Pub Date : 2025-03-02DOI: 10.1016/j.ejmech.2025.117473
Ling-Yun Li, Rong-Sheng Li, Jian Zhou, Jia Fan, Zheng-Lin Wang, Bo Hu, Qing Mu
GG-8-6, a cyclic peptide with effective anti-hepatocellular carcinoma activity in vitro and in vivo, was synthesized based on the lead compound Grifficyclocin B, which was isolated from the plants of Goniothalamus species (Annonaceae family). Based on the previous study, we synthesized 17 analogues of GG-8-6 to find better potential and higher-yield cyclopeptides. Among these analogues, nine increased their yield compared to GG-8-6, and compound 1 reached a high yield of 14.7%. In addition, the bioassay results showed that ten analogues exhibited significant anti-hepatocellular carcinoma activities in vitro, which promoted cell apoptosis and reduced intracellular ATP levels. Among them, the activity of compounds 1, 2 and 3 was significantly better than GG-8-6, while the yield of compounds 1 and 3 reached nearly five times that of GG-8-6. Compound 17 was obtained by deprotection from compound 1, which preserved antitumor activity, and more new derivatives could be synthesized based on the hydroxyl group in its structure. A subcutaneous xenografted mice model confirmed the in vivo antitumor activity of compounds 1 and 17. The results indicated that both compounds significantly inhibited the growth of tumours. At 10 mg/kg and 15 mg/kg doses for compounds 1 and 17, the inhibition rates reached 84.3% and 58.39%, respectively. Furthermore, the potential mechanism of compounds 1 and 17 was analyzed by transcriptomic analysis. Our results indicated that GG-8-6 analogues as new cyclic peptides might be potential candidates for developing new drugs treating hepatocellular carcinoma.
{"title":"Synthesis and bioactivity of cyclic peptide GG-8-6 analogues as anti-hepatocellular carcinoma agents","authors":"Ling-Yun Li, Rong-Sheng Li, Jian Zhou, Jia Fan, Zheng-Lin Wang, Bo Hu, Qing Mu","doi":"10.1016/j.ejmech.2025.117473","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117473","url":null,"abstract":"GG-8-6, a cyclic peptide with effective anti-hepatocellular carcinoma activity <em>in vitro</em> and <em>in vivo,</em> was synthesized based on the lead compound Grifficyclocin B, which was isolated from the plants of <em>Goniothalamus</em> species (Annonaceae family). Based on the previous study, we synthesized 17 analogues of GG-8-6 to find better potential and higher-yield cyclopeptides. Among these analogues, nine increased their yield compared to GG-8-6, and compound <strong>1</strong> reached a high yield of 14.7%. In addition, the bioassay results showed that ten analogues exhibited significant anti-hepatocellular carcinoma activities in <em>vitro</em>, which promoted cell apoptosis and reduced intracellular ATP levels. Among them, the activity of compounds <strong>1, 2</strong> and <strong>3</strong> was significantly better than GG-8-6, while the yield of compounds <strong>1</strong> and <strong>3</strong> reached nearly five times that of GG-8-6. Compound <strong>17</strong> was obtained by deprotection from compound <strong>1</strong>, which preserved antitumor activity, and more new derivatives could be synthesized based on the hydroxyl group in its structure. A subcutaneous xenografted mice model confirmed the <em>in vivo</em> antitumor activity of compounds <strong>1</strong> and <strong>17</strong>. The results indicated that both compounds significantly inhibited the growth of tumours. At 10 mg/kg and 15 mg/kg doses for compounds <strong>1</strong> and <strong>17</strong>, the inhibition rates reached 84.3% and 58.39%, respectively. Furthermore, the potential mechanism of compounds <strong>1</strong> and <strong>17</strong> was analyzed by transcriptomic analysis. Our results indicated that GG-8-6 analogues as new cyclic peptides might be potential candidates for developing new drugs treating hepatocellular carcinoma.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"211 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528188","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 : 2025-03-01DOI: 10.1016/j.ejmech.2025.117463
Xiaohui Miao, Pan Liu, Yangyang Liu, Wenying Zhang, Chunxin Li, Xiujiang Wang
Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease characterized by fibroblast proliferation, excessive extracellular matrix buildup, inflammation, and tissue damage, resulting in respiratory failure and death. Recent studies suggest that impaired interactions among epithelial, mesenchymal, immune, and endothelial cells play a key role in IPF development. Advances in bioinformatics have also linked epigenetics, which bridges gene expression and environmental factors, to IPF. Despite the incomplete understanding of the pathogenic mechanisms underlying IPF, recent preclinical studies have identified several novel epigenetic therapeutic targets, including DNMT, EZH2, G9a/GLP, PRMT1/7, KDM6B, HDAC, CBP/p300, BRD4, METTL3, FTO, and ALKBH5, along with potential small-molecule inhibitors relevant for its treatment. This review explores the pathogenesis of IPF, emphasizing epigenetic therapeutic targets and potential small molecule drugs. It also analyzes the structure-activity relationships of these epigenetic drugs and summarizes their biological activities. The objective is to advance the development of innovative epigenetic therapies for IPF.
