We first demonstrate that carrimycin, as an antibiotic, shows broad-spectrum anti-coronavirus activity by targeting frameshifting element (FSE) RNA. Herein, taking carrimycin as the lead, 26 new 16-membered macrolides were synthesized and evaluated for antiviral activity against coronavirus strains. Compound 2d exhibited the elevated antiviral efficacy against HCoV-OC43 and HCoV-229E with EC50 values of 0.85 μM and 1.45 μM by directly targeting coronaviral FSE RNA pseudoknot. Molecular simulations revealed that the introduction of a 4″-substituent transforms the macrocyclic core into U-shaped conformation, enabling the higher binding with FSE. Meanwhile, using thermal proteome profiling (TPP) technology, we identified DIS3L2 as a potential host target, which probably assisted 2d to exert the antiviral effect. Therefore, the 16-membered macrolides constituted a new class of RNA inhibitors against coronaviruses, and 2d owns a dual-target mechanism that acts on both viral FSE RNA and host DIS3L2.
{"title":"Synthesis and evolution of 16-membered macrolide carrimycin derivatives as a novel class of anti-HCoV-OC43 agents targeting viral FSE RNA","authors":"Xiuli Zhong , Zhihui Yu , Runze Meng, Yue Gong, Jianrui Li, Weiqing He, Hongying Li, Jiayu Li, Zhiyun Wu, Qionglu Duan, Yinghong Li, Yonghua Liu, Zonggen Peng, Danqing Song","doi":"10.1016/j.ejmech.2025.117373","DOIUrl":"10.1016/j.ejmech.2025.117373","url":null,"abstract":"<div><div>We first demonstrate that carrimycin, as an antibiotic, shows broad-spectrum anti-coronavirus activity by targeting frameshifting element (FSE) RNA. Herein, taking carrimycin as the lead, 26 new 16-membered macrolides were synthesized and evaluated for antiviral activity against coronavirus strains. Compound <strong>2d</strong> exhibited the elevated antiviral efficacy against HCoV-OC43 and HCoV-229E with EC<sub>50</sub> values of 0.85 μM and 1.45 μM by directly targeting coronaviral FSE RNA pseudoknot. Molecular simulations revealed that the introduction of a 4″-substituent transforms the macrocyclic core into U-shaped conformation, enabling the higher binding with FSE. Meanwhile, using thermal proteome profiling (TPP) technology, we identified DIS3L2 as a potential host target, which probably assisted <strong>2d</strong> to exert the antiviral effect. Therefore, the 16-membered macrolides constituted a new class of RNA inhibitors against coronaviruses, and <strong>2d</strong> owns a dual-target mechanism that acts on both viral FSE RNA and host DIS3L2.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117373"},"PeriodicalIF":6.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367625","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 : 2025-02-07DOI: 10.1016/j.ejmech.2025.117379
Bo Liu , Ziqing Yao , Lin Song , Chen Sun , Changhong Shen , Fang Cheng , Zefang Cheng , Ruoqi Zhang , Rong Liu
Obesity is recognized as a metabolic disorder, and its treatment and management pose ongoing challenges worldwide. Hawthorn, a traditional Chinese herb used to alleviate digestive issues and reduce blood lipid levels, has unclear mechanisms of action regarding its active components in the treatment of obesity. This study investigated the anti-obesity effects of vitexin, a major flavonoid compound found in hawthorn, in high-fat diet (HFD)-induced C57BL/6 mice. The results demonstrated that vitexin significantly reduced body weight, liver weight, blood lipid levels, and inflammatory markers in obese mice, while also inhibiting hepatic lipid accumulation. Mechanistic studies revealed that vitexin likely suppresses adipogenesis by modulating the PI3K-AKT signaling pathway, as evidenced by reduced expression of PI3K, phosphorylated AKT, phosphorylated mTOR, and SREBP-1c in the livers of vitexin-treated obese mice. Additionally, vitexin inhibited NFκB expression by regulating IκBα phosphorylation, thereby alleviating obesity-induced liver injury. These findings suggest that vitexin may be the primary active component in hawthorn responsible for reducing blood lipid levels, highlighting its potential in the treatment of obesity and its associated metabolic disorders.
