Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第4页

High-throughput virtual screening, identification and in vitro biological evaluation of novel inhibitors of PLK1 and NRP1. 新型PLK1和NRP1抑制剂的高通量虚拟筛选、鉴定及体外生物学评价

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-08-18 DOI: 10.1080/14756366.2025.2514677

Yang Xia, Yuting Chang, Lixia Guan, Yifei Geng, Qi Zhang, Xiaozhou Shen, Qian Bu, Miao-Miao Niu, Gaohua Han

{"title":"High-throughput virtual screening, identification and in vitro biological evaluation of novel inhibitors of PLK1 and NRP1.","authors":"Yang Xia, Yuting Chang, Lixia Guan, Yifei Geng, Qi Zhang, Xiaozhou Shen, Qian Bu, Miao-Miao Niu, Gaohua Han","doi":"10.1080/14756366.2025.2514677","DOIUrl":"10.1080/14756366.2025.2514677","url":null,"abstract":"Overexpression of PLK1 and NRP1 correlate with enhanced proliferative activity in lung cancer cells, thus the development of dual-target PLK1/NRP1 inhibitors holds great therapeutic promise. In this study, five compounds (PLN 1-5) targeting both PLK1 and NRP1 were identified using a multi-step virtual screening approach. PLN-5 showed nanomolar inhibitory potency against PLK1 (IC50 = 2.07 ± 0.13 nM) and NRP1 (IC50 = 5.15 ± 0.24 nM), exceeding the positive controls onvansertib and EG00229 by approximately 9-fold and 124-fold, respectively. Molecular dynamics (MD) simulations revealed that PLN-5 maintained a stable binding to the active sites of PLK1 and NRP1. Importantly, MTT assays showed that PLN-5 had significant antiproliferative activity (IC50 = 0.27 ± 0.02 μM) against human lung cancer cells, with no significant inhibitory effect on normal lung cells. In conclusion, these results demonstrate the therapeutic potential of PLN-5 as a dual-targeting antitumor agent that warrants further development.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2514677"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12364115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

27-Hydroxycholesterol in cancer development and drug resistance. 27-羟基胆固醇在癌症发展和耐药中的作用。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-05-22 DOI: 10.1080/14756366.2025.2507670

Yaxin Hou, Zhiguang Fu, Chenhui Wang, Paulina Kucharzewska, Yuan Guo, Sihe Zhang

{"title":"27-Hydroxycholesterol in cancer development and drug resistance.","authors":"Yaxin Hou, Zhiguang Fu, Chenhui Wang, Paulina Kucharzewska, Yuan Guo, Sihe Zhang","doi":"10.1080/14756366.2025.2507670","DOIUrl":"10.1080/14756366.2025.2507670","url":null,"abstract":"27-Hydroxycholesterol (27HC), a cholesterol metabolite, functions both as a selective oestrogen receptor (ER) modulator and a ligand for liver X receptors (LXRs). The discovery of 27HC involvement in carcinogenesis has unveiled new research avenues, yet its precise role remains controversial and context-dependent. In this review, we provide an overview of the biosynthesis and metabolism of 27HC and explore its cancer-associated signalling, with a particular focus on ER- and LXR-mediated pathways. Given the tissue-specific dual role of 27HC, we discuss its differential impact across various cancer types. Furthermore, we sort out 27HC-contributed drug resistance mechanisms from the perspectives of drug efflux, cellular proliferation, apoptosis, epithelial-mesenchymal transition (EMT), antioxidant defence, epigenetic modification, and metabolic reprogramming. Finally, we highlight the chemical inhibitors to mitigate 27HC-driven cancer progression and drug resistance. This review offers an updated role of 27HC in cancer biology, setting the stage for future research and the development of targeted therapeutics.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2507670"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12100970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery of conformation constrained tetracyclic compounds as potent chitinase OfChi-h inhibitors with a novel binding mode. 发现构象受限的四环化合物作为有效的几丁质酶OfChi-h抑制剂，具有新的结合模式。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-07-07 DOI: 10.1080/14756366.2025.2528056

