Bioorganic Chemistry最新文献

{"title":"Synthesis and exploration of anticancer potential of spirocyclic 1,2,3-triazoline and aziridine derivatives of natural eudesmanolide isoalantolactone","authors":"Sergey S. Patrushev ,&nbsp;Daria O. Kichkina ,&nbsp;Arseny D. Moralev ,&nbsp;Tatyana V. Rybalova ,&nbsp;Vyacheslav I. Krasnov ,&nbsp;Elena I. Chernyak ,&nbsp;Marina A. Zenkova ,&nbsp;Andrey V. Markov ,&nbsp;Elvira E. Shults","doi":"10.1016/j.bioorg.2025.108124","DOIUrl":"10.1016/j.bioorg.2025.108124","url":null,"abstract":"<div><div>Eudesmane-type sesquiterpene lactone isoalantolactone <strong>1</strong> is of great interest due to its availability, biological activity and synthetic application. Respective series of original spirocyclic (11<em>S</em>,5ʹ) (1,2,3-triazoline-eudesma-4,15-enolides) and (11<em>S</em>)-aziridine-eudesma-4,15-enolides were efficiently synthesized <em>via</em> a chemoselective 1,3-dipolar cycloaddition reaction of organic azides to the exocyclic double bond of the lactone ring of isoalantolactone or 13<em>E</em>-(aryl)isoalantolactones by heating in DMF or toluene. The thermal reactions of isoalantolactone with benzyl azide, 2-azidoethanol, or <em>n</em>-butyl azide in 2-methoxyethanol afforded 13-(alkyamino)isoalantolactones formed as a mixture of (<em>Z</em>) and (<em>E</em>)-isomers. The results of <em>in vitro</em> biological assays showed that novel spirocyclic isoalantolactone derivatives exhibited cytotoxicity against human breast cancer and glioblastoma cells at low micromolar concentrations. The most cytotoxic and selective (11<em>S</em>,5ʹ)-spiro-1,2,3-triazoline from 13<em>E</em>-(fluorophenyl)isoalantolactone <strong>20</strong> (IC₅₀^(MCF-7) = 8 ± 0.1 µM, SI^(MCF-7) &gt; 12.5) was found to induce ROS-dependent death of MCF-7 human breast cancer cells via mitochondrial apoptosis. The corresponding (11<em>S</em>)-spiroaziridine derivatives <strong>21</strong> at non-toxic concentrations (10 and 20 µM) effectively suppressed motility, clonogenicity and adhesion of glioblastoma cells and exhibited synergistic cytotoxicity in combination with temozolomide. <em>In silico</em> analysis revealed the potential ability of the 13-aryl (11S)-spiroaziridine derivative <strong>21</strong> to bypass the blood–brain barrier and exhibit anti-glioblastoma activity probably based on the direct interaction with Hsp90α.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108124"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968748","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}

{"title":"Triphenylphosphine-modified cyclometalated iridiumIII complexes as mitochondria-targeting anticancer agents with enhanced selectivity","authors":"Hanxiu Fu,&nbsp;Shuli Wang,&nbsp;Yuwen Gong,&nbsp;Heqian Dong,&nbsp;Kangning Lai,&nbsp;Zhihao Yang,&nbsp;Chunyan Fan,&nbsp;Zhe Liu ,&nbsp;Lihua Guo","doi":"10.1016/j.bioorg.2025.108148","DOIUrl":"10.1016/j.bioorg.2025.108148","url":null,"abstract":"<div><div>This study presents the development and evaluation of triphenylphosphine-modified cyclometalated iridium^III complexes as selective anticancer agents targeting mitochondria. By leveraging the mitochondrial localization capability of the triphenylphosphine group, these complexes displayed promising cytotoxicity in the micromolar range (3.12–7.24 μM) against A549 and HeLa cancer cells, these complexes exhibit significantly higher activity compared to their unmodified counterparts lacking the triphenylphosphine moiety. Moreover, they demonstrate improved specificity for cancer cells over normal cells, achieving selectivity index in the range of 5.46–14.83. Mechanistic studies confirmed that these complexes selectively target mitochondria rather than DNA, as shown by confocal microscopy and flow cytometry, where they accumulate to induce mitochondrial dysfunction. This disruption leads to mitochondrial membrane depolarization (MMP), elevated reactive oxygen species (ROS) levels, and activation of intrinsic apoptosis pathways. Furthermore, the complexes induce cell cycle arrest at the G₂/M phase and suppress the migration of A549 cells.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108148"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968750","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}

