Pub Date : 2025-02-27DOI: 10.1016/j.ejmech.2025.117461
Lu Wang, Yan Geng, Lifang Liu, Jun Wang, Jiaxin Chen, Yunying Li, Jingbo Wang, Liyan Song, Kexin Sun, Yajie Yan, Shiqing Zhou, Dan Tian, Ran Lin, Hongliang Yao
Allergic rhinitis (AR) is a non-infectious inflammatory disease and affects nearly half of the world's population currently, thus becoming a global health problem. In our study, a series of 1,2,4-triazole enamides were designed and used to evaluate the anti-inflammatory activity of AR. We found that compound 11g could significantly reduce the increased expression of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in Raw264.7 cells induced by lipopolysaccharides (LPS), and inhibit the expression of inflammation through MAPK pathway and NF-κB pathway by influencing the expression of cannabinoid-1 receptor (CB1 R). In the AR mice model, 11g can significantly reduce the number of inflammatory cells in Nasal lavage fluids (NLF), showing a good effect on the treatment of AR. This study provides a new and effective candidate for treatment of AR.
{"title":"Synthesis, anti-allergic rhinitis evaluation and mechanism investigation of novel 1,2,4-triazole-enamides as CB1 R antagonist","authors":"Lu Wang, Yan Geng, Lifang Liu, Jun Wang, Jiaxin Chen, Yunying Li, Jingbo Wang, Liyan Song, Kexin Sun, Yajie Yan, Shiqing Zhou, Dan Tian, Ran Lin, Hongliang Yao","doi":"10.1016/j.ejmech.2025.117461","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117461","url":null,"abstract":"Allergic rhinitis (AR) is a non-infectious inflammatory disease and affects nearly half of the world's population currently, thus becoming a global health problem. In our study, a series of 1,2,4-triazole enamides were designed and used to evaluate the anti-inflammatory activity of AR. We found that compound <strong>11g</strong> could significantly reduce the increased expression of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in Raw264.7 cells induced by lipopolysaccharides (LPS), and inhibit the expression of inflammation through MAPK pathway and NF-κB pathway by influencing the expression of cannabinoid-1 receptor (CB1 R). In the AR mice model, <strong>11g</strong> can significantly reduce the number of inflammatory cells in Nasal lavage fluids (NLF), showing a good effect on the treatment of AR. This study provides a new and effective candidate for treatment of AR.","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":"143518533","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}
Substance Use Disorder (SUD) remains a significant global challenge, with current treatment options offering limited efficacy. Agonists targeting the kappa opioid receptor (KOR), especially those with additional mu opioid receptor (MOR) antagonistic activity, have shown promise in addressing SUD. In this study, a series of meta-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized, and their biological activities were assessed, leading to the identification of a KOR/MOR dual modulator, compound 10a. Unlike its para- positional isomer SLL-1062, where KOR activity is completely abolished, compound 10a displayed a single-digit nanomolar affinity for KOR, while its binding profiles for MOR and delta opioid receptor (DOR) were comparable to those of SLL-1062. Functional assays in vitro confirmed that compound 10a exhibited agonistic activity at KOR and antagonistic activity at MOR. The molecular basis for the introduction of a KOR component into compound 10a was further elucidated. Although compound 10a did not produce apparent antinociception in vivo, it effectively blocked morphine-induced antinociception and intestinal motility inhibition in rodent models. This study provides valuable insights into the development of MOR/KOR dual modulators and presents new lead compounds for potential treatments for SUD.
