Pub Date : 2025-12-11DOI: 10.1016/j.ejmech.2025.118478
Beata Żołnowska , Paweł Nowak , Grzegorz Stasiłojć , Jacek Jasiecki , Monika Targońska , Mateusz Kogut , Anna Kawiak
The discovery of potent and selective anticancer agents remains a major focus in medicinal chemistry. Here, we report the rational design, synthesis, and biological evaluation of N-acylated aminoguanidine derivatives incorporating the benzenesulfonamide scaffold, a privileged motif present in several clinically relevant anticancer drugs. The compounds were evaluated for in vitro cytotoxic activity against MCF-7 (breast), HCT-116 (colorectal), and HeLa (cervical) cancer cell lines. Several derivatives exhibited potent cytotoxicity, with IC50 values below 10 μM, highlighting their promising anticancer potential. Mechanistic studies confirmed the induction of apoptosis in treated cancer cells. Structure–activity relationship (SAR) analysis demonstrated that a 4-(trifluoromethyl)phenyl group at R1 consistently enhanced cytotoxicity, while naphthyl, styryl, and coumarin moieties further modulated potency. Methyl or hydroxyl substituents reduced activity, emphasizing the importance of electronic and steric effects. Compounds 8 and 17, the most active derivatives, were further evaluated for VEGFR-2 inhibition. Compound 17 selectively inhibited VEGFR-2 (IC50 = 2.3 μM) and moderately induced apoptosis in MCF-7 cells via non-mitochondrial, VEGFR-2-dependent pathways. In contrast, compound 7, inactive against VEGFR-2, triggered G2/M arrest and pronounced apoptosis in HeLa cells, indicating a VEGFR-2-independent mechanism. These findings support further development of N-acylated aminoguanidine-benzenesulfonamides as promising agents with dual mechanisms of action.
{"title":"N-acylated aminoguanidine-benzenesulfonamides: rational design, synthesis, and dual apoptotic mechanisms of anticancer activity involving VEGFR-2 inhibition and VEGFR-2–independent pathways","authors":"Beata Żołnowska , Paweł Nowak , Grzegorz Stasiłojć , Jacek Jasiecki , Monika Targońska , Mateusz Kogut , Anna Kawiak","doi":"10.1016/j.ejmech.2025.118478","DOIUrl":"10.1016/j.ejmech.2025.118478","url":null,"abstract":"<div><div>The discovery of potent and selective anticancer agents remains a major focus in medicinal chemistry. Here, we report the rational design, synthesis, and biological evaluation of <em>N</em>-acylated aminoguanidine derivatives incorporating the benzenesulfonamide scaffold, a privileged motif present in several clinically relevant anticancer drugs. The compounds were evaluated for in vitro cytotoxic activity against MCF-7 (breast), HCT-116 (colorectal), and HeLa (cervical) cancer cell lines. Several derivatives exhibited potent cytotoxicity, with IC<sub>50</sub> values below 10 μM, highlighting their promising anticancer potential. Mechanistic studies confirmed the induction of apoptosis in treated cancer cells. Structure–activity relationship (SAR) analysis demonstrated that a 4-(trifluoromethyl)phenyl group at R<sup>1</sup> consistently enhanced cytotoxicity, while naphthyl, styryl, and coumarin moieties further modulated potency. Methyl or hydroxyl substituents reduced activity, emphasizing the importance of electronic and steric effects. Compounds <strong>8</strong> and <strong>17</strong>, the most active derivatives, were further evaluated for VEGFR-2 inhibition. Compound <strong>17</strong> selectively inhibited VEGFR-2 (IC<sub>50</sub> = 2.3 μM) and moderately induced apoptosis in MCF-7 cells via non-mitochondrial, VEGFR-2-dependent pathways. In contrast, compound <strong>7</strong>, inactive against VEGFR-2, triggered G2/M arrest and pronounced apoptosis in HeLa cells, indicating a VEGFR-2-independent mechanism. These findings support further development of <em>N</em>-acylated aminoguanidine-benzenesulfonamides as promising agents with dual mechanisms of action.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118478"},"PeriodicalIF":5.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718056","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}
Pub Date : 2025-12-11DOI: 10.1016/j.ejmech.2025.118481
Xiulian Liu , Xuwen Da , Yao Wu , Yunli Xu , Yu Shi , Aifeng Wu , Xinyue Zou , Lingqing Yang , Hongfeng Guan , Xuesong Wang , Qianxiong Zhou
