Bioorganic & Medicinal Chemistry最新文献

Mechanistic study of plasmid DNA delivery by Magainin 2-derived stapled peptides

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-26 DOI: 10.1016/j.bmc.2025.118176

Motoharu Hirano , Yuki Takechi-Haraya , Yasuhiro Abe , Takashi Misawa , Norihito Shibata , Yoji Sato , Yosuke Demizu

{"title":"Mechanistic study of plasmid DNA delivery by Magainin 2-derived stapled peptides","authors":"Motoharu Hirano , Yuki Takechi-Haraya , Yasuhiro Abe , Takashi Misawa , Norihito Shibata , Yoji Sato , Yosuke Demizu","doi":"10.1016/j.bmc.2025.118176","DOIUrl":"10.1016/j.bmc.2025.118176","url":null,"abstract":"<div><div>In this study, the mechanism of the plasmid DNA (pDNA) delivery system using Magainin 2-derived stapled peptides (<strong>st7-5</strong> and <strong>st7-5_R</strong>) was analysed. The effect of different cationic residues (Lys and Arg) on the stability and intracellular transport efficiency of the peptide/pDNA complex was assessed, with both peptides forming stable α-helical structures under neutral conditions and <strong>st7-5_R</strong> showing higher helical strength under acidic conditions. Agarose gel shift assays and PicoGreen staining showed that both peptides formed complete complexes at N/P ratios of 1.5–2 and protected pDNA from nucleases. However, in the presence of heparin sulfate, the <strong>st7-5_R</strong>/pDNA complex maintained higher stability than the <strong>st7-5</strong>/pDNA complex. Interaction analysis with lipid membranes indicated that <strong>st7-5</strong> with Lys residues interacted strongly at pH 7.4 and <strong>st7-5_R</strong> with Arg residues at pH 5.5, suggesting that <strong>st7-5_R</strong> was highly capable of facilitating its escape from endosomes. The Förster resonance energy transfer (FRET) signal observed by confocal laser scanning microscopy (CLSM) indicated that the <strong>st7-5_R</strong>/pDNA complex disintegrated over time after intracellular introduction, releasing the encapsulated pDNA into the cell. These results indicate that Magainin 2-derived stapled peptides are promising carriers for efficient intracellular nucleic acid delivery, especially <strong>st7-5_R</strong> with its excellent stability and delivery efficiency. The findings of this study will contribute to the design of drug delivery system carrier peptides and the improvement of nucleic acid therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118176"},"PeriodicalIF":3.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of novel transforming growth factor β type 1 receptor inhibitors through structure-based virtual screening, preliminary structure–activity relationship study, and biological evaluation in hepatocellular carcinoma

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-26 DOI: 10.1016/j.bmc.2025.118175

Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang

{"title":"Discovery of novel transforming growth factor β type 1 receptor inhibitors through structure-based virtual screening, preliminary structure–activity relationship study, and biological evaluation in hepatocellular carcinoma","authors":"Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang","doi":"10.1016/j.bmc.2025.118175","DOIUrl":"10.1016/j.bmc.2025.118175","url":null,"abstract":"<div><div>The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a pivotal role in the tumor microenvironment, making it an attractive target for therapeutic intervention. Small-molecule inhibitors of TGFβR1 offer a promising approach for the treatment of malignant tumors. In this study, a series of 1<em>H</em>-pyrrolo[2,3-<em>b</em>]pyridine derivatives were identified as novel TGFβR1 inhibitors. The most potent candidate, compound <strong>7w</strong>, demonstrated inhibition of SMAD2/3 phosphorylation and Hep3B cell viability, with IC<sub>50</sub> values of 160.3 nM and 228 μM, respectively. Compound <strong>7w</strong> showed a synergistic anti-proliferation and pro-apoptotic effect when combined with sorafenib, highlighting its potential as a promising lead for the development of potential anticancer therapies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118175"},"PeriodicalIF":3.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unlocking pH-responsive dual payload release through hydrazone linkage chemistry

