Bioorganic & Medicinal Chemistry最新文献

{"title":"Screening of one-bead one-compound cyclic peptide libraries using unpurified proteins from the wheat germ cell-free system to identify protein-protein interaction inhibitors","authors":"Miki Hasegawa ,&nbsp;Akira Nozawa ,&nbsp;Yoshihito Tanaka ,&nbsp;Kohki Kido ,&nbsp;Shinichi Terawaki ,&nbsp;Chikako Takahashi ,&nbsp;Yasumasa Matsumoto ,&nbsp;Yuichi Onda ,&nbsp;Kouhei Tanaka ,&nbsp;Taro Kishimoto ,&nbsp;Hiroshi Sato ,&nbsp;Akihiro Takemiya ,&nbsp;Tatsuya Sawasaki","doi":"10.1016/j.bmc.2025.118492","DOIUrl":"10.1016/j.bmc.2025.118492","url":null,"abstract":"<div><div>Protein-protein interactions (PPIs) are recognized as both attractive and challenging therapeutic targets. Cyclic peptides are particularly well-suited for PPI inhibition due to their ability to effectively interfere with the extensive surface areas involved in these interactions. One-Bead One-Compound (OBOC) libraries have been widely utilized in affinity-based on-bead screening approaches to identify cyclic peptides targeting PPIs. However, a major bottleneck in OBOC library screening is the requirement for purified proteins to ensure screening accuracy. In this study, we present a novel screening platform that integrates an OBOC cyclic peptide library with crude bait proteins produced using a wheat germ cell-free system, eliminating the need for a purification step. This approach facilitates drug discovery for biologically relevant target proteins and those that are difficult to purify. To demonstrate the effectiveness of this method, we selected the p53-murine double minute 2 (MDM2) interaction as a model target and performed a large-scale on-bead binding assay using MDM2. The primary hits identified through this screening exhibited PPI inhibitory activity in the AlphaScreen assay, and docking simulations further verified their binding mode to MDM2. This method offers an efficient strategy for screening cyclic peptides against challenging drug targets, expanding opportunities for PPI-targeted drug discovery.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118492"},"PeriodicalIF":3.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145646970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polynitrogen-containing compounds as multi-target sEH/FAAH inhibitors: Structure-activity relationship and pharmacological studies","authors":"Amanda Tsang ,&nbsp;Cassandra Yuan ,&nbsp;Manuel Berumen ,&nbsp;Leah Duong ,&nbsp;Karen Gomez ,&nbsp;Shelby Seely ,&nbsp;Alex Salgado ,&nbsp;Adim Rai ,&nbsp;Jo Vistosa ,&nbsp;Edith Morales Munoz ,&nbsp;Marcos E. Ortega ,&nbsp;Christophe Morisseau ,&nbsp;Bruce D. Hammock ,&nbsp;Jake E. Zuckerman ,&nbsp;Joseph Yount ,&nbsp;Davin G. Piercey ,&nbsp;Ram Kandasamy ,&nbsp;Stevan Pecic","doi":"10.1016/j.bmc.2025.118495","DOIUrl":"10.1016/j.bmc.2025.118495","url":null,"abstract":"<div><div>Both soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are involved in degradation of anti-inflammatory and antinociceptive lipids, thus inhibition of these enzymatic pathways represents a novel strategy in the discovery of non-opioid drugs for treating inflammatory pain. We previously discovered several multi-targeted designed ligands and described a pharmacophore necessary for inhibition of both sEH and FAAH. The potential for optimization on the left side of the pharmacophore led us to exploration of different heterocyclic moieties with the hope to keep strong inhibition potencies, but to increase the metabolic stability and solubility of new analogs. Eighteen analogs containing various substituted and unsubstituted pyrimidinyl-, quinoxalinyl- and tetrazolyl- rings are synthesized and tested for inhibition potency in human FAAH, and human, rat and mouse sEH. The structure-activity relationship study revealed quinoxalinyl- analog <strong>4 m</strong>, the most potent dual inhibitor reported to date, with IC₅₀ values of 2.9 nM in human FAAH and 0.7 nM, 39.1 nM and 0.3 nM in human, mouse and rat sEH, respectively. <strong>4 m</strong> showed no binding to opioid and most serotonin receptors and was tested in the human, mouse and rat liver microsomes stability assays where it exhibited good and/or moderate clearance rates. Lastly, we evaluated <strong>4 m</strong> in vivo in a wheel running assay to determine its effects on voluntary locomotor behavior. Both <strong>4 m</strong> and the traditional opioid morphine exhibited significant depression of wheel running after intraperitoneal administration indicating that <strong>4 m</strong> may produce undesirable behavioral effects, which will be the basis for future studies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118495"},"PeriodicalIF":3.