RSC medicinal chemistry最新文献

{"title":"Development of small molecule inhibitors of ECM collagen secretion.","authors":"Ross S Mancini, Pierre-Antoine Bissey, Leonardo Massignan, Vaijinath Mane, Donald F Weaver, Kenneth W Yip, Fei-Fei Liu, Mark A Reed","doi":"10.1039/d5md00284b","DOIUrl":"https://doi.org/10.1039/d5md00284b","url":null,"abstract":"<p><p>Tissue fibrosis is a common consequence of many different acute and chronic injuries, which severely impairs the function of affected organs. A significant challenge is the lack of effective strategies to treat fibrotic disorders. The metabolic dysregulation underlying fibrosis may be reversed by the small molecule caffeic acid phenethyl ester (CAPE), but there are limitations which prevent its clinical use. Following the identification of caffeic acid derivative 1 from an in-house library screen, we performed structure-activity relationship studies which led to the discovery of novel small molecule inhibitors of extracellular matrix (ECM) collagen secretion. The small molecules increased PPARG and CD36 expression (markers of fatty acid metabolism), suggesting a mechanism of action involving a metabolic shift from fibrotic-to-normal state. The compounds identified in this study provide a foundation for further development towards a novel, first-in-class therapeutic agent for fibrosis.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12520001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting clathrin-mediated endocytosis: recent advances in inhibitor development, mechanistic insights, and therapeutic prospects.","authors":"Chao Zhang, Jialin Guo, Zixiao Liu, Xuhui Huang, Shiqi Dong, Chun Hu, Junhai Xiao","doi":"10.1039/d5md00650c","DOIUrl":"10.1039/d5md00650c","url":null,"abstract":"<p><p>Clathrin-mediated endocytosis (CME) is a critical pathway for cellular uptake of metabolites, hormones, and pathogens, including viruses. Recent advances in understanding CME mechanisms and developing inhibitors targeting key components (clathrin, dynamin, and HSC70) have opened therapeutic avenues for diseases, such as viral infections, cancer, and neurological disorders. This review comprehensively summarizes current CME inhibitors, including Pitstop, <b>Dynasore</b>, and <b>Dyngo-4a</b>, highlighting their mechanisms, structure-activity relationships (SARs), and limitations. Small molecules like <b>Pitstop 2</b> disrupt clathrin-terminal domain (TD) interactions, while dynamin inhibitors (<i>e.g.</i>, pthaladyns and quinodyns) target GTPase or pleckstrin homology (PH) domains to block vesicle fission. Despite progress, challenges remain: many inhibitors lack specificity, exhibit cytotoxicity, or possess unclear mechanisms. Novel strategies, such as peptide-based inhibitors (<i>e.g.</i>, Wbox2) and non-protonophoric analogs (<i>e.g.</i>, <b>ES9-17</b>), demonstrate improved precision. Future research must prioritize optimizing pharmacokinetics, reducing off-target effects, and exploiting emerging targets like endocytic accessory proteins (EAPs) to advance CME inhibitors toward clinical applications.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of two screens reveals a correlation between antiamoebic and anti-tubulin activities of phenothiazine and triphenylethylene derivatives.","authors":"Oleg Mediannikov, Philipp O Tsvetkov","doi":"10.1039/d5md00715a","DOIUrl":"10.1039/d5md00715a","url":null,"abstract":"<p><p><i>Naegleria fowleri</i> (<i>N.f.</i>), commonly referred to as the \"brain-eating amoeba\", is a free-living amoeboflagellate excavate capable to cause primary amoebic meningoencephalitis (PAM)-a rapidly progressing and typically fatal brain infection. Current treatment options are limited, poorly effective, and highly toxic, underscoring the urgent need for novel therapeutics. In this study, we explore the potential of repurposing FDA-approved microtubule-targeting agents (MTAs) for anti-<i>N.f.