{"title":"Epigenetic Targets and Their Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis","authors":"Xiaohui Miao, Pan Liu, Yangyang Liu, Wenying Zhang, Chunxin Li, Xiujiang Wang","doi":"10.1016/j.ejmech.2025.117463","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117463","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease characterized by fibroblast proliferation, excessive extracellular matrix buildup, inflammation, and tissue damage, resulting in respiratory failure and death. Recent studies suggest that impaired interactions among epithelial, mesenchymal, immune, and endothelial cells play a key role in IPF development. Advances in bioinformatics have also linked epigenetics, which bridges gene expression and environmental factors, to IPF. Despite the incomplete understanding of the pathogenic mechanisms underlying IPF, recent preclinical studies have identified several novel epigenetic therapeutic targets, including DNMT, EZH2, G9a/GLP, PRMT1/7, KDM6B, HDAC, CBP/p300, BRD4, METTL3, FTO, and ALKBH5, along with potential small-molecule inhibitors relevant for its treatment. This review explores the pathogenesis of IPF, emphasizing epigenetic therapeutic targets and potential small molecule drugs. It also analyzes the structure-activity relationships of these epigenetic drugs and summarizes their biological activities. The objective is to advance the development of innovative epigenetic therapies for IPF.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526333","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 : 2025-03-01DOI: 10.1016/j.ejmech.2025.117465
Qi Hao, Wenzhe Zhao, Zhijia Li, Yue Lai, Yan Wang, Qianqian Yang, Lan Zhang
Cyclin-dependent kinases (CDKs) are pivotal regulators of the cell cycle and transcriptional machinery, making them attractive targets for cancer therapy. While CDK inhibitors have demonstrated promising clinical outcomes, they also face challenges in enhancing efficacy, particularly in overcoming drug resistance. Combination therapies have emerged as a key strategy to augment the effectiveness of CDK inhibitors when used alongside other kinase inhibitors or non-kinase-targeted agents. Dual-target inhibitors that simultaneously inhibit CDKs and other oncogenic drivers are gaining attention, offering novel avenues to optimize cancer therapy. Based on the structural characterization and biological functions of CDKs, this review comprehensively examines the structure-activity relationship (SAR) of existing dual-target CDK inhibitors from a drug design perspective. We also thoroughly investigate the preclinical studies and clinical translational potential of combination therapies and dual-target inhibitors. Tailoring CDK inhibitors to specific cancer subtypes and therapeutic settings will inspire innovative approaches to the next generation of CDK-related therapies, ultimately improving patient survival.
