European Journal of Medicinal Chemistry最新文献

{"title":"Design and synthesis of dual-activity biphenyl inhibitors against SARS-CoV-2 and bladder cancer","authors":"Lin Lin Shang ,&nbsp;Teng Long Hu ,&nbsp;Situ Xiong ,&nbsp;Songhui Xu ,&nbsp;Li Ping Cheng","doi":"10.1016/j.ejmech.2026.118581","DOIUrl":"10.1016/j.ejmech.2026.118581","url":null,"abstract":"<div><div>Targeting the crucial SARS-CoV-2 therapeutic target 3CL^pro, a natural product MOL007703 was identified from <em>Stellariae Radix</em>. Through systematic optimization, a series of novel biphenyl derivatives were designed to enhance target engagement. Among them, compound L3 shows superior 3CL^pro inhibition with an IC₅₀ of 0.15 μM, which is 13.6-fold more potent than the reference drug ebselen (IC₅₀ = 2.04 μM). L3 also exhibits potent antiviral activity against SARS-CoV-2 (EC₅₀ = 2.82 μM), comparable to remdesivir (EC₅₀ = 1.47 μM). Molecular docking revealed that the <em>para</em>-trifluoromethyl-substituted benzene ring occupies the hydrophobic S4 pocket of 3CL^pro. The electron-withdrawing fluorine atoms promote electrostatic and dipole interactions and act as hydrogen-bond acceptors with residues in the polar S1 pocket, synergistically enhancing inhibitory potency. Furthermore, L3 displays favorable therapeutic potential with low cytotoxicity in HK-2 fibroblasts (CC₅₀ &gt; 50 μM) and potent concentration-dependent suppression of T24 bladder cancer cell proliferation (IC₅₀ = 10.99 μM), outperforming the reference drug mitomycin (IC₅₀ = 16.95 μM). These results highlight fluorinated biphenyl scaffolds as privileged chemotypes for multitarget drug development, enabling concurrent inhibition of viral protease and cancer cell growth. This work provides a rational strategy for repurposing traditional medicine-derived scaffolds into dual-function therapeutics through structural hybridization.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118581"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of potent bifunctional small molecules targeting DNA-PK and HDAC6 with desirable pharmacokinetic properties for acute myeloid leukemia treatment","authors":"Zongbao Ding ,&nbsp;Xiaoqing Zhao ,&nbsp;Binbin Cheng ,&nbsp;Congcong Wen","doi":"10.1016/j.ejmech.2026.118634","DOIUrl":"10.1016/j.ejmech.2026.118634","url":null,"abstract":"<div><div>DNA-PK serves as a critical mediator in DNA damage repair, with its activity modulated by the epigenetic regulator HDAC6. Building on our previous findings that HDAC inhibitors can enhance the DNA damage response, we rationally designed and evaluated a novel series of dual-targeting inhibitors co-targeting DNA-PK and HDAC6 for their therapeutic potential in acute myeloid leukemia (AML). Among these candidates, <strong>DH-1</strong> exhibits potent and balanced inhibitory activities against DNA-PK (IC₅₀ = 84.2 nM) and HDAC6 (IC₅₀ = 64.8 nM), while potently suppressing the proliferation of AML cells. Mechanistic investigations revealed that <strong>DH-1</strong> can arrest AML-derived HL-60 cells in the G₂/M phase and elevate γ-H2AX levels (a well-recognized hallmark of DNA double-strand breaks). Remarkably, <strong>DH-1</strong> demonstrates favorable pharmacokinetic properties in Sprague-Dawley (SD) rats, featuring moderate oral bioavailability (14.4 %) and a satisfactory half-life (7.9 h, p.o.). Furthermore, <strong>DH-1</strong> exhibits robust antitumor efficacy in multiple AML models, with a tumor growth inhibition (TGI) rate of 67.9 %. In summary, <strong>DH-1</strong> represents a promising DNA-PK/HDAC6 dual-functional inhibitor with superior <em>in vivo</em> efficacy and desirable pharmacokinetic profiles, strongly supporting its further preclinical advancement.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118634"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and structure-activity relationship analyses of 1,2-diphenylethane derivatives as a new class of GPR68 antagonists and the therapeutic effect in an inflammatory bowel disease model","authors":"Wuxin Liu ,&nbsp;Chenyu Tian ,&nbsp;Mengqiu Zhou ,&nbsp;Xinhua Wang ,&nbsp;Lu Yang ,&nbsp;Chong Huang ,&nbsp;Shengyong Yang ,&nbsp;Linli Li","doi":"10.1016/j.ejmech.2026.118611","DOIUrl":"10.1016/j.ejmech.2026.118611","url":null,"abstract":"<div><div>G protein-coupled receptor 68 (GPR68), a proton-sensing GPCR, has emerged as a key player in inflammatory diseases. Its expression is substantially upregulated in the inflamed intestinal mucosa of inflammatory bowel disease (IBD) patients, and pharmacological inhibition of GPR68 has been shown to ameliorate colitis in preclinical models, highlighting GPR68 as a promising therapeutic target. Herein, we report the discovery of diphenylethane derivatives as a novel class of potent GPR68 antagonists. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent GPR68 antagonist (<strong>18l</strong>) with an IC₅₀ value of 0.081 ± 0.006 μM. The lead compound demonstrated significant inhibition of GPR68-mediated signaling and reduced the production of key pro-inflammatory cytokines. In a dextran sulfate sodium (DSS)-induced mouse model of IBD, <strong>18l</strong> effectively alleviated disease symptoms. It also showed good pharmacokinetic properties and a commendable safety profile. Overall, compound <strong>18l</strong> could be a promising lead compound for the treatment of IBD and deserves further in-depth studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118611"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, biological evaluation and mechanism study of 2-benzoyl-quinazolinone derivative as ferroptosis inhibitor for the treatment of Parkinson's disease","authors":"Fengxian Luo ,&nbsp;Yanqing Pang ,&nbsp;Yingjie Wang ,&nbsp;Yanan Wang ,&nbsp;Jun Yan ,&nbsp;Lei Zhou","doi":"10.1016/j.ejmech.2026.118625","DOIUrl":"10.1016/j.ejmech.2026.118625","url":null,"abstract":"<div><div>The development of novel ferroptosis inhibitor reprensents a promising strategy for neurodegenerative diseases, driving the urgent need for developing therapeutic agents that can effectively modulating ferroptosis. In this study, we designed and synthesized a series of novel C2-functionalized quinazolinone derivatives. Systematic screening identified compounds <strong>8f</strong> and <strong>8h</strong> as selective ferroptosis inhibitor in HT-22 cell. Compound <strong>8h</strong> exhibited superior neuroprotective activity in <em>vitro</em> and in zebrafish model <em>in vivo</em>. Preliminary mechanistic studies revealed that compound <strong>8h</strong> exerted synergistic effects through dual activation of Steap4 and glutathione peroxidase 4 (GPX4), thereby maintaining iron metabolism homeostasis, clearing phospholipid hydroperoxides, and attenuating lipid peroxidation and reactive oxygen species accumulation. Overall, this work is the first to report the 2-benzoyl-quinazolinones scaffold as effective ferroptosis inhibitor. Compound <strong>8h</strong>, in particular, emerges as a promising candidate warranting further development for the treatment of Parkinson's disease (PD).</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118625"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photodynamic action of Pd(II)/porphyrin complexes against melanoma cells","authors":"Edynara Cruz de Moraes ,&nbsp;Marcos V. Palmeira-Mello ,&nbsp;Lívia do Carmo Silva ,&nbsp;Juliana Santana De Curcio ,&nbsp;Alex Marchezini Graça ,&nbsp;Jocely Lucena Dutra ,&nbsp;Antonio Alonso ,&nbsp;Guilherme Rocha Lino de Souza ,&nbsp;Alzir Azevedo Batista ,&nbsp;Elisângela de Paula Silveira-Lacerda ,&nbsp;Pablo José Gonçalves","doi":"10.1016/j.ejmech.2026.118751","DOIUrl":"10.1016/j.ejmech.2026.118751","url":null,"abstract":"<div><div>Photodynamic therapy (PDT) is an emerging strategy for cancer treatment and represents a promising approach for melanoma, one of the most aggressive and therapy-resistant forms of skin cancer. In this study, meso-tetra(4-pyridyl)porphyrin complexes coordinated with palladium(II)/diphosphine ligands (Porf@dppe, Porf@dppp, Porf@dppb, and Porf@dppf; dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, dppb = 1,4-bis(diphenylphosphino)butane, and dppf = 1,1′-bis(diphenylphosphino)ferrocene), previously shown to display favorable lipophilicity and efficient singlet oxygen production, were evaluated against human (A375) and murine (B16-F10) melanoma cells, as well as non-cancerous keratinocytes (HaCaT). Cytotoxicity measured after a 90 min incubation period yielded dark IC₅₀ values between 0.6 and 8.6 μM, whereas light irradiation (λ = 415 nm, 1.8 J cm^-2, 36 mW cm^-2) resulted in markedly lower IC₅₀ values in the nanomolar range (2–27 nM). Irradiation increased intracellular ROS levels, induced morphological alterations in A375 cells, inhibited long-term proliferation, and reduced cell migration, particularly for Porf@dppb and Porf@dppf. The highest cytotoxicity was observed for Porf@dppf, likely due to the redox-active ferrocene unit promoting Fenton-type reactions and enhanced hydroxyl radical formation. Electron paramagnetic resonance (EPR) spin-trapping experiments confirmed light-induced generation of singlet oxygen, hydroxyl radicals, and superoxide anion, with significantly higher hydroxyl radical production observed for Porf@dppf. The photodynamic activity of these complexes is attributed to efficient ROS production involving simultaneous contributions from both Type I and Type II mechanisms. Moderate binding to bovine serum albumin suggests possible albumin-mediated plasma