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-22 DOI: 10.1016/j.bmc.2025.118172

Heba S. Abd-Ellah , Dan Zhao , Yayao Zhou , Jonathan B. Baell

{"title":"Unlocking pH-responsive dual payload release through hydrazone linkage chemistry","authors":"Heba S. Abd-Ellah , Dan Zhao , Yayao Zhou , Jonathan B. Baell","doi":"10.1016/j.bmc.2025.118172","DOIUrl":"10.1016/j.bmc.2025.118172","url":null,"abstract":"<div><div>The capacity for simultaneous intracellular delivery of two payloads to various organelles, in a targeted and programmable manner, would represent a powerful tool to probe cellular function and responses or deliver synergistic combination therapies. While only single pathways are currently probed, this work introduces an acid-labile trifunctional hydrazone linker that releases two types of payloads, which we term payload <strong>W</strong> and payload <strong>Z</strong>. As a key and controlling feature, initial acid-mediated release of payload <strong>W</strong> triggers release of payload <strong>Z</strong> with 1:1 stoichiometry via intramolecular cyclization. An azide group is also built into the linker structure to allow optional conjugation to nanoparticles (NPs). Through overcoming significant synthetic challenges, we have prepared six target acylhydrazone linkers and evaluated their stability over a range of pH values. An acyl acetophenone hydrazone linker (linker <strong>3</strong>) displays a particularly promising release profile, supporting the feasibility of the novel dual-release concept through high stability at physiological pH but rapid release of both payloads under pH conditions similar to those in late endosomal and lysosomal compartments (pH 4.5–5.5) or tumor sites (pH 6.5). Therefore, linker <strong>3</strong> holds the potential as an ideal candidate carrier for future nanoparticle conjugation, offering a mechanism for dual drug release after endosomal entrapment. A particularly promising application would be in combination therapy for controlled intracellular delivery of doxorubicin (DOX) and a nitric oxide (NO) donor, or proteins and/or siRNA and small molecules, to enable diverse synergistic treatment strategies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118172"},"PeriodicalIF":3.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fucosyl glycosides for DC-SIGN targeting: Fucosylation strategies, synthesis and binding studies of model compounds

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-20 DOI: 10.1016/j.bmc.2025.118164

Rohit Chavan , Jonathan Lefèbre , Kateřina Jochová , Hana Dvořáková , Christoph Rademacher , Petra Ménová

{"title":"Fucosyl glycosides for DC-SIGN targeting: Fucosylation strategies, synthesis and binding studies of model compounds","authors":"Rohit Chavan , Jonathan Lefèbre , Kateřina Jochová , Hana Dvořáková , Christoph Rademacher , Petra Ménová","doi":"10.1016/j.bmc.2025.118164","DOIUrl":"10.1016/j.bmc.2025.118164","url":null,"abstract":"<div><div>DC-SIGN, a C-type lectin receptor expressed on immune cells, is considered a promising target for immunomodulatory and antiviral therapies. While mannose-based glycomimetics have been extensively studied as DC-SIGN ligands, fucose-based strategies remain underexplored. This study explores the fucosylation of linear alcohols and sugars using eight different fucosyl donors, aiming at designing strategies for the development of fucose-based glycomimetics targeting DC-SIGN. Four types of leaving groups and two different acyl-based protecting groups on the donors were tested. The glycosylation of 3-azidopropan-1-ol exclusively yielded the β-anomer, demonstrating high stereoselectivity. The azido group in the product is versatile, allowing for direct click chemistry reactions or reduction to an amine for further functionalization. Both types of reactions were demonstrated in a model reaction. In the glycosylation of a sugar, a disaccharide moiety of Lewis X antigen was selected as a target molecule. Only one of the eight tested fucosyl donors worked well in this reaction and provided the product in a reasonable yield. The disaccharide was also equipped with the 3-azidopropyl linker, facilitating future modifications. Finally, NMR studies confirmed compatibility of the linker with canonical Ca<sup>2+</sup>-dependent carbohydrate binding to DC-SIGN, suggesting potential for further development of fucose-based glycomimetics targeting this C-type lectin receptor.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118164"},"PeriodicalIF":3.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Computational identification and experimental characterization of an aurora kinase inhibitor