Staphylococcus aureus (S. aureus), especially the drug resistant strains, has emerged as one of the leading causes of lethal bacterial infections. Novel antibacterial agents, which can eradicate resistant pathogens without readily inducing drug resistance during long-term usage, are highly desirable. In this work, TPAMe-BODIPY with a high DNA binding affinity was designed and synthesized to achieve such a goal. Thanks to the two “Y” shape structures with four positive charges, TPAMe-BODIPY can strongly bind to bacterial DNA and activate the Save Our Souls (SOS) response in pathogens, consequently leading to quick generation of a high level of reactive oxygen species (ROS). Antibacterial results indicated that TPAMe-BODIPY can eradicate extra- and intra-cellular S. aureus and methicillin-resistant S. aureus (MRSA), surpassing the performances of traditional antibiotics gentamicin and ampicillin both in vitro and in vivo. Most importantly, S. aureus cells did not exhibit obvious resistance against TPAMe-BODIPY during continual incubation at sub-lethal concentrations for 20 days, which could be ascribed to the appealing multi-targeted antibacterial mechanism exerted by ROS. These results can provide new sights for developing novel antibacterial agents to fight against more and more popular drug resistance.
{"title":"Eradicating extra- and intra-cellular Staphylococcus aureus and MRSA with little accumulation of resistance by a cationic BODIPY derivative","authors":"Xiulian Liu , Xuwen Da , Yao Wu , Yunli Xu , Yu Shi , Aifeng Wu , Xinyue Zou , Lingqing Yang , Hongfeng Guan , Xuesong Wang , Qianxiong Zhou","doi":"10.1016/j.ejmech.2025.118481","DOIUrl":"10.1016/j.ejmech.2025.118481","url":null,"abstract":"<div><div><em>Staphylococcus aureus</em> (<em>S. aureus</em>), especially the drug resistant strains, has emerged as one of the leading causes of lethal bacterial infections. Novel antibacterial agents, which can eradicate resistant pathogens without readily inducing drug resistance during long-term usage, are highly desirable. In this work, TPAMe-BODIPY with a high DNA binding affinity was designed and synthesized to achieve such a goal. Thanks to the two “Y” shape structures with four positive charges, TPAMe-BODIPY can strongly bind to bacterial DNA and activate the Save Our Souls (SOS) response in pathogens, consequently leading to quick generation of a high level of reactive oxygen species (ROS). Antibacterial results indicated that TPAMe-BODIPY can eradicate extra- and intra-cellular <em>S. aureus</em> and methicillin-resistant <em>S. aureus</em> (MRSA), surpassing the performances of traditional antibiotics gentamicin and ampicillin both <em>in vitro</em> and <em>in vivo</em>. Most importantly, <em>S. aureus</em> cells did not exhibit obvious resistance against TPAMe-BODIPY during continual incubation at sub-lethal concentrations for 20 days, which could be ascribed to the appealing multi-targeted antibacterial mechanism exerted by ROS. These results can provide new sights for developing novel antibacterial agents to fight against more and more popular drug resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118481"},"PeriodicalIF":5.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731737","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}
Pub Date : 2025-12-11DOI: 10.1016/j.ejmech.2025.118474
Xingpeng Wang , Lian Zhong , Zhaodi Wang , Wenwen Xia , Dongning Shen , Yuan Sun , Bo Liu , Tingxiu Zhao , Yunshan Wu
Triple-negative breast cancer (TNBC), characterized by high aggressiveness and limited targeted therapeutic options, urgently requires novel therapeutic targets and drugs. Although the Lin28/Let-7 axis has shown great therapeutic potential in refractory tumors, its role and specific regulatory mechanisms in TNBC remain unclear. This study first demonstrated through multi-dimensional bioinformatic analyses that Lin28B is preferentially overexpressed in TNBC, closely associated with poor patient prognosis, and exhibits a distinct expression pattern compared to other breast cancer subtypes, establishing its potential as a TNBC-specific therapeutic target. Subsequently, through tiered computational screening of a natural compound library, ponicidin was identified as a potential Lin28B inhibitor. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) assays suggested that ponicidin binds to the cold-shock domain (CSD) of Lin28B with high affinity, which may competitively block the interaction between Lin28B and Let-7 and potentially promote Lin28B degradation via the ubiquitin-proteasome pathway, thereby relieving Let-7 suppression. Functional experiments demonstrated that ponicidin dose-dependently inhibits proliferation, invasion, and induces apoptosis in TNBC cells (MDA-MB-231, 4T1), with low toxicity to normal mammary epithelial cells. Through bioinformatic analyses including Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) network analysis, PDZ-binding kinase (PBK) was predicted as a core downstream hub gene of the Lin28B/Let-7 axis. Experimental validation confirmed that ponicidin upregulates the expression of Let-7 family members, thereby downregulating multiple oncoproteins including PBK, C-MYC, RAS, and HMGA2. Further verification using a 4T1 cell orthotopic tumor mouse model showed that ponicidin dose-dependently inhibits in vivo tumor growth, reduces Lin28B expression in tumor tissues, increases apoptotic regions. This study is the first to tentatively explore the potential mechanism by which ponicidin inhibits TNBC by targeting the Lin28B/Let-7/PBK axis, clarifying its dual mode of action ("binding inhibition + protein degradation"). It provides a promising candidate compound with both efficacy and safety for TNBC, while laying a theoretical and experimental foundation for the development of Lin28B-targeted drugs.
{"title":"Target validation and drug discovery for TNBC: Targeting the Lin28B/Let-7/PBK with the ponicidin","authors":"Xingpeng Wang , Lian Zhong , Zhaodi Wang , Wenwen Xia , Dongning Shen , Yuan Sun , Bo Liu , Tingxiu Zhao , Yunshan Wu","doi":"10.1016/j.ejmech.2025.118474","DOIUrl":"10.1016/j.ejmech.2025.118474","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC), characterized by high aggressiveness and limited targeted therapeutic options, urgently requires novel therapeutic targets and drugs. Although the Lin28/<em>Let-7</em> axis has shown great therapeutic potential in refractory tumors, its role and specific regulatory mechanisms in TNBC remain unclear. This study first demonstrated through multi-dimensional bioinformatic analyses that <em>Lin28B</em> is preferentially overexpressed in TNBC, closely associated with poor patient prognosis, and exhibits a distinct expression pattern compared to other breast cancer subtypes, establishing its potential as a TNBC-specific therapeutic target. Subsequently, through tiered computational screening of a natural compound library, ponicidin was identified as a potential Lin28B inhibitor. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) assays suggested that ponicidin binds to the cold-shock domain (CSD) of Lin28B with high affinity, which may competitively block the interaction between Lin28B and <em>Let-7</em> and potentially promote Lin28B degradation via the ubiquitin-proteasome pathway, thereby relieving <em>Let-7</em> suppression. Functional experiments demonstrated that ponicidin dose-dependently inhibits proliferation, invasion, and induces apoptosis in TNBC cells (MDA-MB-231, 4T1), with low toxicity to normal mammary epithelial cells. Through bioinformatic analyses including Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) network analysis, <strong>PDZ-binding kinase</strong> (PBK) was predicted as a core downstream hub gene of the Lin28B/<em>Let-7</em> axis. Experimental validation confirmed that ponicidin upregulates the expression of <em>Let-7</em> family members, thereby downregulating multiple oncoproteins including <em>PBK</em>, <em>C-MYC</em>, <em>RAS</em>, and <em>HMGA2</em>. Further verification using a 4T1 cell orthotopic tumor mouse model showed that ponicidin dose-dependently inhibits in vivo tumor growth, reduces <em>Lin28B</em> expression in tumor tissues, increases apoptotic regions. This study is the first to tentatively explore the potential mechanism by which ponicidin inhibits TNBC by targeting the Lin28B/<em>Let-</em>7/PBK axis, clarifying its dual mode of action (\"binding inhibition + protein degradation\"). It provides a promising candidate compound with both efficacy and safety for TNBC, while laying a theoretical and experimental foundation for the development of Lin28B-targeted drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118474"},"PeriodicalIF":5.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718070","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}
Pub Date : 2025-12-10DOI: 10.1016/j.ejmech.2025.118470
Xuehong Qiao, Menghan Cui, Zhiwei Yu, Ling Ma, Hailong Liu, Xingxing Yang, Yuan Chen, Dahong Li, Jinjing Che, Linxiang Zhao, Ruibin Su, Xuhong Ren, Shan Cen, Bin Lin, Xinhua He
The authors regret that the correct number for the National Natural Science Foundation of China for this article is 82341090, not 82273909 as stated in the original article.