{"title":"Structure–Activity Relationship Analysis of Meta-Substituted N-Cyclopropylmethyl-Nornepenthones with Mixed KOR/MOR Activities","authors":"Siyuan Tang, Shuyang Hu, Linghui Kong, Jiangwen Gui, Ying Zhang, Zi-Han Liu, Denggao Zhang, An-An Liu, Xiao Liu, Chuyuan Hu, Yingjie Lan, Xiaoning Liu, Zixiang Li, Panwen Liu, Shaoliang Duan, Lijing Feng, Zeyi Du, Min Liu, Qiong Xie, Jinggen Liu, Wei Li","doi":"10.1016/j.ejmech.2025.117449","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117449","url":null,"abstract":"Substance Use Disorder (SUD) remains a significant global challenge, with current treatment options offering limited efficacy. Agonists targeting the kappa opioid receptor (KOR), especially those with additional mu opioid receptor (MOR) antagonistic activity, have shown promise in addressing SUD. In this study, a series of <em>meta-</em>substituted <em>N</em>-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized, and their biological activities were assessed, leading to the identification of a KOR/MOR dual modulator, compound <strong>10a</strong>. Unlike its <em>para-</em> positional isomer <strong>SLL-1062</strong>, where KOR activity is completely abolished, compound <strong>10a</strong> displayed a single-digit nanomolar affinity for KOR, while its binding profiles for MOR and delta opioid receptor (DOR) were comparable to those of <strong>SLL-1062</strong>. Functional assays <em>in vitro</em> confirmed that compound <strong>10a</strong> exhibited agonistic activity at KOR and antagonistic activity at MOR. The molecular basis for the introduction of a KOR component into compound <strong>10a</strong> was further elucidated. Although compound <strong>10a</strong> did not produce apparent antinociception <em>in vivo</em>, it effectively blocked morphine-induced antinociception and intestinal motility inhibition in rodent models. This study provides valuable insights into the development of MOR/KOR dual modulators and presents new lead compounds for potential treatments for SUD.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496058","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 : 2025-02-26DOI: 10.1016/j.ejmech.2025.117453
Xiaojing Pang , Wen Xu , Jing Liang , Yang Liu , Hua Li , Lixia Chen
The occurrence and development of diseases are complex, and single-target drugs that affect only a single target or pathway often fail to achieve the expected therapeutic effect. The simultaneous effect on two key targets could not only increase patient tolerance but also accelerate disease remission. Dual-target inhibitors have already been studied the most intensively in the development of dual-target drugs. This article briefly introduces the function of drug therapy targets, and mainly summarizes the design strategies and research progress of dual-target inhibitors in neurodegenerative diseases, infectious diseases, metabolic diseases and cardiovascular diseases.
{"title":"Research progress and perspectives of dual-target inhibitors","authors":"Xiaojing Pang , Wen Xu , Jing Liang , Yang Liu , Hua Li , Lixia Chen","doi":"10.1016/j.ejmech.2025.117453","DOIUrl":"10.1016/j.ejmech.2025.117453","url":null,"abstract":"<div><div>The occurrence and development of diseases are complex, and single-target drugs that affect only a single target or pathway often fail to achieve the expected therapeutic effect. The simultaneous effect on two key targets could not only increase patient tolerance but also accelerate disease remission. Dual-target inhibitors have already been studied the most intensively in the development of dual-target drugs. This article briefly introduces the function of drug therapy targets, and mainly summarizes the design strategies and research progress of dual-target inhibitors in neurodegenerative diseases, infectious diseases, metabolic diseases and cardiovascular diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117453"},"PeriodicalIF":6.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507422","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 : 2025-02-26DOI: 10.1016/j.ejmech.2025.117452
Tariq T. Ali , Madiha Merghani , Mohammed Al-Azzani , Luisa Maria Gatzemeier , Michael Hoppert , Dora Kaloyanova , Tiago F. Outeiro , Piotr Neumann , Blagovesta Popova , Gerhard H. Braus
Parkinson's Disease (PD) is characterized by the pathological aggregation of α-synuclein (αSyn) into oligomers and amyloid fibrils, making αSyn aggregation a key target for drug development. Peptides have gained recent attention as potential agents to inhibit aggregation. Two previously identified peptide inhibitors, discovered through large-scale yeast screening, were used as templates for in silico mutagenesis aimed at designing novel peptides with improved efficacy in inhibiting αSyn aggregation and cytotoxicity. The newly designed peptides underwent in silico docking analysis, and the most promising candidates were tested in vitro and in cellular models. Peptides T02 and T05 emerged as the most effective inhibitors, with T02 binding αSyn monomers and T05 targeting lower-order oligomers. Both peptides reduce αSyn fibril and oligomer formation in vitro and significantly suppress αSyn aggregation and cytotoxicity in yeast and human H4 cells. These novel peptides represent antagonists of αSyn aggregation with promising potential for therapeutic intervention for PD.
