2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 4,6-dimorpholino-1,3,5-triazin-2-amine ferrocenecarboxylate derivatives as potent PI3K inhibitors

Design, synthesis and biological evaluation of novel 4,6-dimorpholino-1,3,5-triazin-2-amine ferrocenecarboxylate derivatives as potent PI3K inhibitors

  • Bioorg Chem. 2025 Jul 1:161:108571. doi: 10.1016/j.bioorg.2025.108571.
Yujue Wang 1,  Haifeng Xu 1,  Shiwen Yu 1,  Jinling Zheng 2,  Dandan Meng 3,  Yan Zhang 4,  Wenjun Li 5,  Hongfei Chen 6
Affiliations

Affiliations

  • 1 China Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research [Hunan Provincial Science and Technology Department Document (Approval number: 2019-56)], School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, China.
  • 2 Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China.
  • 3 Tsinghua University, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China.
  • 4 China Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research [Hunan Provincial Science and Technology Department Document (Approval number: 2019-56)], School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, China. Electronic address: yanz@usc.edu.cn.
  • 5 Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: wj.li@siat.ac.cn.
  • 6 China Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research [Hunan Provincial Science and Technology Department Document (Approval number: 2019-56)], School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, China. Electronic address: 2014001764@usc.edu.cn.
PMID: 40349530 DOI: 10.1016/j.bioorg.2025.108571
Abstract

Inhibitors of Phosphatidylinositol-3-kinase (PI3K) represent a classical tumor-specific therapeutic strategy that exerts anti-tumor effects by blocking the PI3K/Akt/mTOR signaling pathway involved in Cancer cell proliferation and survival. However, their clinical efficacy is restricted by resistance mechanisms that are both inherent and acquired, including PI3K self-activation, activation of parallel signaling pathways, and the impact of the tumor microenvironment. Inspired by chemodynamic therapy, a series of ferrocene-modified PI3K inhibitors were synthesized for the first time in this study. These inhibitors were designed by combining the targeting properties of PI3K inhibitors with the chemokinetic effects of ferrocene and demonstrated to exhibit both PI3K-dependent inhibitory effects and PI3K-independent cytotoxicity in the evaluation. In vitro experiments showed that compound 3d possessed excellent antiproliferative activity against breast Cancer 4T1 cells (IC50 = 3.70 ± 1.21 μM) and colon Cancer CT26 cells (IC50 = 1.98 ± 1.33 μM). Further in vivo assays also proved that compound 3d exhibited good antitumor activity, which is worth further studies.

Keywords

Anticancer; Antiproliferative; Chemodynamic therapy; Ferrocene; PI3K inhibitors.

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