{"title":"Combination therapy and dual-target inhibitors based on cyclin-dependent kinases (CDKs): Emerging strategies for cancer therapy","authors":"Qi Hao, Wenzhe Zhao, Zhijia Li, Yue Lai, Yan Wang, Qianqian Yang, Lan Zhang","doi":"10.1016/j.ejmech.2025.117465","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117465","url":null,"abstract":"Cyclin-dependent kinases (CDKs) are pivotal regulators of the cell cycle and transcriptional machinery, making them attractive targets for cancer therapy. While CDK inhibitors have demonstrated promising clinical outcomes, they also face challenges in enhancing efficacy, particularly in overcoming drug resistance. Combination therapies have emerged as a key strategy to augment the effectiveness of CDK inhibitors when used alongside other kinase inhibitors or non-kinase-targeted agents. Dual-target inhibitors that simultaneously inhibit CDKs and other oncogenic drivers are gaining attention, offering novel avenues to optimize cancer therapy. Based on the structural characterization and biological functions of CDKs, this review comprehensively examines the structure-activity relationship (SAR) of existing dual-target CDK inhibitors from a drug design perspective. We also thoroughly investigate the preclinical studies and clinical translational potential of combination therapies and dual-target inhibitors. Tailoring CDK inhibitors to specific cancer subtypes and therapeutic settings will inspire innovative approaches to the next generation of CDK-related therapies, ultimately improving patient survival.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526334","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 : 2025-02-28DOI: 10.1016/j.ejmech.2025.117469
L.A. Prieto, N. Khiar-Fernandez, J.M. Calderón-Montaño, M. López-Lázaro, J. Lucía-Tamudo, J.J. Nogueira, R. León, N. Moreno, V. Valdivia, R. Recio, I. Fernandez
Iberin is a lower homolog of sulforaphane which has shown effectiveness in addressing various pathologies, including its anti-inflammatory properties, antitumor activity against various cancers, and antimicrobial effects. Building on this activity, a series of carbohydrate-based analogues of the natural isothiocyanate (ITC) iberin were synthesized, and their anticancer and antioxidant activities were evaluated. Cytotoxicity studies on three cancer cell lines using Resazurin assays demonstrated significant cytotoxic activity, particularly against bladder cancer. The sulfonyl derivatives exhibited the most potent effects, with IC50 values comparable to those of reference natural isothiocyanates (from 10 to 20 μM). Computational simulations support the hypothesis that carbohydrate-based ITCs can interact with STAT3’s SH2 domain in a manner similar to SFN, laying the groundwork for their potential development as STAT3-targeted anticancer agents. The antioxidant potential of these compounds was assessed by their ability to activate the Nrf2 factor, yielding CD values (concentration required to double luciferase activity compared to basal conditions) between 1.55 and 10.36 μM, without cytotoxicity at these concentrations. Notably, the phenylsulfone derivative 22β displayed slightly higher or comparable antioxidant activity to that of natural isothiocyanates. Based on these findings, this phenylsulfone analogue was selected as the optimal compound due to its dual anticancer and antioxidant activities. An additional advantage of this carbohydrate-based ITC is that it is a solid compound, making it easier to handle than natural isothiocyanates, which are typically liquids.
{"title":"Exploring the broad-spectrum activity of carbohydrate-based Iberin analogues: from anticancer effect to antioxidant properties.","authors":"L.A. Prieto, N. Khiar-Fernandez, J.M. Calderón-Montaño, M. López-Lázaro, J. Lucía-Tamudo, J.J. Nogueira, R. León, N. Moreno, V. Valdivia, R. Recio, I. Fernandez","doi":"10.1016/j.ejmech.2025.117469","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117469","url":null,"abstract":"Iberin is a lower homolog of sulforaphane which has shown effectiveness in addressing various pathologies, including its anti-inflammatory properties, antitumor activity against various cancers, and antimicrobial effects. Building on this activity, a series of carbohydrate-based analogues of the natural isothiocyanate (ITC) iberin were synthesized, and their anticancer and antioxidant activities were evaluated. Cytotoxicity studies on three cancer cell lines using Resazurin assay<del>s</del> demonstrated significant cytotoxic activity, particularly against bladder cancer. The sulfonyl derivatives exhibited the most potent effects, with IC<sub>50</sub> values comparable to those of reference natural isothiocyanates (from 10 to 20 μM). Computational simulations support the hypothesis that carbohydrate-based ITCs can interact with STAT3’s SH2 domain in a manner similar to SFN, laying the groundwork for their potential development as STAT3-targeted anticancer agents. The antioxidant potential of these compounds was assessed by their ability to activate the Nrf2 factor, yielding CD values (concentration required to double luciferase activity compared to basal conditions) between 1.55 and 10.36 μM, without cytotoxicity at these concentrations. Notably, the phenylsulfone derivative <strong>22β</strong> displayed slightly higher or comparable antioxidant activity to that of natural isothiocyanates. Based on these findings, this phenylsulfone analogue was selected as the optimal compound due to its dual anticancer and antioxidant activities. An additional advantage of this carbohydrate-based ITC is that it is a solid compound, making it easier to handle than natural isothiocyanates, which are typically liquids.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518531","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}