{"title":"Rationally designed peptides inhibit the formation of α-synuclein fibrils and oligomers","authors":"Tariq T. Ali , Madiha Merghani , Mohammed Al-Azzani , Luisa Maria Gatzemeier , Michael Hoppert , Dora Kaloyanova , Tiago F. Outeiro , Piotr Neumann , Blagovesta Popova , Gerhard H. Braus","doi":"10.1016/j.ejmech.2025.117452","DOIUrl":"10.1016/j.ejmech.2025.117452","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is characterized by the pathological aggregation of α-synuclein (αSyn) into oligomers and amyloid fibrils, making αSyn aggregation a key target for drug development. Peptides have gained recent attention as potential agents to inhibit aggregation. Two previously identified peptide inhibitors, discovered through large-scale yeast screening, were used as templates for <em>in silico</em> mutagenesis aimed at designing novel peptides with improved efficacy in inhibiting αSyn aggregation and cytotoxicity. The newly designed peptides underwent <em>in silico</em> docking analysis, and the most promising candidates were tested <em>in vitro</em> and in cellular models. Peptides T02 and T05 emerged as the most effective inhibitors, with T02 binding αSyn monomers and T05 targeting lower-order oligomers. Both peptides reduce αSyn fibril and oligomer formation <em>in vitro</em> and significantly suppress αSyn aggregation and cytotoxicity in yeast and human H4 cells. These novel peptides represent antagonists of αSyn aggregation with promising potential for therapeutic intervention for PD.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117452"},"PeriodicalIF":6.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507424","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 : 2025-02-25DOI: 10.1016/j.ejmech.2025.117443
Weiqi Liu, Taiwei Chu
Designing new radiolabeled hypoxia-targeted drugs is of great help in the diagnosis of tumors. Hypoxia-targeted drugs with dual bioactive groups can enhance hypoxia selectivity, strengthen the binding of drugs to targets, and improve diagnostic accuracy compared with traditional hypoxia-targeted drugs containing only one nitroimidazole group. In this study, a series of novel radioiodine labeled tyrosine derivatives containing 2-nitroimidazole and benzenesulfonamide groups were synthesized and in vitro evaluated. In the uptake experiments of S180 cells that didn't express carbonic anhydrase IX (CAIX), the compound [131I]-3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-2-(2-(2-nitro-1H-imidazole-1-yl)acetamido)-N-(2-(2-nitro-1H-imidazole-1-yl)ethyl)propenamide (131I-Tyr-05) containing two 2-nitroimidazole groups was modified from phenolic hydroxyl to methoxy to 2-(2-methoxyethoxy)ethoxy, gradually achieving improved membrane permeability and enhanced hydrophilicity. Compared with other compounds with similar structures but containing only one 2-nitroimidazole, it had higher hypoxic selectivity. In the uptake experiment of HeLa cells that expressed CAIX, [131I]-N-(3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1-((2-(2-nitro-1H-imidazole-1-yl)ethyl)amino)-1-oxopropan-2-yl)-4-sulfamoylbenzamide (131I-Tyr-06), which contained both 2-nitroimidazole and benzenesulfonamide group, achieved enhanced hypoxic uptake and selectivity through the combination of two targeting groups. The S180 cell blocking experiments of 131I-Tyr-05 and 131I-Tyr-06 showed that the benzenesulfonamide group of the compounds didn't inhibit cellular uptake, and inhibition of cytochrome P450 (CYP450) enzyme had no effect on cellular uptake. In silico ADMET evaluation showed that I-Tyr-05 and I-Tyr-06 possessed acceptable physicochemical and ADMET properties. In conclusion, this work demonstrated the advantages of hypoxia-targeted drugs containing dual bioactive groups compared to a single group, and also found it was a feasible approach to design new dual-targeted drugs by combining 2-nitroimidazole and benzenesulfonamide groups.
