Pub Date : 2025-01-24DOI: 10.1016/j.ejmech.2025.117319
Zhaolin Guo, Peng Wang, Yuxuan Han, Sisi Jiang, Xinyu Yang, Shuang Cao
SMARCA2 is an ATPase that regulates chromatin structure via ATP pathways, controlling cell division and differentiation. SMARCA2's bromodomain and ATPase domain, crucial for chromatin remodeling and cell regulation, are therapeutic targets in cancer treatment. This review explores the role of SMARCA2 in cancer development by studying its protein structure and physiological functions. It further discusses the roles and distinctions of SMARCA2 and its related family proteins in cancer. Additionally, this article categorizes known SMARCA2 inhibitors into four classes based on their basic structure and examines their structure-activity relationships (SAR). This review outlines the structural mechanisms of SMARCA2 inhibitors, highlighting interactions with specific amino acids. By analyzing the SAR of inhibitors, we propose a tailored inhibitor model for the bromodomain of SMARCA2, emphasizing α, γ-H-bond donors/acceptors, and β-rigid structures as crucial for effective binding. This research provides guidance for the design and optimization of future drugs targeting the SMARCA2 protein.
{"title":"SMARCA2 protein: structure, function and perspectives of drug design","authors":"Zhaolin Guo, Peng Wang, Yuxuan Han, Sisi Jiang, Xinyu Yang, Shuang Cao","doi":"10.1016/j.ejmech.2025.117319","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117319","url":null,"abstract":"SMARCA2 is an ATPase that regulates chromatin structure via ATP pathways, controlling cell division and differentiation. SMARCA2's bromodomain and ATPase domain, crucial for chromatin remodeling and cell regulation, are therapeutic targets in cancer treatment. This review explores the role of SMARCA2 in cancer development by studying its protein structure and physiological functions. It further discusses the roles and distinctions of SMARCA2 and its related family proteins in cancer. Additionally, this article categorizes known SMARCA2 inhibitors into four classes based on their basic structure and examines their structure-activity relationships (SAR). This review outlines the structural mechanisms of SMARCA2 inhibitors, highlighting interactions with specific amino acids. By analyzing the SAR of inhibitors, we propose a tailored inhibitor model for the bromodomain of SMARCA2, emphasizing α, γ-H-bond donors/acceptors, and β-rigid structures as crucial for effective binding. This research provides guidance for the design and optimization of future drugs targeting the SMARCA2 protein.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"58 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026991","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 : 2025-01-23DOI: 10.1016/j.ejmech.2025.117290
Wen Li, Kun Zhu, Yuyin Liu, Meixi Liu, Qiu Chen
Protein kinase C (PKC) isozymes play critical roles in diverse cellular processes and are implicated in numerous diseases, including cancer, diabetes, and autoimmune disorders. Despite extensive research efforts spanning four decades, only one PKC inhibitor has received clinical approval, highlighting the challenges in developing selective and efficacious PKC-targeting therapeutics. Here we review recent advances in the development of small-molecule PKC inhibitors, focusing on structural design strategies, pharmacological activities, and structure-activity relationships. We analyze emerging approaches including fragment-based drug design, allosteric targeting, and natural product derivatization that have yielded promising new scaffold classes. Special attention is given to innovations in achieving isozyme selectivity, particularly for PKCα and PKCβ, which have proven crucial for therapeutic applications. We discuss how integration of computational methods, structural biology insights, and rational design principles has advanced our understanding of PKC inhibition mechanisms. This comprehensive analysis reveals key challenges in PKC drug development, including the need for enhanced selectivity and reduced off-target effects, while highlighting promising directions for future therapeutic development. Our findings provide a framework for designing next-generation PKC inhibitors with improved clinical potential.