很抱歉，本文国家自然科学基金的正确编号是82341090，而不是原文所述的82273909。
{"title":"Corrigendum to “Thiol esters as chemical warheads of SARS-CoV-2 main protease (3CLpro) peptide-like inhibitors” [Eur. J. Med. Chem. 293 (2025) 117709]","authors":"Xuehong Qiao, Menghan Cui, Zhiwei Yu, Ling Ma, Hailong Liu, Xingxing Yang, Yuan Chen, Dahong Li, Jinjing Che, Linxiang Zhao, Ruibin Su, Xuhong Ren, Shan Cen, Bin Lin, Xinhua He","doi":"10.1016/j.ejmech.2025.118470","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118470","url":null,"abstract":"The authors regret that the correct number for the National Natural Science Foundation of China for this article is 82341090, not 82273909 as stated in the original article.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718057","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}
Pub Date : 2025-12-09DOI: 10.1016/j.ejmech.2025.118473
Liquan Zhu , Haotian Liu , Xin Zeng , Ke Liu , Xiaozhen Liu , Zhuotao Yang , Yuchen Duan , Da Qian , Chaoqi He , Xuli Meng
Lysosome-targeting chimeras (LYTAC) represent a revolutionary technology for targeted protein degradation. However, the scarcity of highly efficient lysosomal transport receptors poses a major bottleneck to LYTAC advancement. In previous studies, we identified the glucagon-like peptide-1 receptor (GLP-1R) as a novel lysosomal transport receptor that promotes the degradation of membrane proteins. Here, leveraging the stability of semaglutide, we developed GLP-1R-mediated lysosomal-targeting chimeras (g-LYTAC), including antibody–peptide conjugate-based chimeras (APCTACs) targeting epidermal growth factor receptor (EGFR) and programmed cell death ligand 1 (PD-L1), and peptide–peptide conjugate-based chimeras (PPCTACs) targeting integrin. Optimized g-LYTAC exhibit enhanced potency in eliminating cell-surface targets, with efficacy dependent on GLP-1R expression and lysosomal activity. Specifically, APCTAC enhances T cell-mediated cytotoxicity against tumor cells. In mouse models, APCTAC mediates robust PD-L1 degradation, driving tumor-specific immune responses by converting the immunosuppressive tumor microenvironment into an immunostimulatory one. Notably, immune-checkpoint degradation therapy with APCTAC achieves comparable or superior antitumor efficacy while causing significantly less inflammatory damage than antibody therapy. This peptide-based LYTAC system offers a safer, minimally invasive strategy for cancer immunotherapy by combining immune-checkpoint degradation with immunomodulation, laying the groundwork for the development of peptide-based LYTAC as an effective cancer therapy.