</i> therapy. By performing a comparative analysis of two large-scale drug screens-one assessing anti-amoebic activity and the other evaluating effects on tubulin polymerization-we identify strong correlations between microtubule disruption and amoebic growth inhibition. Notably, we highlight three major drug families (triphenylethylene, phenothiazine, and miconazole derivatives) and describe how their anti-amoebic effects relate to their MTA activity. In particular, triphenylethylene and phenothiazine compounds demonstrate a high positive correlation between tubulin polymerization inhibition and <i>N.f.</i> suppression, suggesting a shared molecular mechanism. Furthermore, we identify potent MTAs such as ebselen and auranofin-both capable of crossing the blood-brain barrier-as promising candidates for repurposing. These findings demonstrate the value of MTA-based screening in anti-amoebic drug discovery and point toward new therapeutic avenues for treating this devastating disease.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Emerging opportunities in the rewiring of biology through proximity inducing small molecules","authors":"Michael M. Hann","doi":"10.1039/D5MD90040A","DOIUrl":"10.1039/D5MD90040A","url":null,"abstract":"<p >Correction for ‘Emerging opportunities in the rewiring of biology through proximity inducing small molecules’ by Michael M. Hann, <em>RSC Med. Chem.</em>, 2025, https://doi.org/10.1039/d5md00608b.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 5097-5097"},"PeriodicalIF":3.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactive assessment of hexahydroquinoline derivatives prepared <i>via</i> a biochar/Fe₃O₄@APTMS magnetic catalyst: focus on antidiabetic and antibacterial properties.","authors":"A Thoume, I Nait Irahal, Z Dahib, A Chbel, Z Loukhmi, F Abdou-Allah, R Achagar, M Zertoubi, D Benmessaoud Left, N Bourhim, A Elmakssoudi","doi":"10.1039/d5md00594a","DOIUrl":"10.1039/d5md00594a","url":null,"abstract":"<p><p>This study aims to develop a green and effective magnetic catalyst, biochar/Fe₃O₄@APTMS, for the one-pot synthesis of bioactive hexahydroquinolines derivatives. Following synthesis, some biological activities were assessed including antibacterial activity and antidiabetic potential through polyol inhibition assays. The reaction involved four-component condensation of ammonium acetate, malononitrile or ethylcyanoacetate, dimedone (5,5-dimethyl-1,3-cyclohexanedione) and some aromatic aldehydes by refluxing in ethanol to afford products in high yields (91-97%) in a short time (10 minutes). Additionally, heterogeneous catalyst provides several advantages, including operational simplicity, rapid reaction times, easy product isolation, and recyclability of unreacted starting materials. The nano catalyst was fully characterized with Fourier Transform Infrared Spectroscopy (FT-IR), Raman, Field Emission Scanning Electron Microscopy (FE-SEM), and energy dispersive X-ray mapping (EDX-Map) while the characterization of the products with Nuclear magnetic resonance spectroscopy (¹³C NMR and ¹H NMR) confirmed their structure. Some of the compounds tested showed moderate but significant antidiabetic activity against aldose reductase (IC₅₀ values 4.03 to 18.29 μg mL^-1) and antibacterial activity against Gram-positive strains of bacteria, <i>Staphylococcus aureus</i> and <i>Enterococcus faecalis</i>, with inhibition zones up to 15.5 mm. These results showed promise for the compounds being used as dual-function therapeutic agents for diabetic complications and microbial infection.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The lignan compound matairesinol monoglucoside induces type I interferon production in HBV infection immunity by regulating STING signaling.","authors":"Mengxin Lin, Zhijun Su, Dawu Zeng, Jiangfu Liu, Minghui Zheng, Ruyi Guo","doi":"10.1039/d5md00468c","DOIUrl":"10.1039/d5md00468c","url":null,"abstract":"<p><strong>Background: </strong>the urgent need for effective prevention and treatment strategies for hepatitis B virus (HBV) has driven extensive research into natural compounds. This study aims to explore the therapeutic potential of matairesinol monoglucoside (MMG) in the treatment of HBV infection.