{"title":"Recent advances in PKC inhibitor development: Structural design strategies and therapeutic applications","authors":"Wen Li, Kun Zhu, Yuyin Liu, Meixi Liu, Qiu Chen","doi":"10.1016/j.ejmech.2025.117290","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117290","url":null,"abstract":"Protein kinase C (PKC) isozymes play critical roles in diverse cellular processes and are implicated in numerous diseases, including cancer, diabetes, and autoimmune disorders. Despite extensive research efforts spanning four decades, only one PKC inhibitor has received clinical approval, highlighting the challenges in developing selective and efficacious PKC-targeting therapeutics. Here we review recent advances in the development of small-molecule PKC inhibitors, focusing on structural design strategies, pharmacological activities, and structure-activity relationships. We analyze emerging approaches including fragment-based drug design, allosteric targeting, and natural product derivatization that have yielded promising new scaffold classes. Special attention is given to innovations in achieving isozyme selectivity, particularly for PKCα and PKCβ, which have proven crucial for therapeutic applications. We discuss how integration of computational methods, structural biology insights, and rational design principles has advanced our understanding of PKC inhibition mechanisms. This comprehensive analysis reveals key challenges in PKC drug development, including the need for enhanced selectivity and reduced off-target effects, while highlighting promising directions for future therapeutic development. Our findings provide a framework for designing next-generation PKC inhibitors with improved clinical potential.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"109 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026997","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}
RET is a well-recognized drug target for cancer treatment. Despite the promising efficacy of selective second-generation RET inhibitors Selpercatinib and Pralsetinib, the clinical benefits have been compromised due to the quickly developed resistance to these drugs. RET G810 mutations at the solvent front site have been identified as the major on-target mutations contributing to resistance against Selpercatinib and Pralsetinib. Therefore, there is an urgent need for the development of next-generation RET inhibitors to overcome acquired solvent-front resistance mutations. In this study, a series of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives have been identified as selective next-generation RET inhibitors. The representative compound, CQ1373 exhibits potent cellular potency with IC50 values of 13.0, 25.7 and 28.4 nM against BaF3 cells expressing CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R, respectively. A comprehensive selectivity profile across 89 kinases reveals that CQ1373 demonstrates good selectivity toward wild-type RET and solvent front mutants G810C/R with IC50 values of 4.2, 7.1 and 32.4 nM, respectively. Furthermore, western blot analysis reveals that CQ1373 effectively inhibits RET phosphorylation and downstream signaling through SHC. It also induces apoptosis and cell cycle arrest in a dose-dependent manner in BaF3 cells harboring CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R fusions. More significantly, CQ1373 exhibits promising in vivo anti-tumor efficacy in a CCDC6-RET-G810R mice xenograft model, highlighting its potentials for RET-driven cancers treatment.
{"title":"Design, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R)","authors":"Mingjin Xu, Kaifu Wu, Rui He, Jiahuan He, Gangpeng Yang, Haowen Ma, Lijie Peng, Shuyao Zhang, Li Tan, Zhang Zhang, Qian Cai","doi":"10.1016/j.ejmech.2025.117294","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117294","url":null,"abstract":"RET is a well-recognized drug target for cancer treatment. Despite the promising efficacy of selective second-generation RET inhibitors Selpercatinib and Pralsetinib, the clinical benefits have been compromised due to the quickly developed resistance to these drugs. RET G810 mutations at the solvent front site have been identified as the major on-target mutations contributing to resistance against Selpercatinib and Pralsetinib. Therefore, there is an urgent need for the development of next-generation RET inhibitors to overcome acquired solvent-front resistance mutations. In this study, a series of (<em>E</em>)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives have been identified as selective next-generation RET inhibitors. The representative compound, CQ1373 exhibits potent cellular potency with IC<sub>50</sub> values of 13.0, 25.7 and 28.4 nM against BaF3 cells expressing CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R, respectively. A comprehensive selectivity profile across 89 kinases reveals that CQ1373 demonstrates good selectivity toward wild-type RET and solvent front mutants G810C/R with IC<sub>50</sub> values of 4.2, 7.1 and 32.4 nM, respectively. Furthermore, western blot analysis reveals that CQ1373 effectively inhibits RET phosphorylation and downstream signaling through SHC. It also induces apoptosis and cell cycle arrest in a dose-dependent manner in BaF3 cells harboring CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R fusions. More significantly, CQ1373 exhibits promising <em>in vivo</em> anti-tumor efficacy in a CCDC6-RET-G810R mice xenograft model, highlighting its potentials for RET-driven cancers treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026984","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}
Acetylcholinesterase (AChE) is a pivotal enzyme in nerve conduction, controlling its activity with its inhibitor (AChEI) is crucial for the treatment of Alzheimer's disease (AD). However, current AChEIs are associated with considerable adverse effects. Previous work has identified 2α,3β,19α,23-tetrahydroxy-12-ene-28-oic acid (RLMS) as a promising natural AChEI. This study synthesized three novel series of AChEIs to elucidate the interaction mechanisms between the title enzyme and RLMS. Among the compounds, 1 and 22 emerged as the most potent and selective inhibitors exhibiting both irreversible and mixed competitive inhibition types against AChE. Molecular docking studies at the AChE active sites revealed binding modes that justify its potent enzyme inhibitory effects. Additionally, molecular dynamic simulations demonstrated robust and stable interactions of 1 and 22 with the binding sites of their target. In vitro assays showed derivates, especially 22, exhibited potential neuroprotective activities on H2O2-induced SH-SY5Y cell injury model. In vivo experiments showed that zebrafish models of AD treated with varying concentrations of 22 displayed obviously increased movement distance and speed, notably, at 25 μM level, 22 effectively reduced apoptosis in zebrafish brain cells. Collectively, this research delineates the intricate relationship between AChE and 22, suggesting its potential as a therapeutic agent for combating AD.