{"title":"Hederagenin ameliorates ferroptosis-induced damage by regulating PPARα/Nrf2/GPX4 signaling pathway in HT22 cells: An in vitro and in silico study","authors":"Yuxin Feng ,&nbsp;Heran Wang ,&nbsp;Yazhuo Hu ,&nbsp;Xiaoxue Zhang ,&nbsp;XiuLing Miao ,&nbsp;Zihan Li ,&nbsp;JianJun Jia","doi":"10.1016/j.bioorg.2024.108119","DOIUrl":"10.1016/j.bioorg.2024.108119","url":null,"abstract":"<div><h3>Background</h3><div>Hederagenin (HG), derived from ivy seeds, is known to offer protection against Alzheimer’s disease (AD). However, the specific molecular pathways through which it counters ferroptosis-induced neurotoxicity are not fully elucidated. This investigation seeks to delineate the processes by which HG mitigates neurotoxic effects in HT22 cells subjected to glutamate (Glu)-induced ferroptosis.</div></div><div><h3>Methods</h3><div>HT22 cell ferroptosis was prompted by Glu exposure. Cell viability was assessed using CCK-8 and LDH assays, while Fe²⁺ fluorescence and assays of iron-related proteins served to gauge intracellular Fe²⁺ concentrations. Evaluations of mitochondrial structure and functionality employed JC-1 staining and transmission electron microscopy. Assessments of ROS, lipid peroxidation, MDA, 4-HNE, and the GSSG/GSH ratio were conducted to ascertain HG’s antioxidative efficacy. The expression of proteins within the PPARα/Nrf2/GPX4 pathway was quantified via western blotting, with molecular docking (MD), and molecular dynamics simulations (MDS) used to explore protein interactions.</div></div><div><h3>Results</h3><div>HG diminished the cellular toxicity triggered by Glu in HT22 cells, lowered Fe²⁺ within cells, and rejuvenated mitochondrial morphology and performance. Concurrently, it modulated proteins critical to Fe²⁺ metabolism, diminished ROS and lipid peroxidation, and elevated GSH/GSSG ratios. Enhanced PPARα/Nrf2/GPX4 protein levels were corroborated by western blot results. Furthermore, molecular docking revealed favorable binding of HG to the proteins PPARα, Nrf2, and GPX4, with binding energies of −7.751, −7.535, and −7.414 kcal/mol, respectively. MDS confirmed robust interactions between HG and these pivotal targets.</div></div><div><h3>Conclusion</h3><div>The evidence suggests that HG effectively mitigates Glu-induced ferroptosis in HT22 cells by activating the PPARα/Nrf2/GPX4 signaling pathway. These findings endorse HG’s potential as a nutritional adjunct for AD management.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108119"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925871","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}