{"title":"Vitexin alleviates lipid metabolism disorders and hepatic injury in obese mice through the PI3K/AKT/mTOR/SREBP-1c pathway","authors":"Bo Liu , Ziqing Yao , Lin Song , Chen Sun , Changhong Shen , Fang Cheng , Zefang Cheng , Ruoqi Zhang , Rong Liu","doi":"10.1016/j.ejmech.2025.117379","DOIUrl":"10.1016/j.ejmech.2025.117379","url":null,"abstract":"<div><div>Obesity is recognized as a metabolic disorder, and its treatment and management pose ongoing challenges worldwide. Hawthorn, a traditional Chinese herb used to alleviate digestive issues and reduce blood lipid levels, has unclear mechanisms of action regarding its active components in the treatment of obesity. This study investigated the anti-obesity effects of vitexin, a major flavonoid compound found in hawthorn, in high-fat diet (HFD)-induced C57BL/6 mice. The results demonstrated that vitexin significantly reduced body weight, liver weight, blood lipid levels, and inflammatory markers in obese mice, while also inhibiting hepatic lipid accumulation. Mechanistic studies revealed that vitexin likely suppresses adipogenesis by modulating the PI3K-AKT signaling pathway, as evidenced by reduced expression of PI3K, phosphorylated AKT, phosphorylated mTOR, and SREBP-1c in the livers of vitexin-treated obese mice. Additionally, vitexin inhibited NFκB expression by regulating IκBα phosphorylation, thereby alleviating obesity-induced liver injury. These findings suggest that vitexin may be the primary active component in hawthorn responsible for reducing blood lipid levels, highlighting its potential in the treatment of obesity and its associated metabolic disorders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117379"},"PeriodicalIF":6.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367628","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}
In the complex network of cellular physiology, the maintenance of cellular proteostasis emerges as a critical factor for cell survival, particularly under stress conditions. This homeostasis is largely governed by a sophisticated network of molecular chaperones and co-chaperones, among which Bcl-2-associated athanogene 3 (BAG3), able to interact with the ATPase domain of Heat Shock Protein 70 (HSP70), plays a pivotal role. The BAG3-HSP70 functional module is not only essential for cellular homeostasis but is also involved in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and cardiac dysfunction, making it an attractive target for therapeutic intervention. Inspired by our continuous interest in the development of new chemical platforms able to interfere with BAG3 protein, herein we report the discovery of compound 16, the first-in-class BAG3/HSP70 dual modulator, obtained by combining the multicomponent Ugi reaction with the alkyne-azide Huisgen procedure in a sequential tandem reaction approach. Through a combination of biophysical analysis, biochemical assays, and cell-based studies, we elucidated the mechanism of action of this inhibitor and assessed its potential as a therapeutic agent. Hence, this study can open new avenues for the development of novel anticancer strategies that leverage the simultaneous disruption of multiple chaperone pathways.
{"title":"Identification of the first-in-class dual inhibitor targeting BAG3 and HSP70 proteins to disrupt multiple chaperone pathways","authors":"Dafne Ruggiero , Emis Ingenito , Eleonora Boccia , Vincenzo Vestuto , Gilda D'Urso , Alessandra Capuano , Agostino Casapullo , Stefania Terracciano , Giuseppe Bifulco , Gianluigi Lauro , Ines Bruno","doi":"10.1016/j.ejmech.2025.117358","DOIUrl":"10.1016/j.ejmech.2025.117358","url":null,"abstract":"<div><div>In the complex network of cellular physiology, the maintenance of cellular proteostasis emerges as a critical factor for cell survival, particularly under stress conditions. This homeostasis is largely governed by a sophisticated network of molecular chaperones and co-chaperones, among which Bcl-2-associated athanogene 3 (BAG3), able to interact with the ATPase domain of Heat Shock Protein 70 (HSP70), plays a pivotal role. The BAG3-HSP70 functional module is not only essential for cellular homeostasis but is also involved in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and cardiac dysfunction, making it an attractive target for therapeutic intervention. Inspired by our continuous interest in the development of new chemical platforms able to interfere with BAG3 protein, herein we report the discovery of compound <strong>16</strong>, the first-in-class BAG3/HSP70 dual modulator, obtained by combining the multicomponent Ugi reaction with the alkyne-azide Huisgen procedure in a sequential tandem reaction approach. Through a combination of biophysical analysis, biochemical assays, and cell-based studies, we elucidated the mechanism of action of this inhibitor and assessed its potential as a therapeutic agent. Hence, this study can open new avenues for the development of novel anticancer strategies that leverage the simultaneous disruption of multiple chaperone pathways.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117358"},"PeriodicalIF":6.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.ejmech.2025.117349