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing the USFDA-approved small molecules for their affinity against the colchicine binding site (CBS) in the tubulin: Corroborating the in-silico findings through biological assessment","authors":"Kumar Rohit,&nbsp;Bibekananda Sarkar","doi":"10.1016/j.bmc.2025.118488","DOIUrl":"10.1016/j.bmc.2025.118488","url":null,"abstract":"<div><div>The microtubules are known to possess inimitable characteristics termed ‘exquisite dynamic behavior,’ which allows cells to maintain their shape and assist in cellular division. This exquisite dynamicity is lost in the case of cancer, and considering their pivotal role, they are considered as central drug targets in cancer chemotherapy. To target them, microtubule-targeting agents (MTAs) are unique small molecules that inhibit one of the seven unique druggable pockets of microtubules, impacting their dynamicity and leading to cell cycle arrest and apoptosis. In the present work, we employ a drug repurposing strategy to identify plausible leads targeting the colchicine binding site (CBS) from a pool of 2787 FDA-approved drugs. CBS is a unique and flexible druggable pocket site in microtubules that has been targeted for both cancer and non-cancer diseases. Additionally, the inhibition of this site is reported to reverse drug resistance and exhibit synergistic anti-inflammatory and anti-angiogenic properties, further enhancing the anticancer effects. The cumulative analysis led to the identification of Tafenoquine, a well-known antimalarial FDA-approved molecule, as a potential tubulin-targeting agent with predicted binding to the colchicine site. The in-silico analysis was further corroborated using in vitro investigation on breast (MCF-7 and MDA-MB-231), lung (A549), and colon (HCT-116) cancer cells. Tafenoquine was found to exert broad-spectrum antiproliferative effects, with greatest potency against MDA-MB-231 cells (IC₅₀ = 4.75 ± 0.18 μM), a model for aggressive and treatment-resistant triple-negative breast cancer (TNBC). Considering the tubulin polymerization assay, the identified hit was found to inhibit microtubule assembly (low Vmax) in a manner similar to colchicine, and exhibited a similar G2/M arrest, indicating a mode of inhibition similar to that of colchicine.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118488"},"PeriodicalIF":3.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145675992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FPhotocleavable PROTACs as tools for dynamic regulation of protein function","authors":"Hanqiao Xu ,&nbsp;Hidetomo Yokoo ,&nbsp;Yosuke Demizu","doi":"10.1016/j.bmc.2025.118491","DOIUrl":"10.1016/j.bmc.2025.118491","url":null,"abstract":"<div><div>Proteolysis-targeting chimeras (PROTACs) have emerged as valuable tools for targeted protein degradation. However, conventional designs generally lack mechanisms for temporal regulation. In this study, we explored photocleavable PROTACs incorporating a nitrobenzyl linker, aiming to achieve light-triggered inactivation of BET protein degradation. Docking simulations indicated that the linker did not disrupt the formation of the ternary complex, and LC–MS/MS analyses indicated that photocleavage occurred rapidly within cells. Cellular experiments demonstrated that the compounds promoted efficient degradation of the BET protein at low concentrations, and recovery assays with UV irradiation indicated that protein expression could be restored after transient depletion. These results suggest that photocleavable PROTACs offer a practical approach to controlling degradation with temporal precision and may provide useful chemical biology tools for investigating the dynamic functions of BET proteins.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118491"},"PeriodicalIF":3.