{"title":"Design and synthesis three novel series of derivatives using natural acetylcholinesterase inhibitor-RLMS as template and in vitro, in vivo and in silico activities verification","authors":"Fang He, Yongdan Guo, Xin Shen, Lingzhi Li, Danqi Li, Xuegui Liu, Pinyi Gao","doi":"10.1016/j.ejmech.2025.117309","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117309","url":null,"abstract":"Acetylcholinesterase (AChE) is a pivotal enzyme in nerve conduction, controlling its activity with its inhibitor (AChEI) is crucial for the treatment of Alzheimer's disease (AD). However, current AChEIs are associated with considerable adverse effects. Previous work has identified 2α,3β,19α,23-tetrahydroxy-12-ene-28-oic acid (RLMS) as a promising natural AChEI. This study synthesized three novel series of AChEIs to elucidate the interaction mechanisms between the title enzyme and RLMS. Among the compounds, <strong>1</strong> and <strong>22</strong> emerged as the most potent and selective inhibitors exhibiting both irreversible and mixed competitive inhibition types against AChE. Molecular docking studies at the AChE active sites revealed binding modes that justify its potent enzyme inhibitory effects. Additionally, molecular dynamic simulations demonstrated robust and stable interactions of <strong>1</strong> and <strong>22</strong> with the binding sites of their target. <em>In vitro</em> assays showed derivates, especially <strong>22</strong>, exhibited potential neuroprotective activities on H<sub>2</sub>O<sub>2</sub>-induced SH-SY5Y cell injury model. <em>In vivo</em> experiments showed that zebrafish models of AD treated with varying concentrations of <strong>22</strong> displayed obviously increased movement distance and speed, notably, at 25 <em>μ</em>M level, <strong>22</strong> effectively reduced apoptosis in zebrafish brain cells. Collectively, this research delineates the intricate relationship between AChE and <strong>22</strong>, suggesting its potential as a therapeutic agent for combating AD.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"105 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020044","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 : 2025-01-23DOI: 10.1016/j.ejmech.2025.117314
Wen-Bo Liu, Wei-Guang Yang, Ji Wu, Bing-Bing Chen, Yi-Fei Du, Jin-Bo Niu, Jian Song, Sai-Yang Zhang
Based on the molecular hybridization strategy, novel thienopyridine indole derivatives were designed and synthesized as tubulin polymerization inhibitors, and the in vitro antiproliferative potency on MGC-803, KYSE450 and HCT-116 cells was evaluated. Among them, compound 20b showed a broad-spectrum antiproliferative activity against 11 cancer cell lines, with IC50 values below 4 nmol/L. Notably, it demonstrated exceptional efficacy against MGC-803 (IC50 = 1.61 nmol/L) and HGC-27 (IC50 = 1.82 nmol/L) cells. Further mechanism explorations suggested that compound 20b could inhibit tubulin polymerization (IC50 = 2.505 μmol/L) by acting on the colchicine binding site, thereby disrupting intracellular microtubule networks and interfering with cell mitosis. In addition, compound 20b effectively inhibited the colony formation and cell migration activities, and induced G2/M phase cycle arrest and apoptosis in MGC-803 and HGC-27 cells. Besides, compound 20b also displayed potent anti-angiogenesis effects on HUVECs. Importantly, compound 20b demonstrated oral efficacy in inhibiting tumor growth with a TGI of 45.8% (5 mg/Kg/qod) in the mouse xenograft model bearing MGC-803 cells, surpassing that of CA-4 (TGI of 27.1% at 20 mg/Kg/qod), as well as also exhibited a good safety profile. Therefore, these results suggested that the thienopyridine indole derivative 20b represents a novel tubulin inhibitor with potent anticancer efficacy that inhibits gastric cancers.