{"title":"Design, synthesis, and biological evaluation of novel FGFR1 PROTACs","authors":"Yu-Wei Wang ,&nbsp;Yu-Hui Gao ,&nbsp;Cheng Wang,&nbsp;Ping-Fan Zhang,&nbsp;Min Wang,&nbsp;Li Lan,&nbsp;Jing-Ying Liu,&nbsp;Lei Shi,&nbsp;Li-Ping Sun","doi":"10.1016/j.bioorg.2024.108109","DOIUrl":"10.1016/j.bioorg.2024.108109","url":null,"abstract":"<div><div>Dysregulation of the fibroblast growth factor receptor 1 (FGFR1) signaling has prompted efforts to develop therapeutic agents, which is a carcinogenic driver of many cancers, including breast, prostate, bladder, and chronic myeloid leukemia. Despite significant progress in the development of potent and selective FGFR inhibitors, the long-term efficacy of these drugs in cancer therapy has been hampered by the rapid onset of acquired resistance. Therefore, more drug discovery strategies are needed to promote the development of FGFR-targeted drugs. Here, we discovered compound <strong>S2h</strong>, a compound that selectively and effectively degrades FGFR1 at nanomolar concentrations in KG1a cells (IC₅₀ = 26.81 nM; DC₅₀ = 39.78 nM), which incorporates an essential, nine atom-long linkers. The importance of linker length, composition, and tethering site proteolysis-targeting chimeras (PROTACs) design is emphasized, and slight modifications can significantly affect degradation potency. Meanwhile, it was verified that the degradation of FGFR1 protein at compound <strong>S2h</strong> was concentration- and time-dependent and that the protein degradation occurred through the ubiquitin–proteasome system (UPS). In summary, the newly designed heterobifunctional FGFR1 degrader, compound <strong>S2h</strong>, provides new ideas and references for the research of FGFR small-molecule degraders.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108109"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930202","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}

{"title":"Exploring the therapeutic potential of acridines: Synthesis, structure, and biological applications","authors":"Diego Santa Clara Marques,&nbsp;Lisandra da Silva Lima,&nbsp;Josué Filipe de Oliveira Moraes Miranda,&nbsp;Carolina Ávila dos Anjos Santos,&nbsp;Iranildo José da Cruz Filho,&nbsp;Maria do Carmo Alves de Lima","doi":"10.1016/j.bioorg.2024.108096","DOIUrl":"10.1016/j.bioorg.2024.108096","url":null,"abstract":"<div><div>The objective of this review was to explore the trends and chemical characteristics of acridines and their derivatives, analyze their contribution to the scientific literature and international cooperation, identify the most influential authors and articles, and provide an overview of the knowledge produced in elucidating their mechanisms of action. To this end, a bibliometric analysis was performed using RStudio software, along with a systematic review focusing on articles indexed in the “Web of Science” and “Scopus” databases. The keywords used were “acridine$”, “Synthesi$”, “Structure$”, and “Biologic* Application$” for the period from 2020 to 2024. Relevant articles were carefully selected from these databases, and a bibliometric analysis was carried out to comprehensively discuss the most relevant biological activities associated with acridines. The results showed that, during the analyzed period, China and India led in the number of publications, followed by Brazil in third place. However, a decline in the number of publications was observed in the last two years of the period. Keyword analysis revealed that antitumor activity remains the most extensively studied aspect of acridines and their derivatives.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108096"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930204","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}

{"title":"Design, synthesis, and biological evaluation of novel thiourea derivatives as small molecule inhibitors for prostate specific membrane antigen","authors":"Sagnik Sengupta ,&nbsp;Amit Pandit ,&nbsp;Mena Asha Krishnan ,&nbsp;Rajesh Sharma ,&nbsp;Sumith A Kularatne ,&nbsp;Venkatesh Chelvam","doi":"10.1016/j.bioorg.2025.108130","DOIUrl":"10.1016/j.bioorg.2025.108130","url":null,"abstract":"<div><div>Prostate cancer (PCa) has emerged to be the second leading cause of cancer-related deaths in men. Molecular imaging of PCa using targeted radiopharmaceuticals specifically to PCa cells promises accurate staging of primary disease, detection of localized and metastasized tumours, and helps predict the progression of the disease. Glutamate urea heterodimers have been popularly used as high-affinity small molecules in the binding pockets of popular and well-characterized PCa biomarker, prostate specific membrane antigen (PSMA). However, extensive studies in molecular docking and the QSAR model have predicted that bioisotere substitution of an oxygen atom with sulfur in the glutamate urea heterodimer molecules would yield a new library of high-affinity ligands in the nanomolar range to target PSMA. Based on these predictions, a new class of glutamate thiourea derivatives has been designed and developed for binding with PSMA. The <em>in silico</em> guided selection and chemical synthesis of glutamate thiourea small molecule PSMA inhibitors by a new methodology is described in this report. One of the high-affinity glutamate thiourea ligands was further chelated to radioisotopes such as ^99mTechnetium using a chelating moiety via a peptide spacer and targeted to PSMA⁺ LNCaP and 22Rv1 cells. The newly synthesized ^99mTc-bioconjugate has shown nanomolar affinity to selectively target PSMA⁺ cancers during <em>in vitro</em> studies. Collectively, these PSMA-specific small molecule radio-imaging agents show significant promise in monitoring disease prognosis and treatment selection of PCa patients.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108130"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941966","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}