Pengtao Yuan, Xi Jiang, Xintong Ni, Xusheng Shao, Xuhong Qian, Qing Yang

{"title":"Discovery of conformation constrained tetracyclic compounds as potent chitinase OfChi-h inhibitors with a novel binding mode.","authors":"Pengtao Yuan, Xi Jiang, Xintong Ni, Xusheng Shao, Xuhong Qian, Qing Yang","doi":"10.1080/14756366.2025.2528056","DOIUrl":"10.1080/14756366.2025.2528056","url":null,"abstract":"Chitinase h (Chi-h) has been identified as a promising pesticide target due to its exclusive distribution in lepidopteran insects and its essential role in the moulting processes. In this study, we leverage OfChi-h from destructive agricultural pest Ostrinia furnacalis (Asian corn borer) as a model target to identify novel chitinase inhibitors. A conformational restriction approach was employed to design a series of novel OfChi-h inhibitors. Among these, compound 6a showed the highest inhibitory activity against OfChi-h, with a Ki value of 58 nM. Molecular docking analysis suggested that 6a tightly bound to three subsites (-3 to -1) of OfChi-h. The binding mode is further confirmed by the co-crystallization data of 6a with the SmChiA, a bacterial homologue of OfChi-h, at a resolution of 1.8 Å. This research presents a novel approach for the development of highly potent insect chitinase inhibitors, offering potential tools for effective pest control.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2528056"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Identification of potent inhibitors of potential VEGFR2: a graph neural network-based virtual screening and in vitro study. 潜在VEGFR2的有效抑制剂的鉴定：基于图神经网络的虚拟筛选和体外研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-20 DOI: 10.1080/14756366.2025.2518192

Shengzhen Hou, Shuning Diao, Yuxiang He, Taiying Li, Wenhui Meng, Jinping Zhang

{"title":"Identification of potent inhibitors of potential VEGFR2: a graph neural network-based virtual screening and in vitro study.","authors":"Shengzhen Hou, Shuning Diao, Yuxiang He, Taiying Li, Wenhui Meng, Jinping Zhang","doi":"10.1080/14756366.2025.2518192","DOIUrl":"10.1080/14756366.2025.2518192","url":null,"abstract":"VEGFR2 is a transmembrane tyrosine kinase receptor expressed on vascular endothelial cells and is closely associated with tumour cell growth. A comparison of traditional Chinese medicines and natural products with existing VEGFR2 inhibitors revealed that the former exhibited superior anticancer properties while concomitantly showing a reduced incidence of adverse effects. We proposed a novel strategy for screening potential candidates targeting VEGFR2 in a Chinese medicine monomer database using a combination of AI deep learning and structure-based drug design. The graph neural network served as the final predictive model to evaluate the molecular activities within the database, resulting in the selection of six candidate compounds. Kinase inhibition assays showed that the three compounds exhibited significant inhibition of VEGFR2. Molecular docking and molecular dynamics simulations further demonstrated the stability of their binding to VEGFR2. This study identified three compounds that effectively inhibited VEGFR2, making them promising candidates in cancer treatment.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2518192"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333204","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}

引用次数: 0

Enzyme sequence optimisation via Gromov-Wasserstein Autoencoders integrating MSA techniques. 酶序列优化通过Gromov-Wasserstein自动编码器集成MSA技术。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-07-03 DOI: 10.1080/14756366.2025.2524742

Xuze Wang, Yangyang Li, Xiancong Hou, Hao Liu

{"title":"Enzyme sequence optimisation via Gromov-Wasserstein Autoencoders integrating MSA techniques.","authors":"Xuze Wang, Yangyang Li, Xiancong Hou, Hao Liu","doi":"10.1080/14756366.2025.2524742","DOIUrl":"10.1080/14756366.2025.2524742","url":null,"abstract":"Enzyme sequence design has always been a challenging task, particularly in optimising key properties such as enzyme solubility, stability, and activity. This study proposes an innovative approach by utilising a variational autoencoder (VAE) model integrated with the Gromov-Wasserstein (GW) distance for enzyme sequence optimisation. The GWAE model improves representation learning by using the GW distance, thereby generating functional variants with desired characteristics. We also introduce an innovative enzyme dataset construction method that incorporates multiple sequence alignment (MSA) techniques to address sequence length discrepancies, enhancing the accuracy of the optimisation process. Experimental results show that the GWAE model outperforms the traditional VAE on multiple metrics. The generated enzyme sequences demonstrate superior solubility, stability, and hydrophobicity. Additionally, by integrating AlphaFold3 for structural prediction, we verify the structural stability of the generated sequences, further enhancing their practical applicability.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2524742"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics. ATM， ATR和DNA-PK抑制剂作为前瞻性癌症治疗药物的药物化学突破。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-04-21 DOI: 10.1080/14756366.2025.2489720