{"title":"Discovery of novel thienopyridine indole derivatives as inhibitors of tubulin polymerization targeting the colchicine-binding site with potent anticancer activities","authors":"Wen-Bo Liu, Wei-Guang Yang, Ji Wu, Bing-Bing Chen, Yi-Fei Du, Jin-Bo Niu, Jian Song, Sai-Yang Zhang","doi":"10.1016/j.ejmech.2025.117314","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117314","url":null,"abstract":"Based on the molecular hybridization strategy, novel thienopyridine indole derivatives were designed and synthesized as tubulin polymerization inhibitors, and the <em>in vitro</em> antiproliferative potency on MGC-803, KYSE450 and HCT-116 cells was evaluated. Among them, compound <strong>20b</strong> showed a broad-spectrum antiproliferative activity against 11 cancer cell lines, with IC<sub>50</sub> values below 4 nmol/L. Notably, it demonstrated exceptional efficacy against MGC-803 (IC<sub>50</sub> = 1.61 nmol/L) and HGC-27 (IC<sub>50</sub> = 1.82 nmol/L) cells. Further mechanism explorations suggested that compound <strong>20b</strong> could inhibit tubulin polymerization (IC<sub>50</sub> = 2.505 μmol/L) by acting on the colchicine binding site, thereby disrupting intracellular microtubule networks and interfering with cell mitosis. In addition, compound <strong>20b</strong> effectively inhibited the colony formation and cell migration activities, and induced G2/M phase cycle arrest and apoptosis in MGC-803 and HGC-27 cells. Besides, compound <strong>20b</strong> also displayed potent anti-angiogenesis effects on HUVECs. Importantly, compound <strong>20b</strong> demonstrated oral efficacy in inhibiting tumor growth with a TGI of 45.8% (5 mg/Kg/qod) in the mouse xenograft model bearing MGC-803 cells, surpassing that of CA-4 (TGI of 27.1% at 20 mg/Kg/qod), as well as also exhibited a good safety profile. Therefore, these results suggested that the thienopyridine indole derivative <strong>20b</strong> represents a novel tubulin inhibitor with potent anticancer efficacy that inhibits gastric cancers.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"109 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026987","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}
De novo design of antimicrobial peptides is a pivotal strategy for developing new antibacterial agents, leveraging its rapid and efficient nature. (XXYY)n, where X represents cationic residues, Y denotes hydrophobic residues, and n varies from 2 to 4, is a classical α-helix template. Based on which, numerous antimicrobial peptides have been synthesized. Herein, we hypothesize that the amphipathy of this type of α-helix template can be further enhanced based on the principles of α-helical protein folding, characterized by a rotation occurring every 3.6 amino acid residues, and propose the highly amphipathic template XXYYXXYXXYYX (where X represents cationic residues and Y denotes hydrophobic residues). Accordingly, the amino acid composition and arrangement of the α-helix peptide (RRWF)3 are adjusted, yielding the highly amphipathic counterpart H-R (RRWFRRWRRWFR). The structure-activity relationship of which is further explored through the substitution of residues at positions 8 and 12. Notably, the highly amphipathic peptides exhibit enhanced antimicrobial activity and reduced hemolytic toxicity compared to (RRWF)3, resulting in superior bacterial selectivity. The most highly amphipathic peptide, H-R, demonstrates potent activity against biofilms and multidrug-resistant bacteria, low propensity for resistance, and high safety and effectiveness in vivo. The antibacterial mechanisms of H-R are also preliminarily investigated in this study. As noted, H-R represents promising antimicrobial candidates for addressing infections associated with drug-resistant bacteria.