{"title":"Synthesis and in vitro evaluation of radioiodine labeled hypoxia-targeted drugs containing 2-nitroimidazole and benzenesulfonamide groups","authors":"Weiqi Liu, Taiwei Chu","doi":"10.1016/j.ejmech.2025.117443","DOIUrl":"10.1016/j.ejmech.2025.117443","url":null,"abstract":"<div><div>Designing new radiolabeled hypoxia-targeted drugs is of great help in the diagnosis of tumors. Hypoxia-targeted drugs with dual bioactive groups can enhance hypoxia selectivity, strengthen the binding of drugs to targets, and improve diagnostic accuracy compared with traditional hypoxia-targeted drugs containing only one nitroimidazole group. In this study, a series of novel radioiodine labeled tyrosine derivatives containing 2-nitroimidazole and benzenesulfonamide groups were synthesized and <em>in vitro</em> evaluated. In the uptake experiments of S180 cells that didn't express carbonic anhydrase IX (CAIX), the compound [<sup>131</sup>I]-3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-2-(2-(2-nitro-1<em>H</em>-imidazole-1-yl)acetamido)-<em>N</em>-(2-(2-nitro-1<em>H</em>-imidazole-1-yl)ethyl)propenamide (<sup><strong>131</strong></sup><strong>I-Tyr-05</strong>) containing two 2-nitroimidazole groups was modified from phenolic hydroxyl to methoxy to 2-(2-methoxyethoxy)ethoxy, gradually achieving improved membrane permeability and enhanced hydrophilicity. Compared with other compounds with similar structures but containing only one 2-nitroimidazole, it had higher hypoxic selectivity. In the uptake experiment of HeLa cells that expressed CAIX, [<sup>131</sup>I]-<em>N</em>-(3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1-((2-(2-nitro-1<em>H</em>-imidazole-1-yl)ethyl)amino)-1-oxopropan-2-yl)-4-sulfamoylbenzamide (<sup><strong>131</strong></sup><strong>I-Tyr-06</strong>), which contained both 2-nitroimidazole and benzenesulfonamide group, achieved enhanced hypoxic uptake and selectivity through the combination of two targeting groups. The S180 cell blocking experiments of <sup><strong>131</strong></sup><strong>I-Tyr-05</strong> and <sup><strong>131</strong></sup><strong>I-Tyr-06</strong> showed that the benzenesulfonamide group of the compounds didn't inhibit cellular uptake, and inhibition of cytochrome P450 (CYP450) enzyme had no effect on cellular uptake. <em>In silico</em> ADMET evaluation showed that <strong>I-Tyr-05</strong> and <strong>I-Tyr-06</strong> possessed acceptable physicochemical and ADMET properties. In conclusion, this work demonstrated the advantages of hypoxia-targeted drugs containing dual bioactive groups compared to a single group, and also found it was a feasible approach to design new dual-targeted drugs by combining 2-nitroimidazole and benzenesulfonamide groups.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117443"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486368","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 : 2025-02-25DOI: 10.1016/j.ejmech.2025.117434
Xiangyang Le , Qingsong Chen , Qiwan Wen , Shuyang Cao , Lei Zhang , Liqing Hu , Gaoyun Hu , Qianbin Li , Zhuo Chen
Cell division cycle 20 homologue (Cdc20) is an essential mitotic regulator whose overexpression is closely associated with tumorigenesis and poor prognosis in triple-negative breast cancer (TNBC). Targeting Cdc20 has therefore emerged as a promising therapeutic avenue for this aggressive malignancy. In the present study, a receptor-based drug design approach was employed to optimize Apcin analogues as Cdc20 inhibitors. Through a two-step strategy—concept validation followed by structural optimization—we identified compound 14c, which demonstrated remarkable Cdc20 binding affinity (KD: 7.65 μM), potent antiproliferative effects against MDA-MB-231 TNBC cells (IC50: 3.28 μM), and a favorable selectivity index (4.22 for MCF-7 non-TNBC cells and 7.27 for MCF 10A normal cells). 14c effectively inhibited Cdc20 activity, induced G2/M phase arrest, promoted DNA damage accumulation, and stabilized key substrates such as Cyclin B1 and Bim, leading to enhanced apoptosis and suppression of tumor cell proliferation and migration. In vivo, 14c significantly inhibited tumor growth in an MDA-MB-231 xenograft model with a 90 % tumor inhibition rate and no observable toxicity. These results highlight the potential of 14c as a potent Cdc20 inhibitor, offering a promising therapeutic approach for TNBC.