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-20 DOI: 10.1016/j.bmc.2025.118160

Muhammad Muddassar , Muhammad Furqan , Numan Yousaf , Muhammad Saad Khalid , Natasha Mahmood , Saira Dar , Salman Fozail , Rahman Shah Zaib Saleem , Syed Shahzad ul Hussan , Amir Faisal

{"title":"Computational identification and experimental characterization of an aurora kinase inhibitor","authors":"Muhammad Muddassar , Muhammad Furqan , Numan Yousaf , Muhammad Saad Khalid , Natasha Mahmood , Saira Dar , Salman Fozail , Rahman Shah Zaib Saleem , Syed Shahzad ul Hussan , Amir Faisal","doi":"10.1016/j.bmc.2025.118160","DOIUrl":"10.1016/j.bmc.2025.118160","url":null,"abstract":"<div><div>The serine/threonine kinases of the aurora family are critical for completing various stages of mitotic cell division. They are frequently overexpressed in various cancers, associated with poor prognosis, and have been validated as an attractive drug target. Despite promising preclinical results, the clinical development of small molecule inhibitors targeting aurora kinases is often hampered by limited efficacy as single agents and severe side effects. Recent discoveries of the synthetic interaction of aurora A with various tumor suppressors and its involvement in the development of resistance to third-generation EGFR inhibitors have renewed interest in finding aurora kinase inhibitors. This study utilized computational approaches to discover an aurora kinase inhibitor. Chemical features of two structurally distinct inhibitors of aurora kinase were exploited to develop a molecular shape and color-based model for the virtual screening of small synthetic molecules in the Enamine database. Six hit compounds validated through docking and Molecular Dynamics (MD) simulation studies were evaluated in a cell-based assay. Only MC-688 inhibited both aurora kinases (A and B) and bound to both kinases in a competition binding assay. Analysis of STD-NMR and 2D NOESY spectra confirmed the computationally predicted binding mode of MC-688 with the ATP binding pocket of aurora A. MC-688 inhibited cell proliferation and long-term treatment of HCT116 colorectal cancer cells with MC-688 induced abrogated mitosis, ultimately leading to apoptotic cell death. In conclusion, MC-688 was computationally identified and experimentally validated as a new pan-aurora inhibitor that induces aurora phenotype in cells and can be used as a lead for further optimization.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118160"},"PeriodicalIF":3.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A clinical review on third and fourth generation EGFR tyrosine kinase inhibitors for the treatment of non-small cell lung cancer

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-20 DOI: 10.1016/j.bmc.2025.118146