{"title":"Rationally Designed Highly Amphipathic Antimicrobial Peptides Demonstrating Superior Bacterial Selectivity Relative to the Corresponding α-Helix Peptide","authors":"Jingying Zhang, Anqi Chu, Xu Ouyang, Beibei Li, Ping Yang, Zufang Ba, Yinyin Yang, Wenbo Mao, Chao Zhong, Sanhu Gou, Yun Zhang, Hui Liu, Jingman Ni","doi":"10.1016/j.ejmech.2025.117310","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117310","url":null,"abstract":"De novo design of antimicrobial peptides is a pivotal strategy for developing new antibacterial agents, leveraging its rapid and efficient nature. (XXYY)<sub>n</sub>, where X represents cationic residues, Y denotes hydrophobic residues, and n varies from 2 to 4, is a classical <em>α</em>-helix template. Based on which, numerous antimicrobial peptides have been synthesized. Herein, we hypothesize that the amphipathy of this type of <em>α</em>-helix template can be further enhanced based on the principles of <em>α</em>-helical protein folding, characterized by a rotation occurring every 3.6 amino acid residues, and propose the highly amphipathic template XXYYXXYXXYYX (where X represents cationic residues and Y denotes hydrophobic residues). Accordingly, the amino acid composition and arrangement of the <em>α</em>-helix peptide (RRWF)<sub>3</sub> are adjusted, yielding the highly amphipathic counterpart H-R (RRWFRRWRRWFR). The structure-activity relationship of which is further explored through the substitution of residues at positions 8 and 12. Notably, the highly amphipathic peptides exhibit enhanced antimicrobial activity and reduced hemolytic toxicity compared to (RRWF)<sub>3</sub>, resulting in superior bacterial selectivity. The most highly amphipathic peptide, H-R, demonstrates potent activity against biofilms and multidrug-resistant bacteria, low propensity for resistance, and high safety and effectiveness in vivo. The antibacterial mechanisms of H-R are also preliminarily investigated in this study. As noted, H-R represents promising antimicrobial candidates for addressing infections associated with drug-resistant bacteria.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"19 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020285","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 : 2025-01-21DOI: 10.1016/j.ejmech.2025.117304
Sara Stocchetti, Ján Vančo, Giulio Bresciani, Lorenzo Biancalana, Jan Belza, Stefano Zacchini, , Sara Benetti, Tarita Biver, Marco Bortoluzzi, Zdeněk Trávníček, Fabio Marchetti
The novel diiron amine complexes [Fe2Cp2(CO)(NH2R')(μ-CO){μ-CN(Me)(Cy)}]CF3SO3 [R' = H, 3; Cy, 4; CH2CH2NH2, 5; CH2CH2NMe2, 6; CH2CH2(4-C6H4OMe), 7; CH2CH2(4-C6H4OH), 8; Cp = η5-C5H5, Cy = C6H11 = cyclohexyl] were synthesized in 49-92% yields from [Fe2Cp2(CO)2(μ-CO){μ-CN(Me)(Cy)}]CF3SO3, 1a, using a straightforward two-step procedure. They were characterized by IR and multinuclear NMR spectroscopy, and the structure of 7 was confirmed through X-ray diffraction analysis. Complexes 3-8 and the acetonitrile adducts [Fe2Cp2(CO)(NCMe)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (R = Cy, 2a; Me, 2b; Xyl = 2,6-C6H3Me2, 2c) were assessed for their water solubility, octanol-water partition coefficient and stability in physiological-like solutions. The in vitro antiproliferative activity of 2a-c and 3-8 was tested on seven human cancer cell lines (A2780, A2780R, PC3, A549, MCF7, HOS and HT-29), while the selectivity was evaluated using normal MRC-5 cells. Overall, the complexes exhibited variable cytotoxicity, with IC50 values reaching the low micromolar range for 3, 7 and 8 in A2780 and A2780R cells, along with significant selectivity. Targeted experiments covered cell cycle modification, induction of cell death, mitochondrial membrane potential, ROS production and interaction with DNA and bovine serum albumin (BSA) as a model protein. The interaction of 3 with BSA was further investigated through computational studies. Results showed a negligible increase in intracellular ROS levels (except for 2b) and insignificant changes in mitochondrial membrane potential.