{"title":"Design, synthesis and optimization of Apcin analogues as Cdc20 inhibitors for triple-negative breast cancer therapy","authors":"Xiangyang Le , Qingsong Chen , Qiwan Wen , Shuyang Cao , Lei Zhang , Liqing Hu , Gaoyun Hu , Qianbin Li , Zhuo Chen","doi":"10.1016/j.ejmech.2025.117434","DOIUrl":"10.1016/j.ejmech.2025.117434","url":null,"abstract":"<div><div>Cell division cycle 20 homologue (Cdc20) is an essential mitotic regulator whose overexpression is closely associated with tumorigenesis and poor prognosis in triple-negative breast cancer (TNBC). Targeting Cdc20 has therefore emerged as a promising therapeutic avenue for this aggressive malignancy. In the present study, a receptor-based drug design approach was employed to optimize Apcin analogues as Cdc20 inhibitors. Through a two-step strategy—concept validation followed by structural optimization—we identified compound <strong>14c</strong>, which demonstrated remarkable Cdc20 binding affinity (K<sub>D</sub>: 7.65 μM), potent antiproliferative effects against MDA-MB-231 TNBC cells (IC<sub>50</sub>: 3.28 μM), and a favorable selectivity index (4.22 for MCF-7 non-TNBC cells and 7.27 for MCF 10A normal cells). <strong>14c</strong> effectively inhibited Cdc20 activity, induced G2/M phase arrest, promoted DNA damage accumulation, and stabilized key substrates such as Cyclin B1 and Bim, leading to enhanced apoptosis and suppression of tumor cell proliferation and migration. <em>In vivo</em>, <strong>14c</strong> significantly inhibited tumor growth in an MDA-MB-231 xenograft model with a 90 % tumor inhibition rate and no observable toxicity. These results highlight the potential of <strong>14c</strong> as a potent Cdc20 inhibitor, offering a promising therapeutic approach for TNBC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117434"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486374","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 : 2025-02-25DOI: 10.1016/j.ejmech.2025.117446
Yang Zhou , Yuting Wang , Juanjuan Liu , Yu Bai , Jinliang Ma , Miao-Miao Niu , Jindong Li , Haijing Jiang
Syntenin, an intracellular scaffold protein, plays a critical role in renal cell carcinoma (RCC) progression, underscoring its potential as a therapeutic target. Herein, we report a novel, highly efficient, and stable peptide inhibitor (PDPP-3) that exhibits excellent inhibitory effects on syntenin. We have constructed a combined virtual screening scheme based on pharmacophore modeling and molecular docking to identify six potential d-amino acid-containing peptide inhibitors targeting syntenin. Among them, PDPP-3 showed the best inhibitory activity against syntenin. Binding affinity experiments and biostability experiments indicated that the interaction between PDPP-3 and syntenin displayed nanomolar-level binding affinity (Kd = 6.15 ± 0.12 nM) and superior biostability in serum. Molecular dynamics simulation results further confirmed that PDPP-3 could stably bind to the active site of syntenin. Additionally, cytotoxicity test results showed that PDPP-3 exhibited potent inhibitory effects on various types of renal cancer cells, with the best inhibitory effect on SK-RC-20 cells. More importantly, PDPP-3 significantly downregulates the expression of matrix metalloenzymes MT1-MMP and MMP2, which are pivotal for tumor invasion, and demonstrates inhibitory effects on tumor growth in SK-RC-20 derived xenografts. These data suggest that PDPP-3 may be a very promising candidate drug for the treatment of RCC.
