European Journal of Medicinal Chemistry最新文献_第9页

Discovery of a heterocyclic aromatic amide based P-gp inhibitor as coadjutant regulating autophagy against drug resistance in breast cancer 基于杂环芳酰胺的P-gp抑制剂在乳腺癌自噬抗耐药中的辅助调节作用的发现

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-09 DOI: 10.1016/j.ejmech.2025.118151

Wen-han Xue , Xu Zhang , Shuai Guo, Han Yu, Ru-yi Man, Peng-fei Lu, Gong-hui Ge, Hong-ye Liu, Fan-hao Meng, Ting-jian Zhang

{"title":"Discovery of a heterocyclic aromatic amide based P-gp inhibitor as coadjutant regulating autophagy against drug resistance in breast cancer","authors":"Wen-han Xue , Xu Zhang , Shuai Guo, Han Yu, Ru-yi Man, Peng-fei Lu, Gong-hui Ge, Hong-ye Liu, Fan-hao Meng, Ting-jian Zhang","doi":"10.1016/j.ejmech.2025.118151","DOIUrl":"10.1016/j.ejmech.2025.118151","url":null,"abstract":"<div><div>P-glycoprotein (P-gp) plays a vital role in the development of multidrug resistance (MDR) during chemotherapy, which mediated lysosomal sequestration of ADM, leading to the development of drug resistance. Lysosomes fuse with autophagosomes to generate autolysosomes in which contents are degraded, thereby achieving the metabolic needs of the cell itself and the renewal of organelles. In this work, a series of <em>N</em>-(3-cyano-4-(alkoxy)phenyl)heterocyclic aromatic amide derivatives (<strong>A1-A48</strong>) were designed and synthesized as novel P-gp inhibitors. Among them, compound <strong>A38</strong> showed low cytotoxicity and excellent reversal activity, which was considered the most promising P-gp inhibitor. P-gp ATPase assay, MOE and CETSA revealed that <strong>A38</strong> interacts with P-gp. ADM accumulation assay and other studies were conducted to verify that compound <strong>A38</strong> inhibits P-gp function. Further investigation indicated that <strong>A38</strong> in combination with ADM significantly promoted apoptosis and markedly suppressed the proliferation, migration and invasion ability in drug resistant breast cancer. mCherry-GFP-LC3B puncta formation assay verified that P-gp inhibitor <strong>A38</strong> blocks the formation of autophagic flux and ADM combined with <strong>A38</strong> results in the accumulation of autophagosomes, thereby inducing drug-resistant breast cancer cell death. In <em>in vivo</em> and <em>in vitro</em> tumor model experiments, the antitumor activity of ADM combined with P-gp inhibitor <strong>A38</strong> was superior to that of tariquidar. The effectiveness of compound <strong>A38</strong> and its role in regulating autophagy provided a new reference for the development of P-gp inhibitors and the clinical treatment of drug-resistant breast cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118151"},"PeriodicalIF":5.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025734","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}

引用次数: 0

Drugging the undruggable: Chemical and biological insights into molecular glues in the pipeline 给无法治疗的药物下药：化学和生物学对分子胶在管道中的洞察

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-09 DOI: 10.1016/j.ejmech.2025.118132

Kamel Metwally , Galal Yahya , Nader E. Abo-Dya

{"title":"Drugging the undruggable: Chemical and biological insights into molecular glues in the pipeline","authors":"Kamel Metwally , Galal Yahya , Nader E. Abo-Dya","doi":"10.1016/j.ejmech.2025.118132","DOIUrl":"10.1016/j.ejmech.2025.118132","url":null,"abstract":"<div><div>Recent advances in drug discovery have given rise to molecular glues, which present a unique chance to target functional proteins that were previously thought to be \"undruggable\" by traditional techniques. Molecular glues bridge the gap between biologics and conventional small-molecule protein inhibitors. They combine the advantageous pharmacokinetic profile of conventional small-molecule inhibitors with the target specificity of biologics in an innovative way. Furthermore, molecular glues get beyond the main drawbacks of other therapeutic approaches, namely the absence of distinct binding sites in difficult-to-target proteins for conventional small-molecule inhibitors and the drug-induced immunogenicity of biologics. This review delves into the conceptual and mechanistic underpinnings of molecular glues, from the accidental discovery of early immunomodulators like cyclosporin A through the investigation of thalidomide as a glue degrader to the current clinical evaluation of a diverse pipeline of structurally and mechanistically distinct molecular glues. The review identifies important binding motifs, common binding patterns, and hotspots at glue-induced protein interfaces through crystallographic data analysis of glue-induced ternary complexes. We aimed at broadening the therapeutic horizon of precision medicine by providing medicinal chemists with the fundamental concepts required for the rational design of next-generation molecular glues through the establishment of a structure-guided framework.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118132"},"PeriodicalIF":5.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025506","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}