{"title":"Anticancer Diiron Aminocarbyne Complexes with Labile N-Donor Ligands","authors":"Sara Stocchetti, Ján Vančo, Giulio Bresciani, Lorenzo Biancalana, Jan Belza, Stefano Zacchini, , Sara Benetti, Tarita Biver, Marco Bortoluzzi, Zdeněk Trávníček, Fabio Marchetti","doi":"10.1016/j.ejmech.2025.117304","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117304","url":null,"abstract":"The novel diiron amine complexes [Fe<sub>2</sub>Cp<sub>2</sub>(CO)(NH<sub>2</sub>R')(μ-CO){μ-CN(Me)(Cy)}]CF<sub>3</sub>SO<sub>3</sub> [R' = H, <strong>3</strong>; Cy, <strong>4</strong>; CH<sub>2</sub>CH<sub>2</sub>NH<sub>2</sub>, <strong>5</strong>; CH<sub>2</sub>CH<sub>2</sub>NMe<sub>2</sub>, <strong>6</strong>; CH<sub>2</sub>CH<sub>2</sub>(4-C<sub>6</sub>H<sub>4</sub>OMe), <strong>7</strong>; CH<sub>2</sub>CH<sub>2</sub>(4-C<sub>6</sub>H<sub>4</sub>OH), <strong>8</strong>; Cp = η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>, Cy = C<sub>6</sub>H<sub>11</sub> = cyclohexyl] were synthesized in 49-92% yields from [Fe<sub>2</sub>Cp<sub>2</sub>(CO)<sub>2</sub>(μ-CO){μ-CN(Me)(Cy)}]CF<sub>3</sub>SO<sub>3</sub>, <strong>1a</strong>, using a straightforward two-step procedure. They were characterized by IR and multinuclear NMR spectroscopy, and the structure of <strong>7</strong> was confirmed through X-ray diffraction analysis. Complexes <strong>3-8</strong> and the acetonitrile adducts [Fe<sub>2</sub>Cp<sub>2</sub>(CO)(NCMe)(μ-CO){μ-CN(Me)(R)}]CF<sub>3</sub>SO<sub>3</sub> (R = Cy, <strong>2a</strong>; Me, <strong>2b</strong>; Xyl = 2,6-C<sub>6</sub>H<sub>3</sub>Me<sub>2</sub>, <strong>2c</strong>) were assessed for their water solubility, octanol-water partition coefficient and stability in physiological-like solutions. The <em>in vitro</em> antiproliferative activity of <strong>2a-c</strong> and <strong>3-8</strong> was tested on seven human cancer cell lines (A2780, A2780R, PC3, A549, MCF7, HOS and HT-29), while the selectivity was evaluated using normal MRC-5 cells. Overall, the complexes exhibited variable cytotoxicity, with IC<sub>50</sub> values reaching the low micromolar range for <strong>3</strong>, <strong>7</strong> and <strong>8</strong> in A2780 and A2780R cells, along with significant selectivity. Targeted experiments covered cell cycle modification, induction of cell death, mitochondrial membrane potential, ROS production and interaction with DNA and bovine serum albumin (BSA) as a model protein. The interaction of <strong>3</strong> with BSA was further investigated through computational studies. Results showed a negligible increase in intracellular ROS levels (except for 2b) and insignificant changes in mitochondrial membrane potential.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"62 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991931","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 : 2025-01-21DOI: 10.1016/j.ejmech.2025.117302
Enrico Marcantonio, Debora Guazzetti, Crescenzo Coppa, Lucia Battistini, Andrea Sartori, Kelly Bugatti, Becky Provinciael, Claudio Curti, Alessandro Contini, Kurt Vermeire, Franca Zanardi
The recurrent global exposure to highly challenging viral epidemics, and the still limited spectrum of effective pharmacological options step on the accelerator towards the development of new antiviral medicines. In this work we explored the anti-SARS-CoV-2 potential of a recently launched chiral ring system based on the uracil scaffold fused to carbocycle rings. The asymmetric synthesis of two generations of chiral uracil-based compounds (overall 31 different products), and their in vitro cytotoxicity and antiviral screening against wild-type SARS-CoV-2 in U87.ACE cells allowed us to identify seven non-cytotoxic enantioenriched derivatives exhibiting in vitro EC50 in the 6-37 μM range. Among these compounds, bicyclic uracil 10 showed the best antiviral potency against SARS-CoV-2 (EC50 20A.EU2 = 7.41 μM and EC50 Omicron = 19.4 μM), combined with a favourable selectivity index. Additionally, it exhibited single-digit micromolar inhibition of the isolated SARS-CoV-2 RNA-dependent RNA polymerase (IC50 = 2.1 μM). Starting from a reported cryo-EM structure of RdRp, docking and molecular dynamics simulations were performed to rationalize possible binding modes of the active compounds. Interestingly, no inhibition of viral replication in cells was observed against a wide spectrum of human viruses, while some derivatives, and especially hit compound 10, exhibited specific low micromolar antiviral effect against β-coronavirus OC43. Collectively, these data indicate that this novel uracil-based ring system represent a valid starting point for further development of a new class of RdRp inhibitors to treat SARS-CoV-2 and, potentially, other β-coronavirus infections.