{"title":"Development of glucagon-like Peptide-1 lysosomal targeting chimeras for degradation of extracellular and membrane proteins","authors":"Liquan Zhu , Haotian Liu , Xin Zeng , Ke Liu , Xiaozhen Liu , Zhuotao Yang , Yuchen Duan , Da Qian , Chaoqi He , Xuli Meng","doi":"10.1016/j.ejmech.2025.118473","DOIUrl":"10.1016/j.ejmech.2025.118473","url":null,"abstract":"<div><div>Lysosome-targeting chimeras (LYTAC) represent a revolutionary technology for targeted protein degradation. However, the scarcity of highly efficient lysosomal transport receptors poses a major bottleneck to LYTAC advancement. In previous studies, we identified the glucagon-like peptide-1 receptor (GLP-1R) as a novel lysosomal transport receptor that promotes the degradation of membrane proteins. Here, leveraging the stability of semaglutide, we developed GLP-1R-mediated lysosomal-targeting chimeras (g-LYTAC), including antibody–peptide conjugate-based chimeras (APCTACs) targeting epidermal growth factor receptor (EGFR) and programmed cell death ligand 1 (PD-L1), and peptide–peptide conjugate-based chimeras (PPCTACs) targeting integrin. Optimized g-LYTAC exhibit enhanced potency in eliminating cell-surface targets, with efficacy dependent on GLP-1R expression and lysosomal activity. Specifically, APCTAC enhances T cell-mediated cytotoxicity against tumor cells. In mouse models, APCTAC mediates robust PD-L1 degradation, driving tumor-specific immune responses by converting the immunosuppressive tumor microenvironment into an immunostimulatory one. Notably, immune-checkpoint degradation therapy with APCTAC achieves comparable or superior antitumor efficacy while causing significantly less inflammatory damage than antibody therapy. This peptide-based LYTAC system offers a safer, minimally invasive strategy for cancer immunotherapy by combining immune-checkpoint degradation with immunomodulation, laying the groundwork for the development of peptide-based LYTAC as an effective cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118473"},"PeriodicalIF":5.9,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704012","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}
Pub Date : 2025-12-08DOI: 10.1016/j.ejmech.2025.118428
Weijie Jiao , Hui Ye , Duorui Ji , Mengshuang Huang , Ruichen Li , Jian Jia , Bowen Wang , Shurui Wang , Zhen Lei , Nan Qin , Hong Wu , Xiaokun Li , Guiyue Wu , Yinglin Cui , Yihua Zhang , Jianbing Wu , Zhangjian Huang
Ischemic stroke (IS) involves complex pathologies such as excitotoxicity, oxidative stress, and inflammation. Targeting inducible nitric oxide synthase (iNOS) which produces damaging levels of NO, while sparing neuroprotective endothelial NOS (eNOS) activity, represents a promising therapeutic strategy. We designed and synthesized a series of hybrids from both nitrones with eNOS-mimicking activity and iNOS inhibitors. Among them, compound 13h exhibited selectivity for iNOS (49.2- and 43.3-fold selectivity over nNOS and eNOS, respectively). And 13h demonstrated significant neuroprotective effects across multiple in vitro models, including oxygen-glucose deprivation/reoxygenation (OGD/R) and H2O2-induced damage in neuronal and endothelial cells. In a transient middle cerebral artery occlusion (tMCAO) rat model, 13h (30 mg/kg, i.v.) markedly reduced cerebral infarction volume (>80 %) and improved neurological function. Mechanistic studies suggest its efficacy stems from anti-oxidant, selective iNOS inhibition, and 3-nitrotyrosine (3-NT) suppression activities. Thus, 13h serves as a novel compound with a multi-target activity against IS.