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Versatile fluorescent homobifunctional crosslinkers: expedient synthesis and application to di-affibody constructs for specific HER2+ cancer cell recognition","authors":"Eric Kaya,&nbsp;Fabienne Fasani,&nbsp;Carlo Pifferi,&nbsp;Catherine Grillon,&nbsp;Vincent Aucagne,&nbsp;Josef Hamacek","doi":"10.1016/j.bmc.2025.118494","DOIUrl":"10.1016/j.bmc.2025.118494","url":null,"abstract":"<div><div>In this contribution we report on the design of new versatile fluorescent linkers (<strong>L1</strong>−<strong>L3</strong>, <strong>L1</strong>^{<strong>N</strong>}) suitable for the covalent assembly of specific recognition motifs to bind biologically relevant targets such as HER2 receptors. The central fluorescent molecular platform emits in red and represents a key building block for the synthesis of conjugates and their subsequent analyses. The presence of amino groups enables straightforward functionalization with bifunctional PEG linkers (NHS, MI) of variable length for further directional bioconjugation. To demonstrate the value of this approach, the linkers were conjugated with chemically synthesized affibodies (AfB, Z_HER2:2891(M9Nle/D37E)), bearing a unique cysteine at N-terminal or C-terminal end. Indeed, this AfB binds the human epidermal growth factor receptor 2 (HER2), which is often overexpressed in different carcinomas, and it is therefore considered as a tumour marker in bioimaging and drug delivery systems. Seven AfB conjugates—three mono-AfBs (<strong>N1</strong>, <strong>N1</strong>^{<strong>N</strong>}, <strong>C1</strong>) and four di-AfBs (<strong>N2</strong>, <strong>N3, C2, C3</strong>)—were obtained through MI-thiol conjugation. The binding of fluorescent mono- and di-affibody (AfB) constructs was evaluated using flow cytometry to demonstrate their ability to interact with the HER2-expressing SKOV3 cells in relation with their structural properties. All tested conjugates specifically bound to HER2 receptors present on SKOV3 cells with nanomolar affinities, and only small differences between constructs were detected. The presence of our fluorescent conjugates bound to the cell surface was visualized using confocal microscopy. In addition, the internalization mechanism of AfB constructs in SKOV3 cells was investigated due to the measurement of their fluorescence following trypsin treatment. In conclusion, our innovative synthetic approach with the integration of a versatile fluorescent platform offers new perspectives for monitoring molecular therapeutics inside cell and for tuning multivalent conjugates for cancer immunotherapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118494"},"PeriodicalIF":3.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the histone deacetylase inhibitor potential of phorbazole analogues","authors":"Ida Amalie Nystad Reierth ,&nbsp;Yngve Guttormsen ,&nbsp;Jeanette H. Andersen ,&nbsp;Espen H. Hansen ,&nbsp;Ahmed Mossad Abdelhady ,&nbsp;Manuel K. Langer ,&nbsp;Bengt Erik Haug ,&nbsp;Annette Bayer ,&nbsp;Guillaume A. Petit","doi":"10.1016/j.bmc.2025.118489","DOIUrl":"10.1016/j.bmc.2025.118489","url":null,"abstract":"<div><div>Histone deacetylases (HDACs) are enzymes that remove acyl groups from histones and other proteins. This process leads to condensation of DNA and subsequent downregulation in expression of specific genes altering the activity of essential cellular pathways and changing the cell's behaviour. As a result, HDACs have emerged as potential therapeutic targets to treat different forms of cancer. In this study we synthesized and investigated compounds built around a phorbazole scaffold to characterize their histone deacetylase inhibitor (HDACi) activity. Eighteen phorbazole analogues were tested against class I and II HDACs in cell lysate, seven showed moderate activity, of which, three had IC₅₀ values below 50 μM. The five best candidates were evaluated more extensively against HDAC1-11 (except for HDAC10). The best candidate, compound <strong>9</strong>, initially appeared to reduce the activity of HDAC9 and HDAC11 by more than 50 % at 10 μM concentration. The binding mode of compound <strong>9</strong> to HDACs was explored via computational docking, where two poses stood out. These were explored further by molecular