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
  • 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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