Jing Ji , Zhengtao Hu , Fuqiang Zheng , Jiefang Zheng , Jiaxin Cheng , Nuriddinov Zayniddin , Safomuddin Abduahadi , Guan Wang , Xudong Gong , Libiao Pan , Pengcheng Li , Jiangyu Zhao , Tianwen Hu , Weiliang Zhu , Jingshan Shen , Guanghui Tian , Haji Akber Aisa , Yang He
Dextromethorphan (DM) is a dual inhibitor of NMDAR and SERT (IC50 (NMDAR): IC50 (SERT) = 31), but lacks therapeutic clinical value for the treatment of depression due to its low exposure in the human body. In this study, a series of d-morphinan derivatives were designed, synthesized and evaluated both in vitro and in vivo to identify dual inhibitors with improved metabolic stability. Structure-activity relationship studies revealed that a methyl group at the morphinan N-17 position is essential for maintaining SERT activity. Amino-morphinan compounds 24 and 27 exhibited moderate yet more balanced inhibitory activity against both NMDAR and SERT (1< IC50(NMDAR): IC50(SERT) < 5). Compared to DM, compound 24 demonstrated favorable metabolic stability and higher plasma exposure. In vivo, 24 showed significant antidepressant-like effects in the forced swim test in mice after acute administration.
{"title":"D-morphinan analogs with favorable pharmacokinetic profiles as dual-acting antidepressants","authors":"Jing Ji , Zhengtao Hu , Fuqiang Zheng , Jiefang Zheng , Jiaxin Cheng , Nuriddinov Zayniddin , Safomuddin Abduahadi , Guan Wang , Xudong Gong , Libiao Pan , Pengcheng Li , Jiangyu Zhao , Tianwen Hu , Weiliang Zhu , Jingshan Shen , Guanghui Tian , Haji Akber Aisa , Yang He","doi":"10.1016/j.ejmech.2025.117349","DOIUrl":"10.1016/j.ejmech.2025.117349","url":null,"abstract":"<div><div>Dextromethorphan (<strong>DM</strong>) is a dual inhibitor of NMDAR and SERT (IC<sub>50 (NMDAR)</sub>: IC<sub>50 (SERT)</sub> = 31), but lacks therapeutic clinical value for the treatment of depression due to its low exposure in the human body. In this study, a series of <em>d</em>-morphinan derivatives were designed, synthesized and evaluated both <em>in vitro</em> and <em>in vivo</em> to identify dual inhibitors with improved metabolic stability. Structure-activity relationship studies revealed that a methyl group at the morphinan <em>N</em>-17 position is essential for maintaining SERT activity. Amino-morphinan compounds <strong>24</strong> and <strong>27</strong> exhibited moderate yet more balanced inhibitory activity against both NMDAR and SERT (1< IC<sub>50(NMDAR)</sub>: IC<sub>50(SERT)</sub> < 5). Compared to <strong>DM</strong>, compound <strong>24</strong> demonstrated favorable metabolic stability and higher plasma exposure. <em>In vivo</em>, <strong>24</strong> showed significant antidepressant-like effects in the forced swim test in mice after acute administration.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117349"},"PeriodicalIF":6.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192325","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 : 2025-02-06DOI: 10.1016/j.ejmech.2025.117365
Tieqiang Zong , Xing Huang , Wei Zhou , Zhengyu Hu , Long Jin , Peng Zhan , Yuqing Zhao , Jinfeng Sun , Gao Li
Phosphodiesterase 5 (PDE5) can hydrolyze cyclic guanosine monophosphate (cGMP), which is critical for maintaining various physiological processes in organisms. Currently, clinically approved indications for PDE5 inhibitors encompass therapeutic agents for erectile dysfunction (ED), symptoms associated with lower urinary tract symptoms (LUTS), and pulmonary artery hypertension (PAH). Despite the fact that the development of selective PDE5 inhibitors has been a significant focus in drug development for some time following the proven success of sildenafil as a PDE5 inhibitor for ED treatment, fewer than ten drugs in this therapeutic class have been marketed in the past 25 years, often accompanied by adverse effects. Therefore, the development of novel, isozyme-selective PDE5 inhibitors is highly warranted. In this review, we systematically summarize the research progress of PDE5 inhibitors over the past 20 years, focusing on the meticulously combing and categorizing the structures of PDE5 inhibitors and natural products exhibiting PDE5 inhibitory activities, along with their therapeutic potentials. We hope that this summary will aid in better understanding of PDE5 inhibitors and provide insights for developing novel therapies targeting PDE5.