引用次数: 0

Expanding the antiviral arsenal: N-arylated 1,2,4-oxadiazol-5(4H)-ones show high activity against orthopoxviruses 扩展抗病毒武库：n -芳基化1,2,4-恶二唑-5(4H)- 1对正痘病毒具有高活性

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-08 DOI: 10.1016/j.ejmech.2025.118124

Artem V. Semenov , Sergey V. Baykov , Natalia S. Soldatova , Kirill K. Geyl , Anton A. Shetnev , Vadim P. Boyarskiy , Mekhman S. Yusubov , Nikolai I. Bormotov , Olga A. Serova , Larisa N. Shishkina , Alena S. Ovchinnikova , Dmitrii A. Odnoshevsky , Oleg V. Pyankov , Sophia S. Borisevich , Yakov V. Gorohov , Vladimir N. Nikitin , Dmitry N. Shcherbakov , Olga I. Yarovaya , Nariman F. Salakhutdinov , Pavel S. Postnikov

{"title":"Expanding the antiviral arsenal: N-arylated 1,2,4-oxadiazol-5(4H)-ones show high activity against orthopoxviruses","authors":"Artem V. Semenov , Sergey V. Baykov , Natalia S. Soldatova , Kirill K. Geyl , Anton A. Shetnev , Vadim P. Boyarskiy , Mekhman S. Yusubov , Nikolai I. Bormotov , Olga A. Serova , Larisa N. Shishkina , Alena S. Ovchinnikova , Dmitrii A. Odnoshevsky , Oleg V. Pyankov , Sophia S. Borisevich , Yakov V. Gorohov , Vladimir N. Nikitin , Dmitry N. Shcherbakov , Olga I. Yarovaya , Nariman F. Salakhutdinov , Pavel S. Postnikov","doi":"10.1016/j.ejmech.2025.118124","DOIUrl":"10.1016/j.ejmech.2025.118124","url":null,"abstract":"<div><div>The study presents the discovery of a novel class of <em>N</em>-arylated 1,2,4-oxadiazol-5(4<em>H</em>)-ones as potent inhibitors of orthopoxviruses, including the variola virus (VARV). Through systematic structural modifications, two lead compounds, <strong>4</strong> (4-CF<sub>3</sub>/4-NO<sub>2</sub>) and <strong>10</strong> (4-I/4-NO<sub>2</sub>), demonstrated in submicromolar concentration antiviral activity against Vaccinia virus (VACV), cowpox virus (CPXV), ectromelia virus (ECTV), and VARV, with selectivity indices (SI) up to 13738. Studies of mechanisms of action, including time-of-addition experiments and molecular modeling, have shown that these compounds can target the conserved protein p37, which plays a key role in the envelope of the virus. Furthermore, bioinformatic analysis revealed potential interactions with late-stage replication proteins encoded by the A39R and C8L genes. The synthesized derivatives showed activity higher than that of Cidofovir, although they were less effective than that of Tecovirimate. This work highlights the potential of oxadiazolone-based scaffolds as broad-spectrum antipoxviral agents that meet the unmet need for therapy against emerging and re-emerging orthopoxviral threats.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118124"},"PeriodicalIF":5.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009346","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}

引用次数: 0

The synthesis and evaluation of new N-(pyrazin-2-yl)-4-aminopyrimidine derivatives targeted EGFR and JAK 靶向EGFR和JAK的新型N-（吡嗪-2-酰基）-4-氨基嘧啶衍生物的合成与评价

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-08 DOI: 10.1016/j.ejmech.2025.118120

Han Yao , Longcai Cao , Edward Enzhuo Ma , Kaichun Yang , Yuanyuan Ren , Puzhuang Hou , Ming Yan , Xingshu Li