The increasing prevalence of antibiotic-resistant Gram-negative bacteria necessitates the development of novel antimicrobial agents with targeted specificity. In this study, we designed and optimized derivatives of the antimicrobial peptide AA16, which truncated from CD14 protein α-helical region, to selectively target Gram-negative bacteria by enhancing lipopolysaccharide (LPS)-enriched interactions, thereby achieving antibacterial spectrum conversion. Starting from the parent peptide AA16 (Ac-AARIPSRILFGALRVL-Amide), we performed strategic amino acid substitutions based on structure–activity relationship analysis. This led to the identification of AA16-10R, a derivative with a specific substitution at position 10, which demonstrated significantly enhanced antibacterial activity against Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa, while maintaining low hemolytic activity. Mechanistic studies revealed that AA16-10R exhibited a strong binding affinity to LPS (Kd = 0.15 μM), and its interaction with LPS induced the formation of an α-helical structure. This conformational change facilitated its accumulation on the bacterial outer membrane and disrupted membrane integrity. Our innovative approach of exploiting LPS-enriched interactions successfully converted the antimicrobial spectrum of AA16 derivatives from broad-spectrum to Gram-negative-specific. This study highlights a novel strategy for the rational design of antimicrobial peptides based on specific protein–protein interactions, offering a promising avenue for targeted antimicrobial therapy against Gram-negative pathogens.
{"title":"LPS-Enriched Interaction Drives Spectrum Conversion in Antimicrobial Peptides: Design and Optimization of AA16 Derivatives for Targeting Gram-Negative Bacteria","authors":"Wanyang Xiao, Ruize Sun, Jietao Lou, Yanyan Xu, Xiaokun Li, Kaiyun Xin, Weijie Lu, Chenhui Sun, Tianbao Chen, Yitian Gao, Di Wu","doi":"10.1016/j.ejmech.2025.117462","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117462","url":null,"abstract":"The increasing prevalence of antibiotic-resistant Gram-negative bacteria necessitates the development of novel antimicrobial agents with targeted specificity. In this study, we designed and optimized derivatives of the antimicrobial peptide AA16, which truncated from CD14 protein α-helical region, to selectively target Gram-negative bacteria by enhancing lipopolysaccharide (LPS)-enriched interactions, thereby achieving antibacterial spectrum conversion. Starting from the parent peptide AA16 (Ac-AARIPSRILFGALRVL-Amide), we performed strategic amino acid substitutions based on structure–activity relationship analysis. This led to the identification of AA16-10R, a derivative with a specific substitution at position 10, which demonstrated significantly enhanced antibacterial activity against Gram-negative strains such as <em>Escherichia coli</em> and <em>Pseudomonas aeruginosa</em>, while maintaining low hemolytic activity. Mechanistic studies revealed that AA16-10R exhibited a strong binding affinity to LPS (<em>K</em><sub>d</sub> = 0.15 μM), and its interaction with LPS induced the formation of an α-helical structure. This conformational change facilitated its accumulation on the bacterial outer membrane and disrupted membrane integrity. Our innovative approach of exploiting LPS-enriched interactions successfully converted the antimicrobial spectrum of AA16 derivatives from broad-spectrum to Gram-negative-specific. This study highlights a novel strategy for the rational design of antimicrobial peptides based on specific protein–protein interactions, offering a promising avenue for targeted antimicrobial therapy against Gram-negative pathogens.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518530","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 this work, we have carefully designed and synthesized two Ru(II) metal complexes: [Ru(phen)2(HMPIP)](PF6)2 (6a, where phen = 1,10-phenanthroline, HMPIP = 2-(2-hydroxy-3-methylphenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ru(bpy)2(HMPIP)](PF6)2 (6b, where bpy = 2,2’-bipyridine). Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to explore the cytotoxicity of 6a and 6b towards HepG2, B16, A549, SGC-7901, HCT116 and non-cancer LO2. The complexes exhibited cytotoxicity activity against HepG2 cells. The capacity of 6a and 6b to impede the proliferation and dissemination of cancer cells was evaluated by conducting proliferation and migration experiments and 3D model. The anticancer mechanism was investigated in detail. The utilization of cycle blocking assays revealed that 6a and 6b induced a G0/G1 phase arrest in HepG2 cells. The cellular uptake experiments show that the complexes enter the cell nuclei, then escape from the cell nuclei into the cytoplasm, finally accumulate in the mitochondria. Apoptosis assays and the examination of proteins indicated that the complexes were capable of efficiently inducing apoptosis in HepG2 cells. Additionally, the potential induction of autophagy-mediated cell death was explored. The observed reduction in glutathione (GSH) levels and glutathione peroxidase 4 (GPX4) expression suggested a disruption of redox homeostasis within cancer cells, an increment in malondialdehyde (MDA) amount, together with BODIPY staining experiment, confirm that 6a and 6b can induce ferroptosis. Interestingly, in a nude mouse model, 6a showed a significant suppression of tumor growth with an inhibition rate of 63.4%, without causing any weight loss of mice. The studies on the mechanism show that 6a causes immune cell death, increase the amount of TNF-α and IFN-γ, reduce IL-10 content, which further activates immune response to increase CD8+ T cells to prevent tumor growth. Therefore, 6a inhibits the tumor growth through stimulating the immune response to increase CD8+ T cells. In addition, the experiments in vitro show that the complexes through inhibition of PI3K/AKT/mTOR signaling pathway and intrinsic mitochondria pathway to cause cell apoptosis. These results demonstrate that Ru(II) complexes may be potent anticancer candidates for HepG2 tumor.
{"title":"Ruthenium(II) Polypyridyl Complexes Inhibit Tumor Growth Through Stimulating Immune System to Increase CD8+ T Cell","authors":"Shuang Tian, Haixin Xu, Xiaoyu Wu, Yueyao Ding, Lijuan Liang, Hui Yin, Xiandong Zeng, Yunjun Liu, Wenrun Zhu","doi":"10.1016/j.ejmech.2025.117470","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117470","url":null,"abstract":"In this work, we have carefully designed and synthesized two Ru(II) metal complexes: [Ru(phen)<sub>2</sub>(HMPIP)](PF<sub>6</sub>)<sub>2</sub> (<strong>6a</strong>, where phen = 1,10-phenanthroline, HMPIP = 2-(2-hydroxy-3-methylphenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ru(bpy)<sub>2</sub>(HMPIP)](PF<sub>6</sub>)<sub>2</sub> (<strong>6b</strong>, where bpy = 2,2’-bipyridine). Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to explore the cytotoxicity of <strong>6a</strong> and <strong>6b</strong> towards HepG2, B16, A549, SGC-7901, HCT116 and non-cancer LO2. The complexes exhibited cytotoxicity activity against HepG2 cells. The capacity of <strong>6a</strong> and <strong>6b</strong> to impede the proliferation and dissemination of cancer cells was evaluated by conducting proliferation and migration experiments and 3D model. The anticancer mechanism was investigated in detail. The utilization of cycle blocking assays revealed that <strong>6a</strong> and <strong>6b</strong> induced a G0/G1 phase arrest in HepG2 cells. The cellular uptake experiments show that the complexes enter the cell nuclei, then escape from the cell nuclei into the cytoplasm, finally accumulate in the mitochondria. Apoptosis assays and the examination of proteins indicated that the complexes were capable of efficiently inducing apoptosis in HepG2 cells. Additionally, the potential induction of autophagy-mediated cell death was explored. The observed reduction in glutathione (GSH) levels and glutathione peroxidase 4 (GPX4) expression suggested a disruption of redox homeostasis within cancer cells, an increment in malondialdehyde (MDA) amount, together with BODIPY staining experiment, confirm that <strong>6a</strong> and <strong>6b</strong> can induce ferroptosis. Interestingly, in a nude mouse model, <strong>6a</strong> showed a significant suppression of tumor growth with an inhibition rate of 63.4%, without causing any weight loss of mice. The studies on the mechanism show that <strong>6a</strong> causes immune cell death, increase the amount of TNF-α and IFN-γ, reduce IL-10 content, which further activates immune response to increase CD8<sup>+</sup> T cells to prevent tumor growth. Therefore, <strong>6a</strong> inhibits the tumor growth through stimulating the immune response to increase CD8<sup>+</sup> T cells. In addition, the experiments in vitro show that the complexes through inhibition of PI3K/AKT/mTOR signaling pathway and intrinsic mitochondria pathway to cause cell apoptosis. These results demonstrate that Ru(II) complexes may be potent anticancer candidates for HepG2 tumor.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526335","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 : 2025-02-27DOI: 10.1016/j.ejmech.2025.117464
Zhenzhen Zhou, Minghui Xie, Zongji Zhuo, Yalin Wang, Fabao Zhao, Sining Tao, Zhening Liang, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Dongwei Kang, Xinyong Liu
To promote the development of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the “tolerant region I” and “tolerant region II” of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, 13a was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC50 values ranging from 0.0062-0.25 μM, being superior to that of efavirenz (EFV, EC50 = 0.0080-0.37 μM). In addition, 13a was proved to have low cytotoxicity (CC50 = 160.7 μM) and high SI values (SI = 25254). Further HIV-1 RT inhibition assay demonstrated that 13a is a classical NNRTI with an IC50 value of 0.41 μM. Molecular docking and molecular dynamics simulations results illustrated its binding mode with HIV-1 RT. Overall, these enchanting results illuminated the potential of 13a as a promising lead for the development of the new generation HIV-1 NNRTIs drugs.