{"title":"Design, synthesis, and biological evaluation of novel and highly potent peptides targeting syntenin","authors":"Yang Zhou , Yuting Wang , Juanjuan Liu , Yu Bai , Jinliang Ma , Miao-Miao Niu , Jindong Li , Haijing Jiang","doi":"10.1016/j.ejmech.2025.117446","DOIUrl":"10.1016/j.ejmech.2025.117446","url":null,"abstract":"<div><div>Syntenin, an intracellular scaffold protein, plays a critical role in renal cell carcinoma (RCC) progression, underscoring its potential as a therapeutic target. Herein, we report a novel, highly efficient, and stable peptide inhibitor (PDPP-3) that exhibits excellent inhibitory effects on syntenin. We have constructed a combined virtual screening scheme based on pharmacophore modeling and molecular docking to identify six potential <span>d</span>-amino acid-containing peptide inhibitors targeting syntenin. Among them, PDPP-3 showed the best inhibitory activity against syntenin. Binding affinity experiments and biostability experiments indicated that the interaction between PDPP-3 and syntenin displayed nanomolar-level binding affinity (<em>K</em><sub>d</sub> = 6.15 ± 0.12 nM) and superior biostability in serum. Molecular dynamics simulation results further confirmed that PDPP-3 could stably bind to the active site of syntenin. Additionally, cytotoxicity test results showed that PDPP-3 exhibited potent inhibitory effects on various types of renal cancer cells, with the best inhibitory effect on SK-RC-20 cells. More importantly, PDPP-3 significantly downregulates the expression of matrix metalloenzymes MT1-MMP and MMP2, which are pivotal for tumor invasion, and demonstrates inhibitory effects on tumor growth in SK-RC-20 derived xenografts. These data suggest that PDPP-3 may be a very promising candidate drug for the treatment of RCC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117446"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485988","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 : 2025-02-25DOI: 10.1016/j.ejmech.2025.117431
Mi Guo , Yu Zou , Ke Dong , Nan Huang , Zhichao Chen , Chenhui Sun , Pan Chen , Qi Chen , Luxiao Zhu , Yuehua Lv , Kaixin Zhang , Miao Jiang , Yitian Gao , Young-Chang Cho , Qidong Tang , Guang Liang , Di Wu
Acute lung injury (ALI) and ulcerative colitis (UC) are common inflammatory diseases with high mortality rates and unsatisfactory cure rates. Studies have indicated that inhibiting the expression and release of inflammatory factors holds potential for the treatment of inflammatory diseases. In this study, we designed and synthesized 28 derivatives of 6,7-disubstituted-4-cis-cyclohexanequinazoline and assessed their anti-inflammatory activities in mouse macrophages RAW264.7, J774A.1, and human monocyte THP-1 cell lines. Among them, derivative c1 was found to significantly inhibit the expression and release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) induced by lipopolysaccharide (LPS) in the three cells mentioned above. It was also demonstrated that c1 could bind to IRAK4 and affect the expression of these two inflammatory factors by inhibiting the activation of the MAPK pathway. Furthermore, in vivo experiments revealed that c1 effectively ameliorated LPS-induced ALI and dextran sulfate sodium (DSS)-induced UC. Additionally, we evaluated the pharmacokinetic properties and in vivo safety of c1. Therefore, our research has identified the 6,7-disubstituted-4-cis-cyclohexanequinazoline derivative c1 exhibiting promising anti-inflammatory effects as a prospective anti-inflammatory drug candidate.