{"title":"Design, synthesis, and biological evaluation of hybrids from both nitrones with eNOS-mimicking activity and selective iNOS inhibitors for the treatment of ischemic stroke","authors":"Weijie Jiao , Hui Ye , Duorui Ji , Mengshuang Huang , Ruichen Li , Jian Jia , Bowen Wang , Shurui Wang , Zhen Lei , Nan Qin , Hong Wu , Xiaokun Li , Guiyue Wu , Yinglin Cui , Yihua Zhang , Jianbing Wu , Zhangjian Huang","doi":"10.1016/j.ejmech.2025.118428","DOIUrl":"10.1016/j.ejmech.2025.118428","url":null,"abstract":"<div><div>Ischemic stroke (IS) involves complex pathologies such as excitotoxicity, oxidative stress, and inflammation. Targeting inducible nitric oxide synthase (iNOS) which produces damaging levels of NO, while sparing neuroprotective endothelial NOS (eNOS) activity, represents a promising therapeutic strategy. We designed and synthesized a series of hybrids from both nitrones with eNOS-mimicking activity and iNOS inhibitors. Among them, compound <strong>13h</strong> exhibited selectivity for iNOS (49.2- and 43.3-fold selectivity over nNOS and eNOS, respectively). And <strong>13h</strong> demonstrated significant neuroprotective effects across multiple <em>in vitro</em> models, including oxygen-glucose deprivation/reoxygenation (OGD/R) and H<sub>2</sub>O<sub>2</sub>-induced damage in neuronal and endothelial cells. In a transient middle cerebral artery occlusion (tMCAO) rat model, <strong>13h</strong> (30 mg/kg, <em>i.v.</em>) markedly reduced cerebral infarction volume (>80 %) and improved neurological function. Mechanistic studies suggest its efficacy stems from anti-oxidant, selective iNOS inhibition, and 3-nitrotyrosine (3-NT) suppression activities. Thus, <strong>13h</strong> serves as a novel compound with a multi-target activity against IS.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118428"},"PeriodicalIF":5.9,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696969","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}
Pub Date : 2025-12-06DOI: 10.1016/j.ejmech.2025.118458
Abdellah Ezzanad , Felipe Escobar-Montaño , Jesus Sánchez-Márquez , David Zorrilla , Victor Coca , Glen J.P. McCann , Neill Horley , José Manuel Botubol-Ares , Rosa Durán-Patrón , Antonio J. Macías-Sánchez , Alan Christy Hunter , Rosario Hernández-Galán
A library comprising thirty-three natural and semi-synthetic phorbol derivatives was constructed and subsequently evaluated for aromatase (CYP19A1) inhibitory activity. The primary goal was to identify novel aromatase inhibitors through selective esterifications at the C-12, C-13 and C-20 positions of the phorbol skeleton. Twenty-two phorbol esters, fifteen of which were previously undescribed (5–9, 12 and 16–24), were obtained via semi-synthetic modifications. Additionally, ten 12-deoxyphorbol esters (25–34), four bearing an extra acyloxy chain at C-16, isolated from Euphorbia resinifera, were tested. Inhibition studies revealed that 12,13-diesters bearing medium-sized ester moieties (such as isobutyrate, tigliate or phenylacetate) exhibited the highest potency (IC50 = 0.9–6.4 μM). Conversely, shorter or longer ester chains significantly reduced activity (IC50 values ranging from 22.4 to 29.8 μM). An enhancement of potency was observed upon reduction of the α,β-unsaturated ketone at C-3 to an allylic alcohol. Molecular docking suggested that the phorbol derivatives bind within the aromatase activator-binding pocket, exerting their inhibitory actions through hydrogen-bond interactions with protein residues, independent of the heme group. The inhibitory potency correlated with the ability to establish these interactions. The activities of the most potent compounds are comparable to nonsteroidal, non-heme-binding aromatase inhibitors, such as stilbene and coumarin derivatives. Moreover, 3D-QSAR models were developed, with the most robust model (R2 = 0.908) highlighting the molecular descriptors NQC14 and AP as crucial modulators of the anti-aromatase activity. These findings provide a framework for future optimization of phorbol ester as selective aromatase inhibitors.
