Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study
文献类型：期刊论文
| 作者 | Xu, Zhongli2; Shen, Shuting2,3; Ding, Xinyu2,3; Wang, Xiaoyu2,3; Zhang, Dejin2,3; Li, Yuanchao1; Xing, Ping4; Chen, Hongli2; Bai, Fang2,3; Yin, Qianqian2,4 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2026-03-05 |
| 卷号 | 305页码:23 |
| 关键词 | Harringtonine derivative Homoharringtonine (HHT) Structure-activity relationship Anti-leukemic activity Molecular docking Protein synthesis inhibitor |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.118546 |
| 通讯作者 | Chen, Hongli(chenhl@shanghaitech.edu.cn) ; Bai, Fang(baifang@shanghaitech.edu.cn) ; Yin, Qianqian(yinqq@shanghaitech.edu.cn) ; Jiang, Biao(jiangbiao@shanghaitech.edu.cn) |
| 英文摘要 | 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 similar to 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. |
| WOS关键词 | ACUTE MYELOID-LEUKEMIA ; SIDE-CHAINS ; OPEN-LABEL ; HOMOHARRINGTONINE ; PROTEIN ; ACLARUBICIN ; COMBINATION ; CYTARABINE ; ALKALOIDS ; THERAPY |
| 资助项目 | Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University ; National Natural Science Foundation of China (NSFC) - Shanghai Sailing Program[81702600] ; National Natural Science Foundation of China (NSFC) - Shanghai Sailing Program[17YF1412200] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001663914800001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322682]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Hongli; Bai, Fang; Yin, Qianqian; Jiang, Biao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Chinese Acad Sci, CAS Key Lab Synthet Chem Nat Subst, Shanghai Inst Organ Chem, Shanghai 200032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xu, Zhongli,Shen, Shuting,Ding, Xinyu,et al. Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2026,305:23. |
| APA | Xu, Zhongli.,Shen, Shuting.,Ding, Xinyu.,Wang, Xiaoyu.,Zhang, Dejin.,...&Jiang, Biao.(2026).Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,305,23. |
| MLA | Xu, Zhongli,et al."Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 305(2026):23. |
入库方式： OAI收割
来源：上海药物研究所
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