Citation: Ning Tian, Haoyu Ju, Qian Hu, Qifeng Hou, Yiping Lu, Yu Liu, Jinmei Huang, Zhong-Hong Zhu, Bin Zhang, Jin Huang, Ming-Hua Zeng. Solvothermal domino synthesis of an ER-targeted iron(Ⅱ) complex for inducing immunogenic cell death[J]. Chinese Chemical Letters, ;2026, 37(6): 111038. doi: 10.1016/j.cclet.2025.111038 shu

Solvothermal domino synthesis of an ER-targeted iron(Ⅱ) complex for inducing immunogenic cell death

Ning Tian ^{a, 1} ,
Haoyu Ju ^{b, 1} ,
Qian Hu ^b ,
Qifeng Hou ^a ,
Yiping Lu ^b ,
Yu Liu ^a ,
Jinmei Huang ^a ,
Zhong-Hong Zhu ^a ,
Bin Zhang ^a ,
Jin Huang ^{b, *,} ,
Ming-Hua Zeng ^{a, c, *,}

a.
School of Chemistry and Pharmaceutical Sciences, State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China
b.
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
c.
College of Chemistry and Bioengineering, Guilin University of Technology, Guilin 541004, China

huangjin@ecust.edu.cn

zmh@mailbox.gxnu.edu.cn

Received Date: 3 January 2025
Revised Date: 18 February 2025
Accepted Date: 5 March 2025
Available Online: 5 March 2025

Figures(8)

Reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress is a prerequisite for the induction of immunogenic cell death (ICD), and the development of metal-based ICD inducers has garnered significant attention. However, the drug-target mechanisms of ICD inducers still require further exploration. Herein, we reported an ER-targeting iron(Ⅱ) complex (Fe-NBM) as an ICD inducer, which was obtained through a solvothermal domino reaction. Accordingly, pyridin-2-ylmethanamine and 1-methyl-2-formylbenzimidazole underwent consecutive covalent transformations to form a novel N-heterocyclic ligand, which subsequently coordinated with ferrous chloride to directly yield the crystalline Fe-NBM in one pot. Confocal laser scanning microscope (CLSM), molecular docking and cellular thermal shift assay (CETSA) showed that Fe-NBM could specifically target the ER by binding to the IRE1α (Inositol requiring kinase enzyme 1 alpha) and induce ICD by generating ROS-based ER stress. In an immunocompetent mouse model, Fe-NBM could significantly inhibit tumor growth and stimulate anti-tumor immunity, and exhibit an enhanced effect when combined with anti-PD1 therapy, leading to near-complete tumor elimination. To gain deeper understanding of how to synthesize such effective ICD inducers at the molecular level, a combination of electrospray ionization mass spectrometry (ESI-MS) and crystallography was employed for thoroughly tracking the step-economy synthetic process. To the best of our knowledge, Fe-NBM is the first iron-based ICD inducer that directly targets ER through binding to IRE1α. We believe that the ICD-related target information presented in this work will enhance our understanding of the molecular mechanisms underlying ICD and facilitate the design of new ICD inducers.
- Domino reaction,
- Metal complex,
- Antitumor,
- Endoplasmic reticulum targeted,
- Immunogenic cell death
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