{"title":"Exploring novel aromatase cytochrome P450-binding ligands: Molecular docking and QSAR study of phorbol esters as aromatase inhibitors","authors":"Abdellah Ezzanad , Felipe Escobar-Montaño , Jesus Sánchez-Márquez , David Zorrilla , Victor Coca , Glen J.P. McCann , Neill Horley , José Manuel Botubol-Ares , Rosa Durán-Patrón , Antonio J. Macías-Sánchez , Alan Christy Hunter , Rosario Hernández-Galán","doi":"10.1016/j.ejmech.2025.118458","DOIUrl":"10.1016/j.ejmech.2025.118458","url":null,"abstract":"<div><div>A library comprising thirty-three natural and semi-synthetic phorbol derivatives was constructed and subsequently evaluated for aromatase (CYP19A1) inhibitory activity. The primary goal was to identify novel aromatase inhibitors through selective esterifications at the C-12, C-13 and C-20 positions of the phorbol skeleton. Twenty-two phorbol esters, fifteen of which were previously undescribed (<strong>5</strong>–<strong>9</strong>, <strong>12</strong> and <strong>16</strong>–<strong>24</strong>), were obtained via semi-synthetic modifications. Additionally, ten 12-deoxyphorbol esters (<strong>25</strong>–<strong>34</strong>), four bearing an extra acyloxy chain at C-16, isolated from <em>Euphorbia resinifera</em>, were tested. Inhibition studies revealed that 12,13-diesters bearing medium-sized ester moieties (such as isobutyrate, tigliate or phenylacetate) exhibited the highest potency (IC<sub>50</sub> = 0.9–6.4 μM). Conversely, shorter or longer ester chains significantly reduced activity (IC<sub>50</sub> values ranging from 22.4 to 29.8 μM). An enhancement of potency was observed upon reduction of the <em>α</em>,<em>β</em>-unsaturated ketone at C-3 to an allylic alcohol. Molecular docking suggested that the phorbol derivatives bind within the aromatase activator-binding pocket, exerting their inhibitory actions through hydrogen-bond interactions with protein residues, independent of the heme group. The inhibitory potency correlated with the ability to establish these interactions. The activities of the most potent compounds are comparable to nonsteroidal, non-heme-binding aromatase inhibitors, such as stilbene and coumarin derivatives. Moreover, 3D-QSAR models were developed, with the most robust model (R<sup>2</sup> = 0.908) highlighting the molecular descriptors NQC<sub>14</sub> and AP as crucial modulators of the anti-aromatase activity. These findings provide a framework for future optimization of phorbol ester as selective aromatase inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118458"},"PeriodicalIF":5.9,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690090","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}
Pub Date : 2025-12-06DOI: 10.1016/j.ejmech.2025.118471
Yushi Ding , Zhi Wang , Xingyu Xia , Jiayi Wang , Zhenyu Li , Congying Gu , Chenyan Hao , Kang Xu , Mengkang Gao , Hao Yin , Siheng Chen , Xin Gong , Wang Zhou , Min Zhang , Yong Yang , Dayong Zhang , Beiying Dai , Menghan Zhang
Pleiomorphic adenoma-like protein 2 (PLAGL2) is a key player in the development of hepatocellular carcinoma (HCC) and other malignant tumors. High levels of PLAGL2 expression are associated with poor prognosis in cancer. While the potential of PLAGL2 as a therapeutic target for HCC has been recognized, there is a lack of research on small-molecule inhibitors targeting PLAGL2. In this study, a series of small-molecule inhibitors of PLAGL2 transcriptional activity were developed through virtual screening and structure optimization. Among which, compounds C7 and C8 potently suppressed PLAGL2 transcriptional activity, leading to reduced proliferation, colony formation, migration, invasion, cell cycle arrest, and apoptosis in HCC cells. Compound C8 exhibited stronger binding affinity to PLALG2 than compound C7. Furthermore, C8 disrupted extracellular matrix organization and suppressed the PI3K-AKT pathway by reducing AKT phosphorylation. It effectively inhibited tumor growth in HCCLM3 xenograft tumor models while demonstrating a favorable safety profile. Taken together, this study introduces a promising 3-(Phenylsulfonamido) benzamide derivative as a novel approach to targeting PLAGL2 transcriptional activity, laying a foundation for future investigations in anti-tumor therapy.