{"title":"The Chiral 5,6-Cyclohexane-fused Uracil Ring-System: a Molecular Platform with Promising Activity against SARS-CoV-2","authors":"Enrico Marcantonio, Debora Guazzetti, Crescenzo Coppa, Lucia Battistini, Andrea Sartori, Kelly Bugatti, Becky Provinciael, Claudio Curti, Alessandro Contini, Kurt Vermeire, Franca Zanardi","doi":"10.1016/j.ejmech.2025.117302","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117302","url":null,"abstract":"The recurrent global exposure to highly challenging viral epidemics, and the still limited spectrum of effective pharmacological options step on the accelerator towards the development of new antiviral medicines. In this work we explored the anti-SARS-CoV-2 potential of a recently launched chiral ring system based on the uracil scaffold fused to carbocycle rings. The asymmetric synthesis of two generations of chiral uracil-based compounds (overall 31 different products), and their <em>in vitro</em> cytotoxicity and antiviral screening against wild-type SARS-CoV-2 in U87.ACE cells allowed us to identify seven non-cytotoxic enantioenriched derivatives exhibiting <em>in vitro</em> EC<sub>50</sub> in the 6-37 μM range. Among these compounds, bicyclic uracil <strong>10</strong> showed the best antiviral potency against SARS-CoV-2 (EC<sub>50</sub> 20A.EU2 = 7.41 μM and EC<sub>50</sub> Omicron = 19.4 μM), combined with a favourable selectivity index. Additionally, it exhibited single-digit micromolar inhibition of the isolated SARS-CoV-2 RNA-dependent RNA polymerase (IC<sub>50</sub> = 2.1 μM). Starting from a reported cryo-EM structure of RdRp, docking and molecular dynamics simulations were performed to rationalize possible binding modes of the active compounds. Interestingly, no inhibition of viral replication in cells was observed against a wide spectrum of human viruses, while some derivatives, and especially hit compound <strong>10</strong>, exhibited specific low micromolar antiviral effect against β-coronavirus OC43. Collectively, these data indicate that this novel uracil-based ring system represent a valid starting point for further development of a new class of RdRp inhibitors to treat SARS-CoV-2 and, potentially, other β-coronavirus infections.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991071","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 : 2025-01-21DOI: 10.1016/j.ejmech.2025.117306
Ke Kang, You Wu, Xi Zhang, Shuqi Wang, Shaokai Ni, Jiaan Shao, Yushen Du, Yongping Yu, Yong Shen, Yiding Chen, Wenteng Chen
Organelle-localized photosensitizers have been well-developed to enhance the photodynamic therapy (PDT) efficacy through triggering given cell death. The endoplasmic reticulum (ER) and lipid droplets (LDs) are two key organelles mutually regulating ferroptosis. Thus, in this study, small molecular photosensitizer CAR PSs were developed through fragment integration strategy and the heavy-atom modification. It was showed that the integration strategy did not affect the organelle localization and CAR PSs successfully achieved ER/LDs dual location. Besides, the heavy-atom modification help CAR PSs display good ROS generation efficiency. Importantly, ER/LDs dual-localized CAR PSs exhibited superior photo-toxicity and lower dark-toxicity against multiple breast cancer cell lines than the only ER-targeting Ce6, which further explained the superposition effect of dual organelle targeting. Preliminary studies revealed that CAR PSs induced enhanced ferroptosis via simultaneously triggering the ER stress and lipid peroxidation during PDT. Moreover, CAR-2 demonstrated significant in vivo PDT activity to suppress the tumor growth in 4T1 tumor bearing mice. These findings not only provide a promising photosensitizer CAR-2 exerting excellent in vitro and in vivo PDT effect through stimulating ferroptosis, but also propose a design strategy for the development of ER/LDs dual localized PSs.
