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  3. How does ferrocene correlate with ferroptosis? Multiple approaches to explore ferrocene-appended GPX4 inhibitors as anticancer agents

How does ferrocene correlate with ferroptosis? Multiple approaches to explore ferrocene-appended GPX4 inhibitors as anticancer agents

  • Chem Sci. 2024 May 31;15(27):10477-10490. doi: 10.1039/d4sc02002b.
Wei Li 1 2,  Jing Yu 1 2,  Jing Wang 1 2,  Xuejing Fan 1 2,  Ximing Xu 3,  Hui Wang 1 2,  Ying Xiong 4,  Xinyu Li 1 2,  Xiaomin Zhang 1 2,  Qianer Zhang 1 2,  Xin Qi 1 2,  Pascal Pigeon 5 6,  Qing Gu 7,  Julia Bruno-Colmenarez 8,  Gérard Jaouen 5 6,  Michael J McGlinchey 8,  Xue Qiu 1 2,  Shu-Li You 7,  Jing Li 1 2,  Yong Wang 1 2
Affiliations

Affiliations

  • 1 School of Medicine and Pharmacy, Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China Qingdao 26003 Shandong P. R. China lijing_ouc@ouc.edu.cn wangyong8866@ouc.edu.cn.
  • 2 Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology Qingdao 266200 P. R. China.
  • 3 Marine Biomedical Research Institute of Qingdao, School of Medicine and Pharmacy, Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China Qingdao 266003 Shandong P. R. China.
  • 4 School of Pharmacy, Fudan University Shanghai 201203 China.
  • 5 PSL, Chimie ParisTech 11 Rue Pierre et Marie Curie F-75005 Paris France.
  • 6 Sorbonne Université, UMR 8232 CNRS, IPCM 4 Place Jussieu F-75005 Paris France.
  • 7 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 345 Lingling Lu Shanghai 200032 P. R. China.
  • 8 UCD School of Chemistry, University College Dublin Belfield Dublin 4 Ireland.
PMID: 38994406 DOI: 10.1039/d4sc02002b
Abstract

Ferroptosis has emerged as a form of programmed cell death and exhibits remarkable promise for Anticancer therapy. However, it is challenging to discover Ferroptosis inducers with new chemotypes and high ferroptosis-inducing potency. Herein, we report a new series of ferrocenyl-appended GPX4 inhibitors rationally designed in a "one stone kills two birds" strategy. Ferroptosis selectivity assays, GPX4 inhibitory activity and CETSA experiments validated the inhibition of novel compounds on GPX4. In particular, the ROS-related bioactivity assays highlighted the ROS-inducing ability of 17 at the molecular level and their Ferroptosis enhancement at the cellular level. These data confirmed the dual role of ferrocene as both the bioisostere motif maintaining the inhibition capacity of certain molecules with GPX4 and also as the ROS producer to enhance the vulnerability to Ferroptosis of Cancer cells, thereby attenuating tumor growth in vivo. This proof-of-concept study of ferrocenyl-appended Ferroptosis inducers via rational design may not only advance the development of ferroptosis-based Anticancer treatment, but also illuminate the multiple roles of the ferrocenyl component, thus opening the way to novel bioorganometallics for potential disease therapies.

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