{"title":"Structure-based Design of Novel 2,4,5-Trisubstituted Pyrimidine Derivatives as Potent HIV-1 NNRTIs by Exploiting the Tolerant Regions in NNTRIs Binding Pocket","authors":"Zhenzhen Zhou, Minghui Xie, Zongji Zhuo, Yalin Wang, Fabao Zhao, Sining Tao, Zhening Liang, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Dongwei Kang, Xinyong Liu","doi":"10.1016/j.ejmech.2025.117464","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117464","url":null,"abstract":"To promote the development of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the “tolerant region I” and “tolerant region II” of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, <strong>13a</strong> was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC<sub>50</sub> values ranging from 0.0062-0.25 <em>μ</em>M, being superior to that of efavirenz (EFV, EC<sub>50</sub> = 0.0080-0.37 <em>μ</em>M). In addition, <strong>13a</strong> was proved to have low cytotoxicity (CC<sub>50</sub> = 160.7 <em>μ</em>M) and high SI values (SI = 25254). Further HIV-1 RT inhibition assay demonstrated that <strong>13a</strong> is a classical NNRTI with an IC<sub>50</sub> value of 0.41 <em>μ</em>M. Molecular docking and molecular dynamics simulations results illustrated its binding mode with HIV-1 RT. Overall, these enchanting results illuminated the potential of <strong>13a</strong> as a promising lead for the development of the new generation HIV-1 NNRTIs drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518532","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 : 2025-02-27DOI: 10.1016/j.ejmech.2025.117460
Guoliang Liu, Tao Zhang, Shunmeng Qian, Xiaoshuang Zhang, Hongxiang Lou, Peihong Fan
Mitochondria play a crucial role in cellular processes such as growth, differentiation, and energy conversion. Dysfunctional mitochondria have been implicated in Alzheimer’s disease (AD), making mitochondrial improvement a promising therapeutic approach. SIRT3, a mitochondrial deacetylase, modulates mitochondrial function by deacetylating associated proteins. This study aimed to enhance the activity of honokiol, a natural SIRT3 modulator, and improve mitochondrial function for neuroprotective activity, using mitochondria targeting strategy. We synthesized mitochondrial targeting peptide conjugates using XJB as a carrier and found that honokiol conjugates exhibited lower toxicity and higher activity on neuronal injury models in vitro and in vivo (Zebrafish model) at lower concentrations compared to honokiol. The neuroprotective mechanism may involve the activation of cellular autophagy-related pathways, promotion of SIRT3 pathway activation, and up-regulation of mitochondrial fusion-associated protein Mfn-1 expression under damaged conditions. This study offers a promising approach for developing anti-Alzheimer's disease (AD) natural product derivatives based on SIRT3 regulation.