</p><p><strong>Methods: </strong>primary hepatocytes and Kupffer cells were isolated from wild-type (WT) or stimulator of interferon genes (STING) knockout mice and subsequently infected with AAV-HBV to establish an <i>in vitro</i> anti-HBV assay model. The anti-HBV effects of MMG were assessed by measuring HBV DNA, HBsAg, and HBeAg levels, as well as using qRT-PCR and ELISA to evaluate type I interferon markers (IFN-α and IFN-β), and a luciferase assay. <i>In vivo</i> anti-HBV effects were determined by pre-treating mice with MMG prior to AAV-HBV infection.</p><p><strong>Results: </strong>MMG treatment significantly reduced the expression of HBV DNA, HBsAg, and HBeAg in both primary hepatocytes and Kupffer cells. Additionally, MMG enhanced the production of type I interferons (IFN-α and IFN-β) in both cell types. The knockout of STING diminished the effects of MMG on type I interferon production. Mechanistically, MMG was shown to modulate the STING-TBK1-IRF3 signaling axis, leading to increased IFN production.</p><p><strong>Conclusions: </strong>MMG shows promise as a potential therapeutic agent against HBV by targeting the STING signaling pathway.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclodextrin derivatives that exhibit <i>Enterococcus</i>-specific antibacterial properties through the accumulation of guanidino and indole groups.","authors":"Atsushi Miyagawa, Tetsuro Higashino, Hisato Kato, Kazufumi Masuda, Hatsuo Yamamura","doi":"10.1039/d5md00525f","DOIUrl":"10.1039/d5md00525f","url":null,"abstract":"<p><p>In light of the growing challenge posed by drug resistance, the focus of our research has been on the development of novel antibacterial substances. The approach involves the attachment of antibacterial functional groups to oligosaccharide, known as cyclodextrin, utilising antimicrobial peptides possessing hydrophobic groups and cationic groups as a model system. The cyclodextrin derivative, which contains seven pairs of indole rings and guanidino groups, was synthesised and exhibited potent antibacterial properties that were selective for <i>Enterococcus faecalis</i>. Conversely, a compound comprising a single set of functional groups was selectively antibacterial against <i>Staphylococcus aureus</i>. These were unique phenomena in that they were completely different from the peptides containing indole and guanidino groups and the previously reported antibacterial cyclodextrins modified with alkylamino groups that showed a broad antibacterial spectrum. The results will lead to the discovery of new chemical compounds (or functional groups) those will demonstrate specific antibacterial properties for pathogens and may be useful in the fields of cyclodextrin chemistry and development of antibacterial drugs and materials, particularly in the fight against multidrug-resistant pathogens.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging targeted kinase degradation as a novel therapeutic strategy for Alzheimer's disease.","authors":"Elisa Tassinari, Andrea Milelli","doi":"10.1039/d5md00681c","DOIUrl":"10.1039/d5md00681c","url":null,"abstract":"<p><p>Despite recent advances, Alzheimer's disease (AD) remains largely a mystery more than a century after its discovery. Protein kinases are among the new targets under investigation, which is not surprising given their crucial role in maintaining cellular homeostasis and in the development of various diseases. Several protein kinase inhibitors have shown remarkable therapeutic efficacy in the context of AD, although none of them have yet received approval by regulatory agencies. Alongside the use of classic inhibitors, a new therapeutic approach has emerged in recent years, shifting the focus from modulation to targeted degradation of the protein. The purpose of this review is to highlight and discuss novel series of proteolysis-targeting chimeras (PROTACs) directed against protein kinases relevant to the development of AD.