Chandrakant S. Gawli, Chandragouda R. Patil, Harun M. Patel

{"title":"A clinical review on third and fourth generation EGFR tyrosine kinase inhibitors for the treatment of non-small cell lung cancer","authors":"Chandrakant S. Gawli, Chandragouda R. Patil, Harun M. Patel","doi":"10.1016/j.bmc.2025.118146","DOIUrl":"10.1016/j.bmc.2025.118146","url":null,"abstract":"<div><div>“Epidermal growth factor receptor (EGFR)” mutations are pivotal in the pathogenesis of “Non-Small Cell Lung Cancer (NSCLC),” which is associated with high morbidity and mortality rates. The advent of third and fourth-generation EGFR tyrosine kinase inhibitors (TKIs) has significantly advanced the therapeutic landscape for EGFR-mutant NSCLC, particularly in overcoming resistance mutations such as T790M and C797S. This review delves into the current clinical status, efficacy, safety profiles, and regulatory approvals of third-generation EGFR TKIs, including Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Rezivertinib, Befotertinib, Sunvozertinib. Furthermore, it explores emerging fourth-generation EGFR TKIs designed to address resistance mechanisms beyond those targeted by their predecessors. Notable fourth-generation candidates such as TQB3804, BPI-361175, BDTX-1535, WJ13404, QLH11811, H002, HS-10375, BBT-207, JIN-A02, and HS-10504 are highlighted for their potential to overcome the C797S mutation. The review emphasizes the importance of these advanced inhibitors in enhancing “progression-free survival and overall survival rates”. By evaluating the therapeutic potential and limitations of these EGFR TKIs, this review aims to guide future research in the management of EGFR-mutant NSCLC. This acts as guiding beacon for the strategic design and development of third and fourth generation EGFR-TK inhibitors to overcome the drug resistance hurdles in the development of EGFR-TK inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118146"},"PeriodicalIF":3.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

YAT2150: Overcoming limitations of traditional amyloid dyes in aggregation studies

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-19 DOI: 10.1016/j.bmc.2025.118163

Irene Álvarez-Berbel , Salomé Llabrés , Òscar Domènech , Maria Antònia Busquets , Xavier Fernàndez-Busquets , Elsa M. Arce , Rosalina Gavín , José Antonio del Río , Diego Muñoz-Torrero , F. Javier Luque , Raimon Sabate , Alba Espargaró

{"title":"YAT2150: Overcoming limitations of traditional amyloid dyes in aggregation studies","authors":"Irene Álvarez-Berbel , Salomé Llabrés , Òscar Domènech , Maria Antònia Busquets , Xavier Fernàndez-Busquets , Elsa M. Arce , Rosalina Gavín , José Antonio del Río , Diego Muñoz-Torrero , F. Javier Luque , Raimon Sabate , Alba Espargaró","doi":"10.1016/j.bmc.2025.118163","DOIUrl":"10.1016/j.bmc.2025.118163","url":null,"abstract":"<div><div>Amyloid fibrils, which are aggregates of misfolded proteins characterized by β-sheet-rich structures, are implicated in several neurodegenerative and systemic pathologies, including Alzheimer’s and Parkinson’s diseases and type II diabetes mellitus. Traditional amyloid markers, such as Congo Red and Thioflavin T, are widely used for amyloid detection but present limitations, particularly in cellular assays, due to spectral interference and aggregation inhibition. This study investigates YAT2150, a novel fluorescent dye with enhanced amyloid-binding specificity and sensitivity, as a potential alternative to conventional dyes. We evaluated YAT2150’s efficacy for detecting amyloid aggregates in both <em>in vitro</em> and <em>in cellula</em> assays. First, we compared its fluorescence intensity and binding specificity to that of Thioflavin T in amyloid fibril assays, demonstrating that YAT2150 exhibits high affinity and selectivity for amyloid structures, with minimal interference from non-aggregated proteins. Furthermore, we explored YAT2150’s utility in <em>Escherichia coli</em> as a model system for studying protein aggregation and amyloid formation in a procaryotic cellular context. Our findings indicate that YAT2150 effectively labels amyloid-like inclusion bodies in <em>E. coli</em>, producing a robust fluorescence signal with low background noise. These results suggest that YAT2150 is a promising new tool for amyloid research, offering greater sensitivity compared to traditional dyes, even in complex cellular environments.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118163"},"PeriodicalIF":3.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design and synthesis of phenanthridinone and phenanthridine derivatives and their radiosensitizing activity

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-19 DOI: 10.1016/j.bmc.2025.118161

Wen-Ya Liu , Chuan-Sheng Yao , Yue-Wen Li , Xiang Gao , Li-Shuang Guo , Lin-Kun An

