrane depolarization (MMP), elevated Reactive Oxygen Species (ROS) levels, and activation of intrinsic Apoptosis pathways. Furthermore, the complexes induce cell cycle arrest at the G2/M phase and suppress the migration of A549 cells.

Keywords

Cyclometalated complexes; Cytotoxicity; Iridium; Target mitochondria; Triphenylphosphonium.

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