Ram Sharma, Anshul Mishra, Monika Bhardwaj, Gurpreet Singh, Larasati Vanya Indira Harahap, Sakshi Vanjani, Chun Hsu Pan, Kunal Nepali

{"title":"Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics.","authors":"Ram Sharma, Anshul Mishra, Monika Bhardwaj, Gurpreet Singh, Larasati Vanya Indira Harahap, Sakshi Vanjani, Chun Hsu Pan, Kunal Nepali","doi":"10.1080/14756366.2025.2489720","DOIUrl":"https://doi.org/10.1080/14756366.2025.2489720","url":null,"abstract":"This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related Kinase (ATR), and DNA-dependent protein kinase (DNA-PK) in the DNA damage response (DDR) and their implications in cancer. Emphasis is placed on the intricate interplay between these kinases, highlighting their collaborative and distinct roles in maintaining genomic integrity and promoting tumour development under dysregulated conditions. Furthermore, the review covers ongoing clinical trials, patent literature, and medicinal chemistry campaigns on ATM/ATR/DNA-PK inhibitors as antitumor agents. Notably, the medicinal chemistry campaigns employed robust drug design strategies and aimed at assembling new structural templates with amplified DDR kinase inhibitory ability, as well as outwitting the pharmacokinetic liabilities of the existing DDR kinase inhibitors. Given the success attained through such endeavours, the clinical pipeline of DNA repair kinase inhibitors is anticipated to be supplemented by a reasonable number of tractable entries (DDR kinase inhibitors) soon.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2489720"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Pyridine indole hybrids as novel potent CYP17A1 inhibitors. 吡啶吲哚杂化物作为新型有效的CYP17A1抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-14 DOI: 10.1080/14756366.2025.2463014

Tomasz M Wróbel, Angelika Grudzińska, Jibira Yakubu, Therina du Toit, Katyayani Sharma, Jeremiah C Harrington, Fredrik Björkling, Flemming Steen Jørgensen, Amit V Pandey

{"title":"Pyridine indole hybrids as novel potent CYP17A1 inhibitors.","authors":"Tomasz M Wróbel, Angelika Grudzińska, Jibira Yakubu, Therina du Toit, Katyayani Sharma, Jeremiah C Harrington, Fredrik Björkling, Flemming Steen Jørgensen, Amit V Pandey","doi":"10.1080/14756366.2025.2463014","DOIUrl":"10.1080/14756366.2025.2463014","url":null,"abstract":"Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogenic pathway to reduce androgen levels, but their clinical efficacy is limited by drug resistance and adverse effects. This study reports the synthesis and evaluation of novel CYP17A1 inhibitors derived from a previously identified hit compound. Several analogs were synthesised, including an unexpected di-cyano derivative, which demonstrated increased potency against CYP17A1 compared to abiraterone. Biological assays revealed that these compounds significantly inhibited CYP17A1 enzymatic activity and altered steroid biosynthesis. Among the newly synthesised inhibitors, compound 11 showed the highest potency (IC50 = 4 nM) and the related compound 14 presented a template for further development. A combined docking and molecular dynamics approach was used to identify the possible target binding modes of the compounds.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2463014"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Design, synthesis and biological activity of novel Xuetongsu derivatives as potential anticancer agents by inducing apoptosis. 新型血通素衍生物诱导细胞凋亡的设计、合成及生物活性研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-04-08 DOI: 10.1080/14756366.2025.2482140

Qi Jiang, Hui Zhong, Cong Wu, Jia Li, Jingmin Chen, Xudong Zhou, Bin Li, Huanghe Yu, Wei Wang, Wenbing Sheng

{"title":"Design, synthesis and biological activity of novel Xuetongsu derivatives as potential anticancer agents by inducing apoptosis.","authors":"Qi Jiang, Hui Zhong, Cong Wu, Jia Li, Jingmin Chen, Xudong Zhou, Bin Li, Huanghe Yu, Wei Wang, Wenbing Sheng","doi":"10.1080/14756366.2025.2482140","DOIUrl":"10.1080/14756366.2025.2482140","url":null,"abstract":"Xuetongsu (XTS, Schisanlactone E) is one of the main active compounds and considered as the star molecule isolated from Kadsura heteroclita (Roxb.) Craib. In order to improve XTS anti-tumour bioactivities, a series of novel XTS derivatives were designed and synthesised by introducing an amide bond at the parent. Anti-proliferative assays on four different human tumour cell lines (BGC-823, HepG-2, HCT-116, and MCF-7) showed that the anti-tumour activities of most derivatives increased greatly compared to the parent XTS, and especially, compounds A-7, A-14, and A-18 exhibited multiple anti-tumour effects. Among them, compound A-7 has the best biological activities on the four tumour cell lines with the IC50 values ranging from 13.86 to 20.71 μM, which could significantly increase the fraction of apoptotic cells according to flow cytometry experience. Further study demonstrated that A-7 could induce apoptosis on HepG-2 cells through influencing the key apoptotic related proteins, such as Bcl-2, Bax, and cleaved Caspase-3.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2482140"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Structural isomerisation affects the antitubercular activity of adamantyl-isoxyl adducts. 结构异构化影响金刚烷基异氧基加合物的抗结核活性。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-05-21 DOI: 10.1080/14756366.2025.2502600