引用次数: 0

Targeting amyloidogenic proteins through cyclic peptides – A medicinal chemistry perspective

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-19 DOI: 10.1016/j.bmc.2025.118165

Muhammad Kazim Zargaham , Ahsan Ibrahim , Madiha Ahmed , Mustafeez Mujtaba Babar , Jayakumar Rajadas

{"title":"Targeting amyloidogenic proteins through cyclic peptides – A medicinal chemistry perspective","authors":"Muhammad Kazim Zargaham , Ahsan Ibrahim , Madiha Ahmed , Mustafeez Mujtaba Babar , Jayakumar Rajadas","doi":"10.1016/j.bmc.2025.118165","DOIUrl":"10.1016/j.bmc.2025.118165","url":null,"abstract":"<div><div>Alzheimer’s Disease (AD) is characterized by the formation of amyloid-β (Aβ) in the extracellular region, neurofibrillary tangles (NFTs) in the intracellular region accompanied with neuroinflammation and decreased neurotransmitters in various regions of brain leading to neuroinflammation and neurodegeneration. Of the various bioactive molecules, Cyclic Peptides (CPs) are small circular chains of amino acids that can alter the structure and function of the proteins they interact with. They can be synthesized using chemical or genetic approach leading to the generation of diverse libraries of CPs that are screened for binding with desired target proteins. In AD, CPs can interfere at various levels, by either imitating the structure or altering the conformation of amyloidogenic proteins. They can also interfere with signal transduction by competing with amyloid proteins for various receptors which are involved in AD pathology. This review highlights the application of CPs as scaffolds for the identification of novel small molecules that can interfere with amyloid aggregation or for the formulation of vaccination against AD. Other proteins involved in the pathophysiological pathways of AD that can potentially be targeted for CP design have also been discussed.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118165"},"PeriodicalIF":3.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of effective anti-osteosarcoma agents via screening of an in-house NQO1-targeted compound library

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-18 DOI: 10.1016/j.bmc.2025.118162

Xiang Li , Qijie Gong , Jianglin Yu , Jiaqi Liang , Rui Yao , Jian Zhou , Yaxin Chen , Zhijie Lei , Zhan Yu , Xiaojin Zhang , Xusheng Qiu

{"title":"Identification of effective anti-osteosarcoma agents via screening of an in-house NQO1-targeted compound library","authors":"Xiang Li , Qijie Gong , Jianglin Yu , Jiaqi Liang , Rui Yao , Jian Zhou , Yaxin Chen , Zhijie Lei , Zhan Yu , Xiaojin Zhang , Xusheng Qiu","doi":"10.1016/j.bmc.2025.118162","DOIUrl":"10.1016/j.bmc.2025.118162","url":null,"abstract":"<div><div>Osteosarcoma is one of the most prevalent malignant bone tumors, and despite advances in treatment, significant improvements in survival rates for osteosarcoma patients remain elusive. There is an urgent need for developing novel molecules for the targeted treatment of osteosarcoma. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly overexpressed in osteosarcoma. Here, we evaluated a series of in-house NQO1-targeting compounds, including NQO1 substrates and β-lap prodrugs, through phenotypic screening using NQO1-positive methylnitronitrosoguanidine-induced human osteosarcoma cells (MNNG) and NQO1-negative normal human umbilical vein endothelial cells (HUVEC), aiming to identify novel candidate compounds for osteosarcoma therapy. As a result, compound <strong>21</strong>, an NQO1 substrate, was identified as a potent anti-osteosarcoma agent that promotes apoptosis and induces cell cycle arrest in osteosarcoma cells <em>in vitro</em>, while significantly inhibiting tumor growth <em>in vivo</em>. These findings suggest that compound <strong>21</strong> holds promise as a candidate for osteosarcoma treatment. Moreover, NQO1-targeting substrates present a promising pathway for the discovery of novel anti-osteosarcoma agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118162"},"PeriodicalIF":3.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0