{"title":"Advances in the development of phosphodiesterase 5 inhibitors","authors":"Tieqiang Zong , Xing Huang , Wei Zhou , Zhengyu Hu , Long Jin , Peng Zhan , Yuqing Zhao , Jinfeng Sun , Gao Li","doi":"10.1016/j.ejmech.2025.117365","DOIUrl":"10.1016/j.ejmech.2025.117365","url":null,"abstract":"<div><div>Phosphodiesterase 5 (PDE5) can hydrolyze cyclic guanosine monophosphate (cGMP), which is critical for maintaining various physiological processes in organisms. Currently, clinically approved indications for PDE5 inhibitors encompass therapeutic agents for erectile dysfunction (ED), symptoms associated with lower urinary tract symptoms (LUTS), and pulmonary artery hypertension (PAH). Despite the fact that the development of selective PDE5 inhibitors has been a significant focus in drug development for some time following the proven success of sildenafil as a PDE5 inhibitor for ED treatment, fewer than ten drugs in this therapeutic class have been marketed in the past 25 years, often accompanied by adverse effects. Therefore, the development of novel, isozyme-selective PDE5 inhibitors is highly warranted. In this review, we systematically summarize the research progress of PDE5 inhibitors over the past 20 years, focusing on the meticulously combing and categorizing the structures of PDE5 inhibitors and natural products exhibiting PDE5 inhibitory activities, along with their therapeutic potentials. We hope that this summary will aid in better understanding of PDE5 inhibitors and provide insights for developing novel therapies targeting PDE5.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117365"},"PeriodicalIF":6.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257865","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 : 2025-02-06DOI: 10.1016/j.ejmech.2025.117350
Muneeb Ur Rehman , Yujie Zuo , Ni Tu, Ju Guo, Ziwei Liu, Shuang Cao, Sihui Long
β-Carbolines, a class of indole-containing heterocyclic alkaloids, are widely distributed in nature and possess diverse bioactivities, making them promising drug candidates against a wide range of diseases. The remarkable medicinal potential of β-carbolines has spurred the pharmaceutical research community to study their derivatives extensively. This review updates the development of β-carboline derivatives in recent years (2015–2024), particularly with a focus on their anticancer, antiparasitic, antimicrobial, antiviral, and neuroprotective properties, based on the modification approaches such as substitution on indole N (ring B), pyridine or its reduced forms (ring C), and dimerization of β-carbolines. Moreover, the mechanisms of action and structure-activity relationships of these β-carboline derivatives are highlighted to offer valuable insights on the design and development of new β-carbolines with better pharmacological activities.
{"title":"Diverse pharmacological activities of β-carbolines: Substitution patterns, SARs and mechanisms of action","authors":"Muneeb Ur Rehman , Yujie Zuo , Ni Tu, Ju Guo, Ziwei Liu, Shuang Cao, Sihui Long","doi":"10.1016/j.ejmech.2025.117350","DOIUrl":"10.1016/j.ejmech.2025.117350","url":null,"abstract":"<div><div><em>β</em>-Carbolines, a class of indole-containing heterocyclic alkaloids, are widely distributed in nature and possess diverse bioactivities, making them promising drug candidates against a wide range of diseases. The remarkable medicinal potential of <em>β</em>-carbolines has spurred the pharmaceutical research community to study their derivatives extensively. This review updates the development of <em>β</em>-carboline derivatives in recent years (2015–2024), particularly with a focus on their anticancer, antiparasitic, antimicrobial, antiviral, and neuroprotective properties, based on the modification approaches such as substitution on indole N (ring B), pyridine or its reduced forms (ring C), and dimerization of <em>β</em>-carbolines. Moreover, the mechanisms of action and structure-activity relationships of these <em>β</em>-carboline derivatives are highlighted to offer valuable insights on the design and development of new <em>β</em>-carbolines with better pharmacological activities.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117350"},"PeriodicalIF":6.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257863","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 : 2025-02-06DOI: 10.1016/j.ejmech.2025.117329
Yi Gou , Jinlong Li , Boyi Fan , Bohui Xu , Min Zhou , Feng Yang