Yucheng Lu, Daniel Partleton, Filibus M Gugu, Ahmed Y G Alhejaili, Samuel Norris, J Jonathan Harburn, Jason H Gill, Jonathan D Sellars, Alistair K Brown

{"title":"Structural isomerisation affects the antitubercular activity of adamantyl-isoxyl adducts.","authors":"Yucheng Lu, Daniel Partleton, Filibus M Gugu, Ahmed Y G Alhejaili, Samuel Norris, J Jonathan Harburn, Jason H Gill, Jonathan D Sellars, Alistair K Brown","doi":"10.1080/14756366.2025.2502600","DOIUrl":"10.1080/14756366.2025.2502600","url":null,"abstract":"Despite efforts to discover effective treatments to eradicate tuberculosis (TB), it remains a global threat. The increase in drug-resistant bacterial species has made the discovery of new drugs highly coveted. The utilisation of previous efficacious structures is one approach that can be employed to developing novel series of compounds to combat this ever-growing problem. This study sought to re-examine two such compounds, isoxyl (ISO) and SQ109, previously shown to be efficacious in TB treatment. SQ109-ISO hybrid compounds were shown to have demonstrable activity against both drug-sensitive and drug-resistant Mtb whilst displaying limited toxicity in vitro in comparison to other antitubercular agents. Indications from our genetic and biochemical studies suggest that these structurally similar pharmacophores bind to different proteins within Mtb, highlighting the need for careful consideration when producing regioisomeric analogues and that the utilisation of previous efficacious structures is a valid approach to developing promising novel drugs against Mtb.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2502600"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Design and synthesis of 1,4,8-triazaspiro[4.5]decan-2-one derivatives as novel mitochondrial permeability transition pore inhibitors. 新型线粒体通透性过渡孔抑制剂1,4,8-三氮杂螺[4.5]癸烷-2- 1衍生物的设计与合成。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-05-21 DOI: 10.1080/14756366.2025.2505907

Valentina Albanese, Gaia Pedriali, Martina Fabbri, Antonella Ciancetta, Silvia Ravagli, Chiara Roccatello, Remo Guerrini, Giampaolo Morciano, Delia Preti, Paolo Pinton, Salvatore Pacifico

{"title":"Design and synthesis of 1,4,8-triazaspiro[4.5]decan-2-one derivatives as novel mitochondrial permeability transition pore inhibitors.","authors":"Valentina Albanese, Gaia Pedriali, Martina Fabbri, Antonella Ciancetta, Silvia Ravagli, Chiara Roccatello, Remo Guerrini, Giampaolo Morciano, Delia Preti, Paolo Pinton, Salvatore Pacifico","doi":"10.1080/14756366.2025.2505907","DOIUrl":"10.1080/14756366.2025.2505907","url":null,"abstract":"Ischaemia/reperfusion injury (IRI) is a condition that occurs when tissues from different organs undergo reperfusion following an ischaemic event. The mitochondrial permeability transition pore (mPTP), a multiprotein platform including structural components of ATP synthase with putative gate function, is an emerging pharmacological target that could be modulated to facilitate the restoration of organ function after a hypoxic insult. Herein, we reported the synthesis and biological characterisation of new molecules with a 1,4,8-triaza-spiro[4.5]decan-2-one framework of potential interest for the treatment of IRI able to inhibit the opening of mPTP in a cardiac model in vitro. Modelling studies were useful to rationalise the observed structure-activity relationship detecting a binding site for the investigated molecules at the interface between the c8-ring and subunit a of ATP synthase. Compound 14e was shown to display high potency as mPTP inhibitor combined with the capability to counteract cardiomyocytes death in an in vitro model of hypoxia/reoxygenation.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2505907"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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