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  3. Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study

Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study

  • Eur J Med Chem. 2026 Mar 5:305:118546. doi: 10.1016/j.ejmech.2025.118546.
Zhongli Xu 1,  Shuting Shen 2,  Xinyu Ding 2,  Xiaoyu Wang 2,  Dejin Zhang 2,  Yuanchao Li 3,  Ping Xing 4,  Hongli Chen 5,  Fang Bai 6,  Qianqian Yin 7,  Biao Jiang 8
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3 Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.
  • 5 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. Electronic address: [email protected].
  • 6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. Electronic address: [email protected].
  • 7 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. Electronic address: [email protected].
  • 8 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. Electronic address: [email protected].
PMID: 41506044 DOI: 10.1016/j.ejmech.2025.118546
Abstract

Natural harringtonine derivatives, isolated from cephalotaxus species, exhibit potent antiproliferative activity against hematological malignancies, particularly myeloid leukemia. However, systematic structure-activity relationship (SAR) studies for harringtonine derivatization remain limited. Herein, we employed nucleophilic epoxy ring-opening reactions using halogen, azido and thiophenol nucleophiles to rapidly construct a structurally diverse harringtonine derivative library. Subsequent comprehensive SAR investigation was then conducted to explore almost all modifiable positions on the side chain (1', 2', 3', 4', 5') and position 2 of the cephalotaxine core. Significantly, we demonstrated for the first time that the metabolically labile 4'-ester group could be replaced by ether or hydroxyl group. Structure-activity optimization led to the discovery of novel derivative P2, featuring a 3'-ethoxy group and a 5'-(3,4-dimethoxyphenyl) sulfide. P2 exhibited a ∼10-fold increase in antiproliferative potency against human leukemic cell lines compared to homoharringtonine (HHT). The potent mechanism underlying P2's anti-leukemic effects involve potent inhibition of protein synthesis, leading to the preferential reduction of short-lived proteins crucial for cell survival, including c-Myc and Mcl-1. Molecular docking study revealed that P2 adopts a distinct binding mode within the ribosome, resulting in a more favorable interaction profile and enhanced binding stability. Our findings provide valuable insights to guide the future structural optimization of harringtonine derivatives. Furthermore, P2 has been identified as a promising anti-leukemic candidate and warrants further development.

Keywords

Anti-leukemic activity; Harringtonine derivative; Homoharringtonine (HHT); Molecular docking; Protein synthesis inhibitor; Structure-activity relationship.

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