{"title":"Corrigendum to “Structure and biological properties of mixed-ligand Cu(II) Schiff base complexes as potential anticancer agents”[Eur. J. Med. Chem. 134 (2017) 207–217]>","authors":"Yi Gou , Jinlong Li , Boyi Fan , Bohui Xu , Min Zhou , Feng Yang","doi":"10.1016/j.ejmech.2025.117329","DOIUrl":"10.1016/j.ejmech.2025.117329","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117329"},"PeriodicalIF":6.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.ejmech.2025.117332
Wangrui Jin , Yuzhu Zhang , Baozhen Wang , Zhaoyong Kang , Huachao Li , Jingfeng Song , Yihua Chen , Hai Xiong , Jing Chen
Effective targeted treatments for triple-negative breast cancer (TNBC), which has the worst prognosis among various types of breast cancer, are lacking owing to its clinical heterogeneity and malignant nature. STAT3, a key transcription factor, regulates multiple physiological functions. Aberrant activation of STAT3 plays a pivotal role in the initiation and progression of TNBC and is closely associated with a poor prognosis. Therefore, targeting STAT3 is a promising potential therapeutic approach for TNBC. In this study, we further optimized the core structure of 6f, which our research group previously identified as a STAT3 inhibitor and treatment for osteosarcoma, to identify additional potential STAT3 inhibitors for TNBC treatment. We identified WR-S-462 as a high-binding affinity inhibitor of STAT3 that effectively suppresses its phosphorylation and biological functions in vitro. Notably, WR-S-462 significantly inhibits TNBC growth and metastasis in a dose-dependent manner, providing robust evidence for its potential as a clinical intervention for TNBC.
{"title":"Structural optimization and characterization of highly potent and selective STAT3 inhibitors for the treatment of triple negative breast cancer","authors":"Wangrui Jin , Yuzhu Zhang , Baozhen Wang , Zhaoyong Kang , Huachao Li , Jingfeng Song , Yihua Chen , Hai Xiong , Jing Chen","doi":"10.1016/j.ejmech.2025.117332","DOIUrl":"10.1016/j.ejmech.2025.117332","url":null,"abstract":"<div><div>Effective targeted treatments for triple-negative breast cancer (TNBC), which has the worst prognosis among various types of breast cancer, are lacking owing to its clinical heterogeneity and malignant nature. STAT3, a key transcription factor, regulates multiple physiological functions. Aberrant activation of STAT3 plays a pivotal role in the initiation and progression of TNBC and is closely associated with a poor prognosis. Therefore, targeting STAT3 is a promising potential therapeutic approach for TNBC. In this study, we further optimized the core structure of <strong>6f</strong>, which our research group previously identified as a STAT3 inhibitor and treatment for osteosarcoma, to identify additional potential STAT3 inhibitors for TNBC treatment. We identified <strong>WR-S-462</strong> as a high-binding affinity inhibitor of STAT3 that effectively suppresses its phosphorylation and biological functions <em>in vitro</em>. Notably, <strong>WR-S-462</strong> significantly inhibits TNBC growth and metastasis in a dose-dependent manner, providing robust evidence for its potential as a clinical intervention for TNBC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117332"},"PeriodicalIF":6.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192308","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}
A library of 30 novel quinazolinone-dihydropyrimidinone derivatives was synthesized employing a diversity-oriented approach for the identification of potential anti-diabetic therapeutic lead. In vitro evaluation revealed that seven compounds (5d, 5e, 5i, 5j, 5l, 5m and 5s) significantly enhanced the rate of GLUT4 translocation to the cell surface in L6-GLUT4myc myotubes. Out of these, compound, 5m exhibited promising potency to stimulate GLUT4 translocation in skeletal muscle cells via activating AMPK-dependent pathway, but independent to PI-3-K/AKT signaling. Under in vivo conditions, treatment with 5m demonstrated a marked 39.5 % (p < 0.001) reduction in blood glucose levels in a streptozotocin-induced diabetic rat model after 5 h of treatment. Pharmacokinetic analysis indicated compound 5m shows favourable pharmacokinetic properties. Overall, the compound 5m emerged as a promising lead compound for subsequent structural modification and optimization to develop a novel and potent anti-hyperglycemic agent.