{"title":"Conjugation with the XJB Peptide Enhanced Neuroprotective Effect of Honokiol via SIRT3 Modulation","authors":"Guoliang Liu, Tao Zhang, Shunmeng Qian, Xiaoshuang Zhang, Hongxiang Lou, Peihong Fan","doi":"10.1016/j.ejmech.2025.117460","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117460","url":null,"abstract":"Mitochondria play a crucial role in cellular processes such as growth, differentiation, and energy conversion. Dysfunctional mitochondria have been implicated in Alzheimer’s disease (AD), making mitochondrial improvement a promising therapeutic approach. SIRT3, a mitochondrial deacetylase, modulates mitochondrial function by deacetylating associated proteins. This study aimed to enhance the activity of honokiol, a natural SIRT3 modulator, and improve mitochondrial function for neuroprotective activity, using mitochondria targeting strategy. We synthesized mitochondrial targeting peptide conjugates using XJB as a carrier and found that honokiol conjugates exhibited lower toxicity and higher activity on neuronal injury models <em>in vitro</em> and i<em>n vivo (</em>Zebrafish model) at lower concentrations compared to honokiol. The neuroprotective mechanism may involve the activation of cellular autophagy-related pathways, promotion of SIRT3 pathway activation, and up-regulation of mitochondrial fusion-associated protein Mfn-1 expression under damaged conditions. This study offers a promising approach for developing anti-Alzheimer's disease (AD) natural product derivatives based on SIRT3 regulation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"129 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507385","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}
P2Y14R is activated by UDP (uridine diphosphate) and UDP glucose and associated with the development of many inflammatory diseases. P2Y14R antagonists are expected to be a new choice for the treatment of inflammatory diseases. A DNA-encoded chemical library (DEL) of 4 billion molecules was screened, leading to the identification of compound A, a novel benzisoxazole scaffold-based P2Y14 antagonist with an IC50 value of 23.60 nM. Binding mode analysis and SPR analysis (KD = 7.26 μM) demonstrated that Compound A bind strongly to P2Y14R. Molecular dynamics simulations and binding free energy calculations were performed to analyze the binding mode of Compound A with P2Y14R. And in the LPS-induced acute lung injury mice, after treatment with Compound A, the degree of lung injury was greatly reduced, the infiltration of immune cells was decreased, the level of inflammatory factors IL-6, TNF-α and IL-β were considerably decreased. Compound A exhibited good P2Y14R antagonist activity, demonstrated efficacy both in vitro and in vivo, possessed favorable druggability, and featured a novel benzisoxazole scaffold with potential for further optimization, providing a new strategy for developing subsequent P2Y14 antagonists.
{"title":"Discovery of a Potent and in Vivo Anti-inflammatory Efficacious, P2Y14R Antagonist with a Novel Benzisoxazoles Scaffold by DNA-Encoded Chemical Library Technology","authors":"ZhiYi Wei, Bingqian Han, Longhua Yang, Jiannan Zhao, Takashi Nakai, Suyi Chen, Yongfang Yao, Chuanjun Song, Yongtao Duan","doi":"10.1016/j.ejmech.2025.117451","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117451","url":null,"abstract":"P2Y<sub>14</sub>R is activated by UDP (uridine diphosphate) and UDP glucose and associated with the development of many inflammatory diseases. P2Y<sub>14</sub>R antagonists are expected to be a new choice for the treatment of inflammatory diseases. A DNA-encoded chemical library (DEL) of 4 billion molecules was screened, leading to the identification of compound A, a novel benzisoxazole scaffold-based P2Y<sub>14</sub> antagonist with an IC<sub>50</sub> value of 23.60 nM. Binding mode analysis and SPR analysis (KD = 7.26 μM) demonstrated that Compound A bind strongly to P2Y<sub>14</sub>R. Molecular dynamics simulations and binding free energy calculations were performed to analyze the binding mode of Compound A with P2Y<sub>14</sub>R. And in the LPS-induced acute lung injury mice, after treatment with Compound <strong>A,</strong> the degree of lung injury was greatly reduced, the infiltration of immune cells was decreased, the level of inflammatory factors IL-6, TNF-α and IL-β were considerably decreased. Compound A exhibited good P2Y<sub>14</sub>R antagonist activity, demonstrated efficacy both <em>in vitro</em> and <em>in vivo</em>, possessed favorable druggability, and featured a novel benzisoxazole scaffold with potential for further optimization, providing a new strategy for developing subsequent P2Y14 antagonists.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518534","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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