{"title":"Recent advancements in the quest of benzazoles as anti-Mycobacterium tuberculosis agents","authors":"Kshitij I. Patel ,&nbsp;Nirjhar Saha ,&nbsp;Tejas M. Dhameliya ,&nbsp;Asit K. Chakraborti","doi":"10.1016/j.bioorg.2024.108093","DOIUrl":"10.1016/j.bioorg.2024.108093","url":null,"abstract":"<div><div>Tuberculosis (TB) remains a global health challenge, claiming numerous lives each year, despite recent advancements in drug discovery and treatment strategies. Current TB treatment typically involves long-duration chemotherapy regimens that are often accompanied by adverse effects. The introduction of new anti-TB drugs, such as Bedaquiline, Delamanid, and Pretomanid, offers hope for more effective treatment, although challenges persist keeping the quest to find new anti-TB chemotypes an incessant exercise of medicinal chemists. Towards this initiative, the benzazoles continue to draw attention and have been recognised as new anti-TB scaffolds. Benzazole-containing compounds emerged as new chemotypes with potential to offer a versatile platform for new anti-TB drug design to generate new leads for further optimization. The elucidation of their chemical properties, biological effects, and potential mechanisms of action, would lead to identify innovative candidates for TB therapy. As medicinal chemists delve deeper into the SARs and mechanisms of action of benzazole derivatives, new opportunities for creating effective and safe anti-TB medications arise. This review highlights the potential impact of benzazole-based compounds on the search for new therapeutic agents against tuberculosis, emphasizing the importance of continued research and innovation in the field.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108093"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021423","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}

{"title":"Exploration of triazole derivatives, SAR profiles, and clinical pipeline against Mycobacterium tuberculosis","authors":"Kakarla Pakeeraiah ,&nbsp;Krishna Kartheek Chinchilli ,&nbsp;Rambabu Dandela ,&nbsp;Sudhir Kumar Paidesetty","doi":"10.1016/j.bioorg.2024.108114","DOIUrl":"10.1016/j.bioorg.2024.108114","url":null,"abstract":"<div><div>Tuberculosis is a highly infectious disease and it is a global threat in particular affecting people from developing countries. It is thought that nearly one-third of the global population lives with this causative bacterium in its dominant form. The spread of HIV and the development of resistance to both multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) aggravates the spread of the disease and needs novel drugs which combat this disease effectively. Triazole-containing anti-tubercular drugs are promising and need further tuning to develop as a potent scaffold for tuberculosis. In this review, we highlight the structural activity relationships of triazole-containing drugs and detailed understanding for the researchers in the field of medicinal chemistry to further explore these triazole-based compounds as well as synthesize new compounds for antitubercular activity against drug-sensitive and resistant strains.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108114"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930203","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}