{"title":"The synthesis and evaluation of new N-(pyrazin-2-yl)-4-aminopyrimidine derivatives targeted EGFR and JAK","authors":"Han Yao , Longcai Cao , Edward Enzhuo Ma , Kaichun Yang , Yuanyuan Ren , Puzhuang Hou , Ming Yan , Xingshu Li","doi":"10.1016/j.ejmech.2025.118120","DOIUrl":"10.1016/j.ejmech.2025.118120","url":null,"abstract":"<div><div>To discover novel active compounds against non-small cell lung cancer, thirty one amino pyrazine derivatives were synthesized and evaluated as inhibitors against EGFR-mutation cancers. The optimal compound <strong>14a</strong>, exhibited 15.4 nM and 18.5 nM of the IC<sub>50</sub> values against PC9 and H1975 cancer cell lines, respectively. In H1975 xenograft nude mice, <strong>14a</strong> exhibited 90.0 % of the TGI when oral administration at dosage of 10 mg/kg. Kinase activity assay showed that <strong>14a</strong> not only has excellent inhibitory activity against EGFR kinase, but also has good activity against JAK2 and JAK3 kinases, exhibiting a dual target characteristics. Mechanism study indicated that <strong>14a</strong> could inhibit the phosphorylation of EGFR protein and decrease the active form p-JAK2 for JAK2, induce an increase in intracellular ROS, which may disrupt the balance of the redox system in cancer cells and cause the death of tumor cells. In addition, <strong>14a</strong> could increase cellular lipid oxide MDA, meanwhile decrease GSH content, which suggests that <strong>14a</strong> have caused ferroptosis in cancer cells, Finally, <strong>14a</strong> exhibited high selectivity towards EGFR<sup>wt</sup> cells with a selectivity ratio of 583.76, which is significant to avoid toxic side effects of drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118120"},"PeriodicalIF":5.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017607","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}

引用次数: 0

HPDAF: A practical tool for predicting drug-target binding affinity using multimodal features HPDAF：使用多模态特征预测药物-靶标结合亲和力的实用工具

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-08 DOI: 10.1016/j.ejmech.2025.118153

An Gong , Bing Yu , Lekai Zhang , Anxuan Jia , Yuyang Zhan , Yong Liu , Shuhui Wu

{"title":"HPDAF: A practical tool for predicting drug-target binding affinity using multimodal features","authors":"An Gong , Bing Yu , Lekai Zhang , Anxuan Jia , Yuyang Zhan , Yong Liu , Shuhui Wu","doi":"10.1016/j.ejmech.2025.118153","DOIUrl":"10.1016/j.ejmech.2025.118153","url":null,"abstract":"<div><div>Accurate prediction of drug-target binding affinity is crucial for efficient drug discovery and design, enabling researchers to better understand molecular interactions and accelerate the identification of promising drug candidates. Despite recent advances, existing computational methods often face difficulties in effectively combining detailed structural information from drug-binding sites with broader molecular features. Here, we introduce HPDAF, a practical multimodal deep learning tool designed to improve the accuracy of drug-target binding affinity predictions. HPDAF uniquely integrates three types of biochemical information: protein sequences, drug molecular graphs, and structural interaction data from protein-binding pockets. Each of these data types is carefully processed using specialized modules that capture essential molecular characteristics. A novel hierarchical attention-based mechanism then effectively combines these diverse features, enabling the model to dynamically emphasize the most relevant structural and sequential information. Extensive evaluations using widely recognized benchmark datasets, including CASF-2016 and CASF-2013, demonstrate that HPDAF consistently achieves superior predictive performance compared to current state-of-the-art methods. The practical applicability and enhanced accuracy of HPDAF highlight its potential as a valuable computational tool for medicinal chemists involved in drug design and virtual screening efforts.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118153"},"PeriodicalIF":5.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009349","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}

引用次数: 0

A medicinal chemistry overview of direct-acting antivirals approved in 2013–2024 by US FDA 2013-2024年美国FDA批准的直接作用抗病毒药物的药物化学概述

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-08 DOI: 10.1016/j.ejmech.2025.118105

Maria Giulia Nizi, Serena Massari, Oriana Tabarrini, Giuseppe Manfroni

{"title":"A medicinal chemistry overview of direct-acting antivirals approved in 2013–2024 by US FDA","authors":"Maria Giulia Nizi, Serena Massari, Oriana Tabarrini, Giuseppe Manfroni","doi":"10.1016/j.ejmech.2025.118105","DOIUrl":"10.1016/j.ejmech.2025.118105","url":null,"abstract":"<div><div>Remarkable progress in understanding molecular, cellular and structural viral biology over the last ten years has paved the way for a prosperous age of antivirals. The U.S. FDA has approved 27 new direct-acting antivirals (DAAs), marking a clear step forward compared to the previous 50 years (from 1962, when the first DAA was introduced into therapy, to 2012).</div><div>Antiviral agents have been shown to play a crucial role in modern medicine, fighting infections, reducing disease severity and preventing viral spread. Their importance has been underscored during numerous global health crises affecting humans over the centuries.</div><div>In this review, we provide a comprehensive analysis of the 27 newer FDA-approved DAAs, from discovery to final approval. We focus particularly on medicinal chemistry, covering design, optimization, mechanisms of action and co-crystallographic/Cryo-EM structures. In the final section, we provide a detailed discussion of the achievements made during the period under review. Additionally, given that the current antiviral arsenal is characterized by numerous limitations and is solely effective against a small number of viruses, leaving many others without effective treatment, an overview of innovative approaches and targets that could potentially address unmet clinical needs was also provided.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118105"},"PeriodicalIF":5.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009347","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}

