Chemical Biology & Drug Design最新文献

{"title":"Novel N9-Substituted 6-Cycloalkylaminoadenines as Promising Compounds Against Triple Negative Breast Cancer","authors":"Ana Catarina Pereira,&nbsp;Soraia P. Fernandes,&nbsp;Bruna Leite,&nbsp;Rafael Vieira,&nbsp;Cátia Santos-Pereira,&nbsp;Débora Ferreira,&nbsp;Sérgio F. Sousa,&nbsp;Alice Dias,&nbsp;Lígia Rodrigues","doi":"10.1111/cbdd.70336","DOIUrl":"10.1111/cbdd.70336","url":null,"abstract":"<div>\u0000 \u0000 <p>Triple negative breast cancer (TNBC) accounts for 15% of breast cancers, exhibiting high proliferation and resistance to conventional treatments, highlighting the need for innovative therapies. Purine derivatives are recognised for their anticancer potential, making them valuable candidates for drug development. In the present study, we sought to uncover the anticancer potential of novel 6-cycloalkylaminoadenine compounds and elucidate their mechanism of action. A versatile synthetic pathway was developed to prepare two series of new 6-cycloalkylaminoadenines that combine the adenine scaffold with morpholino and <i>N</i>-methylpiperazine units. The method starts with the preparation of imidazole-based amidrazone precursors, which were obtained from 5-amino-4-cyanoformimidoylimidazoles and 4-aminomorpholine or 4-methylaminopiperazine. The reaction of these amidrazone precursors with triethyl orthoformate under reflux gave the target 6-cycloalkylaminoadenines. The compounds' cytotoxicity on the TNBC cell line MDA-MB-231 was assessed, with the best IC₅₀ values around 60–70 μM. The most promising compound, <b>3.2a</b>, inhibits the migratory and invasive capacities of TNBC cells and promotes actin cytoskeleton reorganisation. Additionally, this compound induces caspase-3 activation, which promotes DNA fragmentation and ultimately leads to cell death. Molecular docking studies with key proteins involved in major signalling pathways associated with cancer progression further revealed that compound <b>3.2a</b> has a higher affinity for CDK1. Altogether, our findings provide preliminary evidence supporting the potential of 6-cycloalkylaminoadenines in TNBC treatment.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148165926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Autophagy-Associated Molecular Signatures in Osteoarthritis Revealed by Integrative Multi-Omics and Experimental Validation","authors":"Xiaoqing Wang,&nbsp;Xingye Luo,&nbsp;Hong Li,&nbsp;Ting Li,&nbsp;Yanyuan Wang,&nbsp;Ruoer Li,&nbsp;Yufeng Qing,&nbsp;Quanbo Zhang","doi":"10.1111/cbdd.70315","DOIUrl":"10.1111/cbdd.70315","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;p&gt;Osteoarthritis (OA) is a complex degenerative disorder characterized by progressive joint deterioration and synovial dysfunction. Emerging evidence implicates autophagy as a key regulatory process in OA development; however, its molecular signatures, diagnostic value, and interaction with the synovial microenvironment remain incompletely defined. This study aimed to delineate autophagy-associated molecular signatures in OA and characterize their biological relevance across bulk and single-cell transcriptomic landscapes. An integrative analytical framework was applied to four synovial bulk transcriptome datasets (GSE55235, GSE12021, GSE55457, and GSE1919) and one single-cell RNA-sequencing dataset (GSE216651) obtained from the GEO database. Autophagy-related genes were curated from publicly available repositories and intersected with differentially expressed genes identified following batch-effect correction and data integration. Key autophagy-associated genes associated with OA were prioritized through weighted gene co-expression network analysis (WGCNA) combined with multiple machine learning algorithms. Diagnostic utility was assessed using receiver operating characteristic (ROC) analysis and nomogram modeling. Regulatory networks involving upstream microRNAs and transcription factors were inferred in silico. Immune landscape alterations were quantified using ssGSEA, while functional pathways were interrogated by single-gene GSEA. Experimental validation included RT-qPCR analysis in peripheral blood mononuclear cells (PBMCs), single-cell resolution mapping of cellular heterogeneity, and ELISA-based quantification of IL-6 with correlation to clinical parameters. Through integrative multi-omics and machine learning analyses, eight autophagy-associated hub genes (XIST, JUN, TNFAIP3, PPP1R15A, IL6, NAMPT, TRAF4, and MYC) were robustly identified as OA-associated molecular features. All candidates demonstrated satisfactory diagnostic performance (AUC &gt; 0.7), which was consistently reproduced in independent validation cohorts and experimental assays. Immune deconvolution revealed widespread alterations in synovial immune cell composition, with significant correlations observed between hub gene expression and nine immune cell populations. Single-cell transcriptomic profiling further uncovered distinct cell-type-specific expression patterns and highlighted intensified fibroblast–macrophage communication networks within OA synovium, suggesting their central involvement in disease progression. By integrating bulk and single-cell transcriptomic analyses with experimental validation, this study defines a set of autophagy-associated molecular markers with diagnostic relevance in osteoarthritis. The identified hub genes not only enhance the understanding of OA-related autophagy dysregulation but also represent potential targets for future mechanistic studies and translational intervention strategies. Importantly, these findings","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148152530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Peptide SS-31 Modulates Membrane Binding and Aggregation of α-Synuclein and Restores Impaired Mitochondrial Function","authors":"Ewelina