{"title":"An Endoplasmic Reticulum and Lipid Droplets Dual-localized Strategy to Develop Small Molecular Photosensitizers that Induce Ferroptosis during Photodynamic Therapy","authors":"Ke Kang, You Wu, Xi Zhang, Shuqi Wang, Shaokai Ni, Jiaan Shao, Yushen Du, Yongping Yu, Yong Shen, Yiding Chen, Wenteng Chen","doi":"10.1016/j.ejmech.2025.117306","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117306","url":null,"abstract":"Organelle-localized photosensitizers have been well-developed to enhance the photodynamic therapy (PDT) efficacy through triggering given cell death. The endoplasmic reticulum (ER) and lipid droplets (LDs) are two key organelles mutually regulating ferroptosis. Thus, in this study, small molecular photosensitizer <strong>CAR PSs</strong> were developed through fragment integration strategy and the heavy-atom modification. It was showed that the integration strategy did not affect the organelle localization and <strong>CAR PSs</strong> successfully achieved ER/LDs dual location. Besides, the heavy-atom modification help <strong>CAR PSs</strong> display good ROS generation efficiency. Importantly, ER/LDs dual-localized <strong>CAR PSs</strong> exhibited superior photo-toxicity and lower dark-toxicity against multiple breast cancer cell lines than the only ER-targeting <strong>Ce6</strong>, which further explained the superposition effect of dual organelle targeting. Preliminary studies revealed that <strong>CAR PSs</strong> induced enhanced ferroptosis <em>via</em> simultaneously triggering the ER stress and lipid peroxidation during PDT. Moreover, <strong>CAR-2</strong> demonstrated significant <em>in vivo</em> PDT activity to suppress the tumor growth in 4T1 tumor bearing mice. These findings not only provide a promising photosensitizer <strong>CAR-2</strong> exerting excellent <em>in vitro</em> and <em>in vivo</em> PDT effect through stimulating ferroptosis, but also propose a design strategy for the development of ER/LDs dual localized PSs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991929","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 severe impact of COVID-19 on global health and economies highlights the critical need for innovative treatments. Recently, lapatinib, a drug initially used for breast cancer, has been identified as a potential inhibitor of the main protease (Mpro) of SARS-CoV-2, meriting further investigation. Utilizing rational design strategies and guided by MD simulations, we developed novel aminoquinazoline analogs based on fragmented lapatinib's structure. Preliminary computational screenings identified promising candidates, which were synthesized using a concise 3-4 step process. In vitro assays demonstrated notable antiviral efficacy against SARS-CoV-2-infected cells for all analogs, with Bb1 showing an EC50 of 1.10 μM and significantly lower toxicity (13.55% at 50 μM) compared to lapatinib. Further studies confirmed that these analogs effectively inhibit SARS-CoV-2 Mpro, with Bb7 displaying the highest activity. MD simulations revealed that Bb7 achieves stability within the Mpro binding pocket through interactions with specific residues. These findings indicate that aminoquinazoline analogs hold significant promise as therapeutic candidates for COVID-19.
{"title":"Design, Synthesis, and Antiviral Activity of Fragmented-Lapatinib Aminoquinazoline Analogs towards SARS-CoV-2 Inhibition","authors":"Ayomide Adediji, Akeanan Sroithongmoon, Aphinya Suroengrit, Patcharin Wilasluck, Peerapon Deetanya, Kamonpan Sanachai, Kun Karnchanapandh, Siwaporn Boonyasuppayakorn, Kittikhun Wangkanont, Thanyada Rungrotmongkol, Tanatorn Khotavivattana","doi":"10.1016/j.ejmech.2025.117303","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117303","url":null,"abstract":"The severe impact of COVID-19 on global health and economies highlights the critical need for innovative treatments. Recently, lapatinib, a drug initially used for breast cancer, has been identified as a potential inhibitor of the main protease (Mpro) of SARS-CoV-2, meriting further investigation. Utilizing rational design strategies and guided by MD simulations, we developed novel aminoquinazoline analogs based on fragmented lapatinib's structure. Preliminary computational screenings identified promising candidates, which were synthesized using a concise 3-4 step process. In vitro assays demonstrated notable antiviral efficacy against SARS-CoV-2-infected cells for all analogs, with <strong>Bb1</strong> showing an EC<sub>50</sub> of 1.10 μM and significantly lower toxicity (13.55% at 50 μM) compared to lapatinib. Further studies confirmed that these analogs effectively inhibit SARS-CoV-2 Mpro, with <strong>Bb7</strong> displaying the highest activity. MD simulations revealed that <strong>Bb7</strong> achieves stability within the Mpro binding pocket through interactions with specific residues. These findings indicate that aminoquinazoline analogs hold significant promise as therapeutic candidates for COVID-19.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991073","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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