引用次数: 0

Small-molecule FGFR-targeted medicinal chemistry: Advances since 2020 and future perspectives 小分子fgfr靶向药物化学：自2020年以来的进展和未来展望

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-08 DOI: 10.1016/j.ejmech.2025.118117

Hao Yue , Yu Wang , Na Zhang , Jialong Xing , Tingjun Wang , Yu Bao , Yunlei Hou , Yanfang Zhao

{"title":"Small-molecule FGFR-targeted medicinal chemistry: Advances since 2020 and future perspectives","authors":"Hao Yue , Yu Wang , Na Zhang , Jialong Xing , Tingjun Wang , Yu Bao , Yunlei Hou , Yanfang Zhao","doi":"10.1016/j.ejmech.2025.118117","DOIUrl":"10.1016/j.ejmech.2025.118117","url":null,"abstract":"<div><div>FGFR alterations, including fusions, amplifications, rearrangements, and mutations, exist as pathogenic drivers or bypass mechanisms in numerous diseases and cancers. Thus, FGFRs represent crucial therapeutic targets, particularly in oncology. Various agents, especially selective FGFR inhibitors, have shown promising therapeutic potential in oncological diseases. However, off-target toxicities (e.g., hyperphosphatemia) and acquired drug resistance associated with FGFR inhibitors often result in disease progression and unfavorable outcomes for patients, constraining clinical utility. This drives next-generation FGFR therapeutics development, particularly enhancing isoform selectivity and overcoming resistance mutations. This review summarizes FGFR protein architecture, biological functions, and disease associations, while highlighting advances (2020–present) in FGFR inhibitors and degraders, including design strategies, SARs, binding modes, and biological evaluation. Additionally, the unique mechanisms underlying subtype selectivity and resistance to drug-resistant mutations are discussed, providing strategic insights for developing improved FGFR-targeted agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118117"},"PeriodicalIF":5.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009353","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}

引用次数: 0

Verubulin and its derivatives: Progress and promise in tubulin-targeted cancer therapy 微管蛋白及其衍生物：微管蛋白靶向癌症治疗的进展和前景

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-08 DOI: 10.1016/j.ejmech.2025.118112

Alireza Mousavi , Mahfam Moradi , Loghman Firoozpour , Alireza Foroumadi

{"title":"Verubulin and its derivatives: Progress and promise in tubulin-targeted cancer therapy","authors":"Alireza Mousavi , Mahfam Moradi , Loghman Firoozpour , Alireza Foroumadi","doi":"10.1016/j.ejmech.2025.118112","DOIUrl":"10.1016/j.ejmech.2025.118112","url":null,"abstract":"<div><div>Verubulin (MPC-6827) is a microtubule-destabilizing agent that binds to the colchicine site of tubulin and has been primarily investigated for the treatment of glioblastoma and other malignancies. Its ability to interfere with microtubule dynamics, induce mitotic arrest, and retain efficacy in multidrug-resistant tumour cells has positioned it as a valuable scaffold in the development of next-generation anticancer agents. Over the past decade, extensive efforts have been dedicated to optimizing verubulin and its derivatives through modifications that enhance potency and selectivity. Additional strategies have aimed to improve metabolic stability and brain penetration to expand their therapeutic window and clinical utility. In addition to its therapeutic applications, the small molecular size and high affinity of verubulin for tubulin have also enabled its exploration as a molecular imaging agent in brain-targeted diagnostic research. This review provides a comprehensive overview of the pharmacological profile, clinical development, and structural evolution of verubulin-based compounds, emphasizing their role in advancing tubulin-targeting strategies in oncology. It also offers a future perspective on the potential of verubulin derivatives and the prospects for new candidates to enter clinical evaluation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118112"},"PeriodicalIF":5.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009348","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}

引用次数: 0

Development of novel 18F-labelled FAP-targeting tracers with improved pharmacokinetics: From preclinical optimization to clinical translation 改进药代动力学的新型18f标记fap靶向示踪剂的开发：从临床前优化到临床转化