{"title":"Discovery of novel small molecule inhibitor targeting the tumor promoting effect of transcription factor PLAGL2","authors":"Yushi Ding , Zhi Wang , Xingyu Xia , Jiayi Wang , Zhenyu Li , Congying Gu , Chenyan Hao , Kang Xu , Mengkang Gao , Hao Yin , Siheng Chen , Xin Gong , Wang Zhou , Min Zhang , Yong Yang , Dayong Zhang , Beiying Dai , Menghan Zhang","doi":"10.1016/j.ejmech.2025.118471","DOIUrl":"10.1016/j.ejmech.2025.118471","url":null,"abstract":"<div><div>Pleiomorphic adenoma-like protein 2 (PLAGL2) is a key player in the development of hepatocellular carcinoma (HCC) and other malignant tumors. High levels of PLAGL2 expression are associated with poor prognosis in cancer. While the potential of PLAGL2 as a therapeutic target for HCC has been recognized, there is a lack of research on small-molecule inhibitors targeting PLAGL2. In this study, a series of small-molecule inhibitors of PLAGL2 transcriptional activity were developed through virtual screening and structure optimization. Among which, compounds C7 and C8 potently suppressed PLAGL2 transcriptional activity, leading to reduced proliferation, colony formation, migration, invasion, cell cycle arrest, and apoptosis in HCC cells. Compound C8 exhibited stronger binding affinity to PLALG2 than compound C7. Furthermore, C8 disrupted extracellular matrix organization and suppressed the PI3K-AKT pathway by reducing AKT phosphorylation. It effectively inhibited tumor growth in HCCLM3 xenograft tumor models while demonstrating a favorable safety profile. Taken together, this study introduces a promising 3-(Phenylsulfonamido) benzamide derivative as a novel approach to targeting PLAGL2 transcriptional activity, laying a foundation for future investigations in anti-tumor therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118471"},"PeriodicalIF":5.9,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690088","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}
Pub Date : 2025-12-05DOI: 10.1016/j.ejmech.2025.118447
Yuanguang Chen , Sumei Yang , Xingyu Zhou , Hongyang Yi , Dizhen Liang , Guanguan Li , Xiang Liu , Peisen Zheng , Yongqing Liu , Xinshan Deng , Xumu Zhang , Qifan Zhou , Hongzhou Lu
Among orthopoxviruses, monkeypox virus (MPXV) is currently the most significant human pathogen due to ongoing outbreaks and global spread. Tecovirimat, an FDA-approved antiviral for orthopoxviruses, inhibits the viral p37 protein essential for viral egress and is used under expanded access for monkeypox treatment. To develop more accessible inhibitors and enhance structure-activity relationship (SAR) research, a new library of tecovirimat derivatives has been designed and synthesized. These compounds underwent phenotype determination to evaluate their antiviral properties, leading to the identification of C12 (EC50 = 12.14 nM, CC50 = 304.63 μM) as a promising lead compound. C12 demonstrated stable high plasma exposure following oral administration in mice, achieving a bioavailability (F) of 162 % and extensive distribution within the plasma. It also demonstrated low toxicity and good tolerability in mice, with a single dose of 2000 mg/kg or repeated doses of 100 mg/kg once daily for 14 days. Additionally, the P37 protein structure of VACN was employed for molecular docking to investigate potential binding interactions. Computational simulations suggest that C12 targets the same protein as tecovirimat, offering valuable insights for the rational design of next-generation analogs.
{"title":"Ligand-based design and optimization of tecovirimat derivatives as potent antiviral agents against monkeypox virus","authors":"Yuanguang Chen , Sumei Yang , Xingyu Zhou , Hongyang Yi , Dizhen Liang , Guanguan Li , Xiang Liu , Peisen Zheng , Yongqing Liu , Xinshan Deng , Xumu Zhang , Qifan Zhou , Hongzhou Lu","doi":"10.1016/j.ejmech.2025.118447","DOIUrl":"10.1016/j.ejmech.2025.118447","url":null,"abstract":"<div><div>Among <em>orthopoxviruses</em>, monkeypox virus (MPXV) is currently the most significant human pathogen due to ongoing outbreaks and global spread. Tecovirimat, an FDA-approved antiviral for <em>orthopoxviruses</em>, inhibits the viral p37 protein essential for viral egress and is used under expanded access for monkeypox treatment. To develop more accessible inhibitors and enhance structure-activity relationship (SAR) research, a new library of tecovirimat derivatives has been designed and synthesized. These compounds underwent phenotype determination to evaluate their antiviral properties, leading to the identification of C12 (EC<sub>50</sub> = 12.14 nM, CC<sub>50</sub> = 304.63 μM) as a promising lead compound. C12 demonstrated stable high plasma exposure following oral administration in mice, achieving a bioavailability (F) of 162 % and extensive distribution within the plasma. It also demonstrated low toxicity and good tolerability in mice, with a single dose of 2000 mg/kg or repeated doses of 100 mg/kg once daily for 14 days. Additionally, the P37 protein structure of VACN was employed for molecular docking to investigate potential binding interactions. Computational simulations suggest that C12 targets the same protein as tecovirimat, offering valuable insights for the rational design of next-generation analogs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118447"},"PeriodicalIF":5.9,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690086","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}
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