Stefaniak,&nbsp;Beiyuan Cui,&nbsp;Xucheng Yan,&nbsp;Kexin Sun,&nbsp;Xiangyu Teng,&nbsp;Liming Ying","doi":"10.1111/cbdd.70332","DOIUrl":"10.1111/cbdd.70332","url":null,"abstract":"<p>Membrane binding and aggregation properties of α-synuclein are closely associated with Parkinson's disease and a class of related syndromes named as synucleinopathy. This study explored the potential of SS-31 (Elamipretide), a therapeutic tetrapeptide with alternating cationic and aromatic residues and known properties of mitochondrial inner membrane binding and oxidative stress reduction, in modulating α-synuclein interaction with the lipid membranes and mitigating the impairment of mitochondrial function induced by α-synuclein oligomers. It was demonstrated by both fluorescence correlation spectroscopy and fluorescence anisotropy that SS-31 displaces both wild-type and N-terminal acetylated α-synuclein from negatively charged small unilamellar vesicles in a dose-dependent manner. Thioflavin-T assay and transmission electron microscopy showed that SS-31 inhibits membrane-induced α-synuclein aggregation and alters the morphology of α-synuclein fibrils. Moreover, MTT assay and Seahorse Mito Stress Test indicated that SS-31 enhances cell viability and restores impaired mitochondrial function in α-synuclein oligomer-treated neuroblastoma cells. Finally, confocal imaging revealed that SS-31 hinders cellular uptake of α-synuclein oligomers, possibly by modifying cell membrane electrostatics. These findings suggest that SS-31 potentially attenuates α-synuclein induced mitochondrial impairment via its interaction with the lipid membranes, justifying further development of a peptide-based intervention against α-synuclein mediated pathology.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70332","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140153","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":"Investigating the Anticancer Promise of Synthesized Methylated N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides: Biological and Computational Characterization","authors":"Batool Al-lahowani,&nbsp;Tahrer AL-Bo Aswad,&nbsp;Rima Hajjo,&nbsp;Reem A. Islim,&nbsp;Sanaa K. Bardaweel,&nbsp;Kamal Sweidan,&nbsp;Swapnaa Balaji,&nbsp;Amit K. Tiwari,&nbsp;Ghassan Abushaikha,&nbsp;Dima A. Sabbah","doi":"10.1111/cbdd.70324","DOIUrl":"10.1111/cbdd.70324","url":null,"abstract":"<div>\u0000 \u0000 <p>Cancer is a multifaceted disease that places a significant burden on healthcare systems and economies, driving the urgent need for novel therapeutic agents to curb its prevalence and impact. Thirty-three analogues of <i>N</i>-substituted-7-and 8-methyl-4-hydroxy-2-quinolone-3-carboxamides were synthesized and characterized using FT-IR, NMR (¹H and ¹³C), HRMS, and elemental analysis. The analogues displayed potential cytotoxicity against human colon cancer (HCT-116) and epithelial colorectal adenocarcinoma (Caco-2) cells. Compounds bearing a phenyl ring tailored with <i>o</i>-CF₃ (<b>26</b>) and a phenyl ring substituted with <i>o</i>-COOH and <i>p</i>-CH₃ (<b>29</b>) exert preferential inhibitory activity against HCT-116 with IC_50s 9.4 and 7.8 μM. The bioinformatics calculations interpret the selectivity of analogues against HCT-116. The principal component analysis (PCA) discloses that the analogues are regarded as lead-like and nominated for hit-to-lead and lead optimization stages of drug discovery. Docking studies illustrate that analogues accommodate the kinase domain of PI3Kα and engage with key binding residues. The promising outcome of this work emphasizes the significance of this scaffold as anticancer agents.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Virtual Screening to Cell Phenotype: 4-Thiazolidone Scaffolds Targeting LOXL2 in Breast Cancer","authors":"Sandra Ferreira,&nbsp;Beatriz Santos,&nbsp;Matilde Tavares,&nbsp;Serhii Holota,&nbsp;Dmytro Khylyuk,&nbsp;Roman Lesyk,&nbsp;Natalia Finyuk,&nbsp;Daniel J. V. A. dos Santos,&nbsp;Ana M. Díaz-Lanza,&nbsp;João G. Costa,&nbsp;Nuno Saraiva,&nbsp;Ana S. Fernandes","doi":"10.1111/cbdd.70320","DOIUrl":"10.1111/cbdd.70320","url":null,"abstract":"<div>\u0000 \u0000 <p>Lysyl Oxidases (LOXs) catalyse elastin and collagen cross-linking in the extracellular matrix and have been implicated in cancer cell progression and metastases, particularly in breast cancer. In this study, we sought small-molecule inhibitors of LOXL2 using a library of 4-thiazolidones supported by molecular docking. Five candidates were prioritised, with Les 5740 displaying the highest LOXL2 inhibitory activity (IC₅₀ of 27 μM). Although Les 5740 showed low cytotoxicity in various cancer and normal-like cell lines, the triple-negative breast cancer (TNBC) cell line MDA-MB-231 showed increased susceptibility to this molecule. Les 5740 did not induce DNA damage in mammary cells. At 30 μM, it increased TNBC cells' necrosis. The impact of a non-toxic concentration of Les 5740 (5 μM) on TNBC cell motility was evaluated. Les 5740 reduced 2D chemoinvasion and altered cell morphology. These findings are consistent with a potential reduction in extracellular matrix stiffness as a consequence of LOXL2 inhibition. Les 5740 mildly inhibited tubulin polymerisation, supporting a multi-target profile. Overall, Les 5740 should be viewed as a starting scaffold with LOXL2 inhibitory activity and broader cellular effects, motivating optimisation toward more potent and selective LOXL2 inhibitors for breast cancer therapy.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148093700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148093893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148091997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148088467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148088319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}