{"title":"Anti-inflammatory agents design via the fragment hybrid strategy in the discovery of compound c1 for treating ALI and UC","authors":"Mi Guo , Yu Zou , Ke Dong , Nan Huang , Zhichao Chen , Chenhui Sun , Pan Chen , Qi Chen , Luxiao Zhu , Yuehua Lv , Kaixin Zhang , Miao Jiang , Yitian Gao , Young-Chang Cho , Qidong Tang , Guang Liang , Di Wu","doi":"10.1016/j.ejmech.2025.117431","DOIUrl":"10.1016/j.ejmech.2025.117431","url":null,"abstract":"<div><div>Acute lung injury (ALI) and ulcerative colitis (UC) are common inflammatory diseases with high mortality rates and unsatisfactory cure rates. Studies have indicated that inhibiting the expression and release of inflammatory factors holds potential for the treatment of inflammatory diseases. In this study, we designed and synthesized 28 derivatives of 6,7-disubstituted-4-cis-cyclohexanequinazoline and assessed their anti-inflammatory activities in mouse macrophages RAW264.7, J774A.1, and human monocyte THP-1 cell lines. Among them, derivative <strong>c1</strong> was found to significantly inhibit the expression and release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) induced by lipopolysaccharide (LPS) in the three cells mentioned above. It was also demonstrated that <strong>c1</strong> could bind to IRAK4 and affect the expression of these two inflammatory factors by inhibiting the activation of the MAPK pathway. Furthermore, <em>in vivo</em> experiments revealed that <strong>c1</strong> effectively ameliorated LPS-induced ALI and dextran sulfate sodium (DSS)-induced UC. Additionally, we evaluated the pharmacokinetic properties and <em>in vivo</em> safety of <strong>c1</strong>. Therefore, our research has identified the 6,7-disubstituted-4-cis-cyclohexanequinazoline derivative <strong>c1</strong> exhibiting promising anti-inflammatory effects as a prospective anti-inflammatory drug candidate.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117431"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485985","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 : 2025-02-25DOI: 10.1016/j.ejmech.2025.117450
Huatai Zhu , Xuan Liu , Jing He , Jiandu Lei , Jingyang Zhao
Over the past two decades, various coronaviruses have posed a severe threat to human life and health, with the spike protein (S protein) being a critical protein for infecting host cells. Glycyrrhizic acid (GA), as a natural drug, can inhibit the infection of coronaviruses by binding to the receptor-binding domain (RBD) of the S protein. However, issues like poor water solubility and weak binding affinity with the S protein have hindered its further application. Therefore, drawing inspiration from the biological structure of centipedes, a ROS-responsive multi-branched drug conjugate (ODPAG) was constructed through a "polymer-drug linkage" strategy using dextran as the backbone and GA as the active "claw". ODPAG exhibited drug loading of 22.0 ± 0.2% (OD40kPAG) and 19.7 ± 0.1% (OD450kPAG), showing ROS responsiveness with a half-life 6.4 times that of GA (OD40kPAG) and 5.4 times longer (OD450kPAG). In in vitro antiviral experiments, ODPAG exhibited an enhanced binding affinity to the S protein, with IC50 values of 1.33 μM (OD40kPAG) and 0.89 μM (OD450kPAG) against SARS-CoV-2 pseudovirus, demonstrating exceptional antiviral efficacy. These results collectively indicate that ODPAG can block coronavirus infection by binding to the S protein, exhibiting significant potential in addressing the current challenges posed by the novel coronavirus. Additionally, the "polymer-drug conjugate" strategy employed in this process is efficient, cost-effective, and offers new insights for combating future emergent coronaviruses.