{"title":"N-glycosylation-modifications-driven conformational dynamics attenuate substrate inhibition of d-lactonohydrolase","authors":"Ruobin Sun ,&nbsp;Qipeng Yan ,&nbsp;Wenhao Deng ,&nbsp;Pengcheng Chen ,&nbsp;Dan Wu ,&nbsp;Pu Zheng","doi":"10.1016/j.bioorg.2025.108122","DOIUrl":"10.1016/j.bioorg.2025.108122","url":null,"abstract":"<div><div>Achieving enzyme catalysis at high substrate concentrations is a substantial challenge in industrial biocatalysis, and the role of glycosylation in post-translational modifications that modulate enzyme substrate inhibition remains poorly understood. This study provides insights into the role of <em>N</em>-glycosylation in substrate inhibition by comparing the catalytic properties of <span>d</span>-lactonohydrolase (<span>d</span>-Lac) derived from <em>Fusarium moniliforme</em> expressed in prokaryotic and eukaryotic hosts. Experimental evidence indicates that recombinant <span>d</span>-Lac expressed in <em>Pichia pastoris</em> (<em>Pp</em>Lac-WT) exhibits higher hydrolysis rates at a substrate concentration of 400 g/L, with reduced substrate inhibition and enhanced stability compared to the recombinant <span>d</span>-Lac expressed in <em>Escherichia coli</em> (<em>Ec</em>Lac-WT). Mutant <em>Pp</em>Lac-M1 achieves a conversion rate of 40 % at a substrate concentration of 400 g/L, with a space–time yield of <span>d</span>-pantoic acid reaching 91.1 g/L/h. Proteomics analysis reveals that residues N29 and N278, located approximately 10–20 Å from the active site undergo <em>N</em>-glycosylation in <em>Pp</em>Lac-WT. Using microsecond-scale molecular dynamics simulations and Markov state models, we elucidate the effects of glycosylation on the conformational flexibility of two key loops at the entrance of the binding pocket. Specifically, the loops in <em>Pp</em>Lac-WT can transition between open and closed states, whereas those in <em>Ec</em>Lac-WT tend to remain open. In high substrate concentration conditions, the open state causes congestion, leading to substrate inhibition. Shortest-path map analysis confirms that substrate entry is dynamically controlled by residue N29 on the loops surrounding the active site. Our findings enhance the understanding of the effects of glycosylation on enzyme conformational dynamics and provide insights into mitigating inhibition at high substrate concentrations.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108122"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941968","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}

{"title":"Design, synthesis, and biological evaluation of N1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N2-(substituent)-1,2-dicarboxamides as anticancer agents targeting Nur77-mediated endoplasmic reticulum stress","authors":"Hongyu Hu ,&nbsp;Fangfang Wen ,&nbsp;Tidong Zhen ,&nbsp;Minda Zhang ,&nbsp;Jingbo Qin ,&nbsp;Jiangang Huang ,&nbsp;Zhirong Chen ,&nbsp;Mingyue Yu ,&nbsp;Shengwei Hu ,&nbsp;Meijuan Fang ,&nbsp;Jin-Zhang Zeng","doi":"10.1016/j.bioorg.2024.108113","DOIUrl":"10.1016/j.bioorg.2024.108113","url":null,"abstract":"<div><div>Targeting endoplasmic reticulum (ER) stress-induced apoptosis has attracted considerable research interest in anti-cancer drug development. Nur77 is a potential therapeutic target in many cancers and several Nur77 modulators have recently been identified as effective anticancer agents by activating ER stress. As an ongoing work, this study reports a new series of novel <em>N</em>¹-(2-(adamantan-1-yl)-1<em>H</em>-indol-5-yl)-<em>N</em>²-(substituent)-1,2-dicarboxamides as potent Nur77 modulators that cause ER stress-induced apoptosis. Among this new series, most compounds show improved cytotoxicity against liver cancer (HepG2 and Huh7) and breast cancer (MCF-7 and MDA-MB-231) cell lines. The representative analog <strong>15h</strong> dramatically induces Nur77 expression and cell apoptosis, showing excellent growth inhibition of HepG2 and MCF-7 cells (IC₅₀ &lt; 5.0 μM). Mechanistically, <strong>15h</strong> binds (<em>K</em>_D = 0.477 μM) and activates Nur77-mediated ER stress through the PERK-ATF4 and IRE1 signaling pathways, thereby inducing cell apoptosis. <em>In vivo</em>, <strong>15h</strong> treatment strongly suppresses HepG2 xenograft tumor growth (tumor shrink by 54.06 %). In summary, we synthesize a series of novel indole derivatives, among which <strong>15h</strong> has significantly improved pharmacological activity against various cancer cells. We further identify <strong>15h</strong> as a novel ligand of Nur77, which may serve a therapeutic lead for developing new cancer therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108113"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941992","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}