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145293699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a first-in-class SLIT2 binder disrupting the SLIT2/ROBO1 axis <i>via</i> DNA-encoded library (DEL) screening.","authors":"Shaoren Yuan, Somaya A Abdel-Rahman, Nelson García Vázquez, Hossam Nada, Laura Calvo-Barreiro, Katarzyna Kuncewicz, Moustafa T Gabr","doi":"10.1039/d5md00555h","DOIUrl":"10.1039/d5md00555h","url":null,"abstract":"<p><p>The SLIT2/ROBO1 signaling axis plays a critical role in neural development, immune regulation, and tumor progression, including glioblastoma. However, small molecule inhibitors targeting this protein-protein interaction remain unexplored. Herein, we report the discovery and validation of DEL-S1, a first-in-class small molecule that binds to SLIT2 and disrupts its interaction with ROBO1. Using a DNA-encoded library (DEL) screen of 4.2 billion compounds, DEL-S1 was identified and confirmed to bind SLIT2 <i>via</i> temperature-related intensity change (TRIC) assay. Functional inhibition of the SLIT2/ROBO1 complex by DEL-S1 was demonstrated using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay, yielding an IC₅₀ of 68.8 ± 12.5 μM. Molecular docking and molecular dynamics (MD) simulations revealed key interaction hotspots at the SLIT2 binding interface and confirmed that DEL-S1 impairs SLIT2/ROBO1 complex formation by inducing conformational rearrangements. DEL-S1 exhibited favorable ADME properties, including satisfactory plasma and microsomal stability, low cytotoxicity, and minimal hERG liability. To facilitate structure-activity relationship (SAR) exploration, we designed and implemented a modular, one-pot synthetic route leveraging cyanuric chloride reactivity, enabling rapid derivatization of the triazine scaffold of DEL-S1. This strategy yielded structurally diverse analogs, including water-soluble carboxylate derivatives with preserved SLIT2/ROBO1 inhibitory activity. Together, this work establishes a novel chemical scaffold targeting SLIT2 and introduces a flexible synthetic platform to support further optimization toward therapeutic development.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-cancer analysis reveals HMOX1 as a cancer prognosis and immune infiltration-related biomarker.","authors":"Yingli Men, Hui Wang, Xiaoyan Xu, Miling Yang, Ruiting Feng, Jizhi Zhao, Ying Liu, Lu Yang, Yinsen Song, Cong Ding","doi":"10.1039/d5md00616c","DOIUrl":"10.1039/d5md00616c","url":null,"abstract":"<p><p>HMOX1 has gained increasing recognition across multiple malignancies; however, its precise oncogenic or tumor-suppressive roles remain incompletely defined. In this study, we comprehensively investigated HMOX1 across diverse tumor types utilizing the cancer genome atlas (TCGA). We further integrated data from multiple bioinformatics platforms, including TIMER2, UALCAN, GEPIA2, cBioPortal, R, GSCA, and LinkedOmics. Western blotting and quantitative real-time PCR (qRT-PCR) confirmed differential HMOX1 expression between normal renal epithelial cells and KIRC cells. Functional assays <i>in vitro</i> and <i>in vivo</i> demonstrated that HMOX1 regulates proliferation, migration, and cell-cycle progression in 786-O and Caki-1 cells. Pan-cancer analyses revealed that HMOX1 is aberrantly expressed across multiple malignancies with significant associations with the tumor stage. Survival analyses indicated that elevated HMOX1 expression predicted poor overall survival (OS) in LGG (<i>P</i> = 0.025) but favorable OS and disease-free survival (DFS) in KIRC (OS: <i>P</i> = 0.00062; DFS: <i>P</i> = 9 × 10^-4). Moreover, mutations were the predominant genetic alteration affecting HMOX1, while promoter methylation was broadly reduced across cancers. HMOX1 expression positively correlated with immune infiltration by CD8⁺ T cells (KIRC: Spearman <i>ρ</i> = 0.26, FDR = 2.56 × 10^-8) and macrophages (KIRC: Spearman <i>ρ</i> = 0.32, FDR = 2.77 × 10^-13). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses in KIRC implicated HMOX1 in the chemokine and NF-κB signaling pathways. Both <i>in vitro</i> and <i>in vivo</i> experiments demonstrated that HMOX1 knockdown accelerates cell-cycle progression and enhances proliferation and migration in 786-O and Caki-1 cells. Collectively, our findings establish HMOX1 as a promising prognostic biomarker and potential immunotherapeutic target across multiple cancers.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}