{"title":"High-affinity, broad-spectrum, \"centipede-like\" multi-branched drug conjugates, anchored to the S protein, for blocking coronavirus infection","authors":"Huatai Zhu , Xuan Liu , Jing He , Jiandu Lei , Jingyang Zhao","doi":"10.1016/j.ejmech.2025.117450","DOIUrl":"10.1016/j.ejmech.2025.117450","url":null,"abstract":"<div><div>Over the past two decades, various coronaviruses have posed a severe threat to human life and health, with the spike protein (S protein) being a critical protein for infecting host cells. Glycyrrhizic acid (GA), as a natural drug, can inhibit the infection of coronaviruses by binding to the receptor-binding domain (RBD) of the S protein. However, issues like poor water solubility and weak binding affinity with the S protein have hindered its further application. Therefore, drawing inspiration from the biological structure of centipedes, a ROS-responsive multi-branched drug conjugate (ODPAG) was constructed through a \"polymer-drug linkage\" strategy using dextran as the backbone and GA as the active \"claw\". ODPAG exhibited drug loading of 22.0 ± 0.2% (OD<sub>40k</sub>PAG) and 19.7 ± 0.1% (OD<sub>450</sub>kPAG), showing ROS responsiveness with a half-life 6.4 times that of GA (OD<sub>40k</sub>PAG) and 5.4 times longer (OD<sub>450</sub>kPAG). In in vitro antiviral experiments, ODPAG exhibited an enhanced binding affinity to the S protein, with IC<sub>50</sub> values of 1.33 μM (OD<sub>40k</sub>PAG) and 0.89 μM (OD<sub>450k</sub>PAG) against SARS-CoV-2 pseudovirus, demonstrating exceptional antiviral efficacy. These results collectively indicate that ODPAG can block coronavirus infection by binding to the S protein, exhibiting significant potential in addressing the current challenges posed by the novel coronavirus. Additionally, the \"polymer-drug conjugate\" strategy employed in this process is efficient, cost-effective, and offers new insights for combating future emergent coronaviruses.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117450"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485986","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 : 2025-02-25DOI: 10.1016/j.ejmech.2025.117444
Deyan Zhang , Lu Liu , Ming Li , Xinyi Hu , Xi Zhang , Wenyang Xia , Zhen Wang , Xiaomin Song , Yue Huang , Ze Dong , Cai-Guang Yang
Fat mass and obesity-associated protein (FTO) is the first discovered RNA N6-methyladenosine (m6A) demethylase. The highly expressed FTO protein is required to trigger oncogenic pathways in acute myeloid leukemia (AML), which makes FTO a promising antileukemia drug target. In this study, we identify 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors with good antileukemia activity. We replaced the phenyl A-ring in FB23, the first-generation of FTO inhibitor, with five-membered heterocycles and synthesized a new class of FTO inhibitors. Compound 12o/F97 shows strong enzymatic inhibitory activity and potent antiproliferative activity. 12o/F97 selectively inhibits m6A demethylation by FTO rather than ALKBH5, and has minimal effect on m1A demethylation by ALKBH3. Additionally, 12o/F97 increases the protein levels of RARA and ASB2, while decreasing that of MYC in AML cell lines. Lastly, 12o/F97 exhibits antileukemia activity in a xenograft mice model without significant side-effects. The identification of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors not only expands the chemical space but also holds potential for antileukemia drug development.
{"title":"Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities","authors":"Deyan Zhang , Lu Liu , Ming Li , Xinyi Hu , Xi Zhang , Wenyang Xia , Zhen Wang , Xiaomin Song , Yue Huang , Ze Dong , Cai-Guang Yang","doi":"10.1016/j.ejmech.2025.117444","DOIUrl":"10.1016/j.ejmech.2025.117444","url":null,"abstract":"<div><div>Fat mass and obesity-associated protein (FTO) is the first discovered RNA N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) demethylase. The highly expressed FTO protein is required to trigger oncogenic pathways in acute myeloid leukemia (AML), which makes FTO a promising antileukemia drug target. In this study, we identify 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors with good antileukemia activity. We replaced the phenyl A-ring in FB23, the first-generation of FTO inhibitor, with five-membered heterocycles and synthesized a new class of FTO inhibitors. Compound <strong>12o</strong>/F97 shows strong enzymatic inhibitory activity and potent antiproliferative activity. <strong>12o</strong>/F97 selectively inhibits m<sup>6</sup>A demethylation by FTO rather than ALKBH5, and has minimal effect on m<sup>1</sup>A demethylation by ALKBH3. Additionally, <strong>12o</strong>/F97 increases the protein levels of RARA and ASB2, while decreasing that of MYC in AML cell lines. Lastly, <strong>12o</strong>/F97 exhibits antileukemia activity in a xenograft mice model without significant side-effects. The identification of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors not only expands the chemical space but also holds potential for antileukemia drug development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117444"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486058","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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