transport. Overall, palladium(II)/diphosphine porphyrin complexes emerge as promising photosensitizers for melanoma photodynamic therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"309 ","pages":"Article 118751"},"PeriodicalIF":5.9,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147392874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small-molecule modulators of the androgen receptor N-terminal domain: Advances in medicinal chemistry for prostate cancer","authors":"Inderpal Sekhon,&nbsp;Dennis Ashong,&nbsp;Guanglin Chen,&nbsp;Qiao-Hong Chen","doi":"10.1016/j.ejmech.2026.118580","DOIUrl":"10.1016/j.ejmech.2026.118580","url":null,"abstract":"<div><div>Resistance to androgen receptor (AR) therapies in prostate cancer frequently arises from ligand-binding domain (LBD) mutations or the expression of LBD-truncated splice variants such as AR-V7. As these variants retain a functional N-terminal domain (NTD) essential for transcriptional activity, the intrinsically disordered NTD has become an attractive therapeutic target. This review integrates recent advances in targeting the AR NTD, emphasizing both classical antagonists and emerging mechanistic strategies. The pioneering EPI compounds established proof of concept for small-molecule inhibition of the AR NTD, with two analogues progressing to clinical trials. Subsequent discovery efforts have yielded structurally diverse NTD antagonists from natural products and synthetic libraries. Mechanism-focused approaches have garnered increasing interest; small molecules such as UT-143 and ET-516 disrupt AR-driven condensates formed via liquid-liquid phase separation, impairing oncogenic transcription. To complement these approaches, other innovative modalities are also being developed, including bispecific antibodies delivering intracellular anti-NTD fragments, NTD-targeting degraders (e.g., PROTACs), and urea-based antagonists selective for AR splice variants. Disrupting critical protein-protein interactions, such as those between the AR NTD and coactivators, offers an additional strategy to suppress AR activity. Advances in screening platforms and the optimization of structure-activity relationships are beginning to address the challenges of targeting disordered protein domains. With agents like EPI-7386 entering clinical evaluation and others advancing through preclinical development, AR NTD-targeted therapies represent a promising avenue to overcome resistance in castration-resistant prostate cancer (CRPC), potentially in combination with existing LBD-directed treatments to achieve more durable disease control.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118580"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-targeting ketolide-quinolone hybrids overcome erm-mediated resistant pathogens via ribosomal and DNA gyrase inhibition","authors":"Rui-Chen Liu ,&nbsp;Jue-Ru Zhang ,&nbsp;Cong-Xuan Ma ,&nbsp;Wen-Tian Liu ,&nbsp;Si-Xi Wang ,&nbsp;Si-Meng Liu ,&nbsp;Yun Li ,&nbsp;Yi-Lan Li ,&nbsp;Jing Ding ,&nbsp;Li-Fan Guo ,&nbsp;Ming-Jia Yu ,&nbsp;Jian-Hua Liang","doi":"10.1016/j.ejmech.2026.118562","DOIUrl":"10.1016/j.ejmech.2026.118562","url":null,"abstract":"<div><div>Macrolide antibiotics are classical protein synthesis inhibitors. However, the frequent development of clinical resistance significantly limits their utility. We report a novel series of ketolide-quinolone hybrids (<strong>26</strong>–<strong>31</strong>) that uniquely disrupt both protein synthesis and DNA replication. The new lead <strong>26l</strong> exhibited balanced dual inhibition with IC₅₀ values of 1.11 μM against ribosomes and 3.31 μM against DNA gyrases. <em>In vivo</em> mechanistic studies, including resistance mutation mapping in <em>E. coli</em> SQ110DTC strains and MIC profiling against ribosome- or/and gyrase-mutated <em>E. coli</em> SQ110DTC, confirmed concurrent target engagement of <strong>26l</strong>. This bifunctional activity not only restored <em>in vitro</em> efficacy against macrolide-resistant erm-mediated resistant Gram-positive pathogens (<em>S. pneumoniae</em> and <em>S. pyogenes</em>), but also significantly enhanced activity against Gram-negative <em>H. influenzae</em> and <em>M. catarrhalis</em>. Notably, compound <strong>26l</strong> demonstrated reduced CYP3A4 inhibition—a common side effect associated with macrolide antibiotics—compared to telithromycin. Compound <strong>26l</strong> exhibited good stability in both mouse plasma and liver microsomes. Molecular docking studies elucidated how the hybrid simultaneously occupies two key bacterial targets—the ribosome and DNA gyrase—through specific interactions mediated by its macrolide core and quinolone moiety. With its dual-targeting mechanism, expanded spectrum coverage, and optimized safety properties, the new lead <strong>26l</strong> emerges as a strategic solution to the escalating crisis of macrolide resistance in community-acquired bacterial pneumonia.