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-07 DOI: 10.1016/j.ejmech.2025.118152

Dan Feng , Baoyuan Li , Jiaqi Yang , Simin Peng , Hongxin Li , Zexin Xu , Yang Liu , Xiaoxu Zhuo , Yuhua Zhong , Pengcheng Ran , Kongzhen Hu

{"title":"Development of novel 18F-labelled FAP-targeting tracers with improved pharmacokinetics: From preclinical optimization to clinical translation","authors":"Dan Feng , Baoyuan Li , Jiaqi Yang , Simin Peng , Hongxin Li , Zexin Xu , Yang Liu , Xiaoxu Zhuo , Yuhua Zhong , Pengcheng Ran , Kongzhen Hu","doi":"10.1016/j.ejmech.2025.118152","DOIUrl":"10.1016/j.ejmech.2025.118152","url":null,"abstract":"<div><div>Fibroblast activation protein (FAP) has emerged as a promising theranostic target in malignancies. Although numerous radiolabelled FAP-targeting tracers have been clinically used for tumour imaging, the development of <sup>18</sup>F-labelled tracers remains an unmet clinical need. This study synthesized two NOTA-conjugated FAP-2286 derivatives, modified with cysteic acid (C1) and/or tranexamic acid (C2) moieties. Both tracers exhibited >96 % radiochemical purity with molar activities >14.3 GBq/μmol. High stability and FAP specificity were demonstrated in vitro. [<sup>18</sup>F]AlF-C1-FAP-2286 demonstrated superior pharmacokinetics with higher tumour-to-kidney (2.19 ± 0.74 vs 1.54 ± 0.72) and tumour-to-liver ratios (18.32 ± 6.32 vs 13.74 ± 4.61) compared to [<sup>18</sup>F]AlF-FAP-2286. Clinical PET imaging with [<sup>18</sup>F]AlF-C1-FAP-2286 enabled the clear delineation of the recurrent lesion at the surgical site and metastatic tumours, demonstrating favourable imaging characteristics, high tumour uptake, and contrast quality. Overall, [<sup>18</sup>F]AlF-C1-FAP-2286 exhibited optimized pharmacokinetic properties and enhanced tumour contrast. The above findings support its potential as a promising <sup>18</sup>F-labelled FAP-targeting tracer, warranting its further exploration in clinical applications.</div></div><div><h3>Trial registration</h3><div>ChiCTR2400090727. Registered October 12, 2024</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118152"},"PeriodicalIF":5.9,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007206","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}

引用次数: 0

Design, synthesis, and anti-cancer evaluation of NQO1-responsive prodrug of gemcitabine 吉西他滨nqo1应答前药的设计、合成及抗癌评价

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-07 DOI: 10.1016/j.ejmech.2025.118146

Tian-Yu Hu, Xin Jin, Ze-Tao Qi, Guangji Wang, Le Zhen

{"title":"Design, synthesis, and anti-cancer evaluation of NQO1-responsive prodrug of gemcitabine","authors":"Tian-Yu Hu, Xin Jin, Ze-Tao Qi, Guangji Wang, Le Zhen","doi":"10.1016/j.ejmech.2025.118146","DOIUrl":"10.1016/j.ejmech.2025.118146","url":null,"abstract":"<div><div>Enhancing the efficacy of gemcitabine (dFdC), a widely used nucleoside analogue in cancer therapy, through prodrug strategies to address clinical issues such as drug resistance and safety is a highly appealing and promising approach. This study focused on NQO1, a redox enzyme highly expressed in tumor cells, and designed a novel class of NQO1-responsive dFdC prodrugs. Among these prodrugs, prodrug <strong>2</strong> remained stable in plasma and liver/intestinal S9 fractions, releasing dFdC in an NQO1-dependent manner. Prodrug <strong>2</strong> demonstrated significant antitumor activity against both A549 and MCF-7 cell lines, primarily inducing S-phase arrest and apoptosis. It also inhibited tumor cell colony formation and migration. Additionally, prodrug <strong>2</strong> had the potential to overcome dFdC resistance and can efficiently generate dFdC within cells while producing fewer inactive metabolites (dFdU) than dFdC. Furthermore, in an A549 xenograft tumor model in mice, prodrug <strong>2</strong> significantly reduced tumor volume without affecting survival or body weight. Overall, our study demonstrates that an NQO1-responsive prodrug strategy can effectively enhance the antitumor properties of dFdC. The optimized prodrug <strong>2</strong> warrants further development as a preclinical candidate drug.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118146"},"PeriodicalIF":5.9,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009351","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}

引用次数: 0