dynamic simulation. We found that <strong>9</strong> likely binds HDAC9 with the pyrrole group buried in the active site and forming H-bonds with the backbone oxygen of one of the glycine residues lining the cavity. But neither of the poses explored offered convincing arguments to describe the mode of action of the phorbazole, especially when comparing <strong>9</strong> to other analogues tested in this study. Additional experiments found that <strong>9</strong> interfered with the cell lysate assays by inhibiting luciferase in a dose-dependent manner (IC₅₀ &lt; 1 μM) and by exhibiting autofluorescence when tested on purified HDAC proteins, thereby confounding the obtained results during both the pan-HDAC screening and the single point HDAC inhibition assay. To address this, we employed fluorophores with excitation and emission wavelengths outside of the emission range of <strong>9</strong> and found that the HDAC inhibition potential of <strong>9</strong> was weaker than first observed. Finally, Compound <strong>9</strong> was found to be very soluble in water (418 μM) and membrane permeable (&gt;48 % flux). This study highlights the need for rigorous validation of results. In our case, two orthogonal testing methods were not sufficient to catch all the confounding factors involved in measurement of HDAC inhibition, and a third approach was required to identify the actual inhibition of <strong>9</strong> against HDAC9 and 11.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118489"},"PeriodicalIF":3.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The modulation of lipase from Candida rugosa activity by peptidomimetics","authors":"Anna Brodzka,&nbsp;Anna Mazur,&nbsp;Dominik Koszelewski,&nbsp;Ryszard Ostaszewski","doi":"10.1016/j.bmc.2025.118490","DOIUrl":"10.1016/j.bmc.2025.118490","url":null,"abstract":"<div><div>The library of selected peptidomimetics was synthesised <em>via</em> Passerini 3-component reaction. The SAR study of obtained α-acyloxy carboxamides for the catalytic activity of lipase from <em>Candida rugosa</em> was undertaken. The compounds were tested as potential CRL modulators on model 4-nitrophenol laurate hydrolysis reaction. Subsequently, three activators (EC50: 33–41 nM) and one inhibitor (IC50: 3.35 μM) were identified. The highest activity was observed in the presence of 1-((4-methoxybenzyl)amino)-1-oxo-3-phenylpropan-2-yl 2-phenylacetate, then the CRL was 2.3-fold more active than native enzyme, which was confirmed by kinetic parameters (V_max). The best identified enhancer acts also as an activator of other bacteria lipases, however inhibits enzymes from other species – animal and plant. SAR studies revealed that the amide group has crucial impact on the activity of peptidomimetic. The replacement of substituent at <em>para</em> position in phenyl ring of benzyl amide moiety from methoxy group to hydrogen changes the action of modulator from enhancer to inhibitor. The best activator was also successfully used for enzymatic kinetic resolution of chiral epoxyester shortening the reaction time and increasing more than 10 times the enantioselectivity of this process.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118490"},"PeriodicalIF":3.0,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of Psidium meroterpenoids with anti-hepatocellular carcinoma activities","authors":"Zhuo Wang ,&nbsp;Chunngai Hui","doi":"10.1016/j.bmc.2025.118481","DOIUrl":"10.1016/j.bmc.2025.118481","url":null,"abstract":"<div><div>Liver cancer presents as a significant human disease, and hepatocellular carcinoma appears as the most common form of liver cancer. Several therapeutic agents, such as sorafenib, are currently in Phase III clinical trials for the treatment of liver cancer. However, the development of potent and effective pharmaceuticals is undoubtedly crucial to managing the status of liver cancer and improving the quality of life of patients. <em>Psidium</em> meroterpenoids are natural products isolated from the leaves of <em>Psidium guajava</em> L., exhibiting potent cytotoxicity to hepatocellular carcinoma cell lines. Being synthetically accessible, <em>Psidium</em> meroterpenoids show tremendous potential as a therapeutic agent for hepatocellular carcinoma. This perspective outlines the biological profile, biosynthetic pathway, and chemical synthesis of <em>Psidium</em> meroterpenoids, as well as future directions and opportunities.