{"title":"Design, synthesis, and biological evaluation of quinazolinone-dihydropyrimidinone as a potential anti-diabetic agent via GLUT4 translocation stimulation","authors":"Arvind Kumar Jaiswal , Ajay Kishor Kushawaha , Pawan kumar , Alisha Ansari , Nikita Chhikara , Hemlata bhatt , Sarita Katiyar , Ishbal Ahmad , Abhijit Deb Choudhury , Rabi Sankar Bhatta , Akhilesh K. Tamrakar , Koneni V. Sashidhara","doi":"10.1016/j.ejmech.2025.117366","DOIUrl":"10.1016/j.ejmech.2025.117366","url":null,"abstract":"<div><div>A library of 30 novel quinazolinone-dihydropyrimidinone derivatives was synthesized employing a diversity-oriented approach for the identification of potential anti-diabetic therapeutic lead. <em>In vitro</em> evaluation revealed that seven compounds (<strong>5d, 5e, 5i, 5j, 5l, 5m</strong> and <strong>5s</strong>) significantly enhanced the rate of GLUT4 translocation to the cell surface in L6-GLUT4<em>myc</em> myotubes. Out of these, compound, <strong>5m</strong> exhibited promising potency to stimulate GLUT4 translocation in skeletal muscle cells via activating AMPK-dependent pathway, but independent to PI-3-K/AKT signaling. Under <em>in vivo</em> conditions, treatment with <strong>5m</strong> demonstrated a marked <strong>39.5</strong> % (p < 0.001) reduction in blood glucose levels in a streptozotocin-induced diabetic rat model after 5 h of treatment. Pharmacokinetic analysis indicated compound <strong>5m</strong> shows favourable pharmacokinetic properties. Overall, the compound <strong>5m</strong> emerged as a promising lead compound for subsequent structural modification and optimization to develop a novel and potent anti-hyperglycemic agent.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117366"},"PeriodicalIF":6.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257864","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 : 2025-02-05DOI: 10.1016/j.ejmech.2024.117155
Fangjie Wang , Lairong Song , Qianqian Xu , Ang Jia , Xiangwei Meng , Hongfei Jiang , Renshuai Zhang
Hypoxia is a common feature of various solid tumors, which reduces the sensitivity of tumor cells to both radiotherapy and chemotherapy. However, hypoxia also presents an opportunity for tumor-selective therapy. The prodrug strategy, leveraging the hypoxic nature of the tumor microenvironment, shows significant potential for clinical application. Here we present CHD-1, a hypoxia-activated antitumor prodrug that activates in hypoxic environments, effectively inhibiting hypoxic tumor cells while exhibiting no toxicity to normoxic cells. CHD-1 impairs mitochondrial morphology and membrane potential of hypoxic tumor cells, further triggers excessive mitophagy and induces apoptosis. Moreover, prodrug CHD-1 significantly inhibits HeLa xenograft growth in vivo, and shows lower toxicity than parent molecule in an acute toxicity assessment in animal models. This study introduces a promising hypoxia-activated antitumor prodrug with strong potential for further development in hypoxic tumor therapy.
{"title":"Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis","authors":"Fangjie Wang , Lairong Song , Qianqian Xu , Ang Jia , Xiangwei Meng , Hongfei Jiang , Renshuai Zhang","doi":"10.1016/j.ejmech.2024.117155","DOIUrl":"10.1016/j.ejmech.2024.117155","url":null,"abstract":"<div><div>Hypoxia is a common feature of various solid tumors, which reduces the sensitivity of tumor cells to both radiotherapy and chemotherapy. However, hypoxia also presents an opportunity for tumor-selective therapy. The prodrug strategy, leveraging the hypoxic nature of the tumor microenvironment, shows significant potential for clinical application. Here we present <strong>CHD-1</strong>, a hypoxia-activated antitumor prodrug that activates in hypoxic environments, effectively inhibiting hypoxic tumor cells while exhibiting no toxicity to normoxic cells. <strong>CHD-1</strong> impairs mitochondrial morphology and membrane potential of hypoxic tumor cells, further triggers excessive mitophagy and induces apoptosis. Moreover, prodrug <strong>CHD-1</strong> significantly inhibits HeLa xenograft growth <em>in vivo</em>, and shows lower toxicity than parent molecule in an acute toxicity assessment in animal models. This study introduces a promising hypoxia-activated antitumor prodrug with strong potential for further development in hypoxic tumor therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117155"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788449","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号