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118562"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Promiscuously bioactive compounds are prevalent in widely used commercial drug repurposing libraries","authors":"Huabin Hu ,&nbsp;James Bowers ,&nbsp;Justin Shumate ,&nbsp;Louis Scampavia ,&nbsp;Timothy P. Spicer ,&nbsp;Xiangyan Yi ,&nbsp;Albert A. Antolin ,&nbsp;Jonathan B. Baell","doi":"10.1016/j.ejmech.2025.118550","DOIUrl":"10.1016/j.ejmech.2025.118550","url":null,"abstract":"<div><div>The discovery of new therapeutics typically begins with screening compound collections against specific disease targets to identify bioactive small molecules. However, subsequent optimization is both time-consuming and costly, leading researchers to search for desired bioactivity in already-approved drugs with the hope of accelerating clinical development – a strategy often termed drug repurposing. While this strategy may seem beneficial, it carries significant risks, in particular with respect to lack of intellectual property control required to navigate regulatory pathways to the clinic. In this study, we have identified the more concerning phenomenon that widely used drug repurposing libraries are disproportionately populated by promiscuous compounds. Researchers lacking adequate medicinal chemistry expertise may overlook the spurious behaviors linked to certain molecular scaffolds, which can result in the advancement of misleading compounds into clinical trials. This misstep not only wastes scientific and financial resources but also could pose serious risks to patient safety by potentially enrolling them in ineffective trials. We call upon the biomedical community to implement rigorous validation processes for screening hits and to systematically exclude problematic compounds from drug repurposing libraries, thereby increasing the translational rate of future drug repurposing initiatives.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118550"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent development of ATR inhibitors for cancer therapy","authors":"Jiao Wang ,&nbsp;Yuan Quan ,&nbsp;Ying Shen ,&nbsp;Liang Chang ,&nbsp;Huijie Zhang ,&nbsp;Wancheng Zhao","doi":"10.1016/j.ejmech.2026.118560","DOIUrl":"10.1016/j.ejmech.2026.118560","url":null,"abstract":"<div><div>Ataxia Telangiectasia and Rad3-related (ATR) kinase belongs to the PIKK (phosphatidylinositol 3-kinase–related kinase) family and serves as a pivotal hub for preserving genomic stability and regulating responses to replication stress and DNA damage. Dysregulation of ATR signaling is strongly associated with tumorigenesis, resistance to therapy, and other pathological states (such as neurodegenerative diseases), making it a highly attractive target in cancer therapy. To date, no ATR inhibitors have achieved regulatory approval; however, several candidate molecules, most notably berzosertib, ceralasertib, and gartisertib, are advancing in clinical trials. This review focuses on the medicinal chemistry progress in ATR inhibitor development since 2018. Throughout this review, we systematically interweave major chemical scaffolds. We anticipate that this review will offer insightful guidance for rational design of future ATR inhibitors and help accelerate the emergence of next-generation ATR inhibitors with superior potency, selectivity, and clinical feasibility.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118560"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study","authors":"Zhongli Xu ,&nbsp;Shuting Shen ,&nbsp;Xinyu Ding ,&nbsp;Xiaoyu Wang ,&nbsp;Dejin Zhang ,&nbsp;Yuanchao Li ,&nbsp;Ping Xing ,&nbsp;Hongli Chen ,&nbsp;Fang Bai ,&nbsp;Qianqian Yin ,&nbsp;Biao Jiang","doi":"10.1016/j.ejmech.2025.118546","DOIUrl":"10.1016/j.ejmech.2025.118546","url":null,"abstract":"<div><div>Natural harringtonine derivatives, isolated from <em>cephalotaxus</em> 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 <strong>P2</strong>, featuring a 3′-ethoxy group and a 5′-(3,4-dimethoxyphenyl) sulfide. <strong>P2</strong> exhibited a ∼10-fold increase in antiproliferative potency against human leukemic cell lines compared to homoharringtonine (HHT). The potent mechanism underlying <strong>P2</strong>'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 <strong>P2</strong> 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, <strong>P2</strong> has been identified as a promising anti-leukemic candidate and warrants further development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118546"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}