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118481"},"PeriodicalIF":3.0,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel oxadiazole analogs as anticancer agents: Design, synthesis, in vitro and in vivo biological evaluation, and computer studies of sphingosine kinase inhibitors","authors":"Fuxun Huang ,&nbsp;Xinmei Yang ,&nbsp;Haiyang Wang ,&nbsp;Xiujuan Shi ,&nbsp;Xiaodong Zhao ,&nbsp;Junru Liu ,&nbsp;Yueyang Sun ,&nbsp;Xingbo Song ,&nbsp;Tong Li ,&nbsp;Zhaoyang Li ,&nbsp;Xi Qiu ,&nbsp;Jingtong Feng ,&nbsp;Yuanyuan Liu ,&nbsp;Yuqi Gao ,&nbsp;Yanling Mu ,&nbsp;Zhengguo Cui ,&nbsp;Peng Zhan ,&nbsp;Bo Liu","doi":"10.1016/j.bmc.2025.118487","DOIUrl":"10.1016/j.bmc.2025.118487","url":null,"abstract":"<div><div>Sphingosine kinases (SphKs) have emerged as novel therapeutic targets for treating cancer and inflammation <em>via</em> the SphK/S1P signaling pathway. However, the development of selective SphK inhibitors has been challenging because of their limited specificity. In this study, we used pharmacophore- and docking-based virtual screening to identify the lead compound <strong>DTD-8</strong> (SphK1 IC₅₀ = 79 ± 0.73 μM) and then optimized the structure through structure-based drug design. Our newly synthesized 1,2,4-oxadiazole derivative, compound <strong>22c</strong>, demonstrated selective inhibition against SphK2 (IC₅₀ = 2.24 ± 0.60 μM) over SphK1 (IC₅₀ = 64.20 ± 1.53 μM), representing 28-fold selectivity for SphK2. It also exhibited more potent anticancer activity against DU145 cells (IC₅₀ = 3.09 ± 0.67 μM) than cisplatin (IC₅₀ = 10.67 ± 1.00 μM) owing to its ability to induce S/G2 phase arrest and apoptosis.</div><div>In rats, Compound <strong>22c</strong> showed favorable pharmacokinetic properties, including good metabolic stability (T₁_/₂ = 19.6 h) and high plasma exposure (AUC₀–<em>t</em> = 1077.40 ng h/mL), along with promising <em>in vivo</em> tumor growth inhibition (TGI = 65.96 %). Given its moderate oral bioavailability (F = 54.88 %) and potent anticancer effects, <strong>22c</strong> requires further investigation. These findings provide valuable insights for developing novel SphK2-targeted anticancer agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118487"},"PeriodicalIF":3.0,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exogenous/endogenous stimuli-responsive antitumor prodrugs advance precision chemotherapy","authors":"Luo Wang ,&nbsp;Jingao Li ,&nbsp;Xuanwei Zeng ,&nbsp;Qinyue Lu ,&nbsp;Yifeng Wang ,&nbsp;Zulhumar Anwar ,&nbsp;Li Xue ,&nbsp;Heli Fan ,&nbsp;Huabing Sun","doi":"10.1016/j.bmc.2025.118485","DOIUrl":"10.1016/j.bmc.2025.118485","url":null,"abstract":"<div><div>Precision chemotherapy aims to selectively target cancer cells while sparing healthy cells, thereby addressing a major challenge in traditional chemotherapy, off-target toxicity. Stimuli-responsive antitumor prodrugs leverage exogenous or endogenous triggers for targeted drug activation, which represents a significant advancement in this field. Exogenous stimuli, such as light, ionizing radiation, and ultrasound, usually offer spatiotemporal precision at tumor sites to minimize systemic side effects. Similarly, endogenous stimuli, including hypoxia, acidic pH, the overexpression of specific enzymes, and elevated levels of reactive oxygen species (ROS) and glutathione (GSH), exploit the unique tumor microenvironment to facilitate selective activation. These prodrugs undergo specific chemical or enzymatic reactions in response to their respective triggers, releasing active therapeutic agents at desired sites. This review provides an overall analysis of recent advances in both exogenous and endogenous stimuli-responsive prodrugs, with a focus on their design principles, activation mechanisms, and therapeutic efficacy. By highlighting these emerging strategies, we aim to underscore the potential of stimuli-responsive prodrugs to enhance therapeutic efficacy and safety, paving the way for precision chemotherapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118485"},"PeriodicalIF":3.0,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}