European Journal of Medicinal Chemistry最新文献

{"title":"Discovery, total synthesis, and biological evaluation of tyrcinnamins as antibacterial agents and tyrosinase activators","authors":"Di Mao ,&nbsp;Baoyue Wei ,&nbsp;Chao Liu ,&nbsp;Bing Zhang ,&nbsp;Zhiwei Zhang ,&nbsp;Yuhan Zhang ,&nbsp;Zhuang Li ,&nbsp;Boxiang Ding ,&nbsp;Hai Ye ,&nbsp;Jingjing Wang ,&nbsp;Lijuan Sun ,&nbsp;Yanan Gai ,&nbsp;Pengwei Yu ,&nbsp;Hideaki Kakeya ,&nbsp;Shan Lu","doi":"10.1016/j.ejmech.2025.117665","DOIUrl":"10.1016/j.ejmech.2025.117665","url":null,"abstract":"<div><div>Microorganisms serve as critical resources for the discovery of new antibacterial drug leads. Herein, we report the screening, isolation, and identification of tyrcinnamin (<strong>1</strong>) from the endophytic <em>Streptomyces</em> sp. JS-B1. The total synthesis, biological evaluation, and structural-activity relationship study of tyrcinnamin and its synthetic derivatives led to the discovery of <strong>7a</strong>, a promising lead compound with significant antibacterial activity, notable tyrosinase activation activity, and an excellent safety profile. The analysis of molecular docking of <strong>7a</strong> with mushroom tyrosinase reveals that <strong>7a</strong> may competitively occupy the binding site of <span>l</span>-DOPA on the surface of tyrosinase without interfering with the substrate binding at the active center, thereby reducing the ineffective occupancy of <span>l</span>-DOPA on the tyrosinase surface and improving the binding efficiency of <span>l</span>-DOPA at the active center. The structure of <strong>7a</strong> represents a new chemical scaffold for the development of new antibiotics and tyrosinase activators, making valuable contributions to both drug discovery and cosmetics development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117665"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858207","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 and synthesis of novel styrylquinolinium derivatives for the treatment of breast Cancer: Targeting the c-Myc G-quadruplex","authors":"Xutong Wang ,&nbsp;Yu Liu ,&nbsp;Zeyu Gao ,&nbsp;Xiaodong Fang ,&nbsp;Kejing Ma ,&nbsp;Meng Sun ,&nbsp;Qiming Li ,&nbsp;Bing Wang ,&nbsp;Yong Zhang ,&nbsp;Xin Zhao ,&nbsp;Weina Han","doi":"10.1016/j.ejmech.2025.117663","DOIUrl":"10.1016/j.ejmech.2025.117663","url":null,"abstract":"<div><div>Inhibiting <em>c-Myc</em> gene expression by targeting the <em>c-Myc</em> G-quadruplex (G4) represents an effective strategy for breast cancer treatment. In order to find ligands that can specifically target the <em>c-Myc</em> G4, we utilized styrylquinolinium as the core element to anchor G4, and proposed three guiding principles for the design and synthesis of G4 ligands. Finally, compound <strong>W11</strong> was identified as the compound skeleton which has the potential to target <em>c-Myc</em> G4. On this basis, compound <strong>X3</strong> with higher <em>c-Myc</em> G4 selectivity was developed. Both <strong>W11</strong> and <strong>X3</strong> demonstrate significant inhibitory effects on breast cancer. Subsequently, we used molecular docking and molecular dynamics simulation to analyze the relationship between the targeting ability and chemical structure of <strong>W11</strong> derivatives, and proposed a detailed structure-activity relationship model. Additionally, we found that the free energy landscape (FEL) of ligands with high selectivity and affinity for G4 is “centralized and singular” during this process. Cell experiments and MCF-7 tumor xenograft experiments demonstrated that <strong>W11</strong> inhibited the proliferation and metastasis of breast cancer cells by downregulating the transcription and translation of the <em>c-Myc</em> gene. Moreover <strong>W11</strong> significantly inhibited tumor tissue growth <em>in vivo</em> without causing obvious damage to major organs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117663"},"PeriodicalIF":6.0,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852063","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":"Tumor-specific cathepsin B-triggered fluorescence imaging and prodrug activation","authors":"Luyang Wang ,&nbsp;Houchi Yang ,&nbsp;Wanyun Huang ,&nbsp;Guojun Ran ,&nbsp;Xiaolong He ,&nbsp;Mark Bradley ,&nbsp;Shan Qian","doi":"10.1016/j.ejmech.2025.117661","DOIUrl":"10.1016/j.ejmech.2025.117661","url":null,"abstract":"<div><div>Bioorthogonal activation chemistries have great potential in the development of novel drug treatments due to their versatility, tunability, and the ability to generate therapies with improved spatial targeting. The upregulation of Cathepsin B is highly correlated with the development of cancers, however, few fluorescent probes or prodrugs-based on Cathepsin B activity have demonstrated high tumor selectivity, since Cathepsin B is expressed in a variety of normal tissues.</div><div>In this study, we report a strain-promoted azide−alkyne cycloaddition-activation strategy whereby a para-azido safety-catch linker is triggered by the tumor locating Biotin-TCO (<em>trans</em>-cyclooctene) conjugate, with subsequent tumor-specific Cathepsin B-triggered activation, generating a fluorescent reporter/cytotoxic drug, with high tumor selectivity. Our results suggest that this dual AND-Gate strategy of orthogonal Biotin AND Cathepsin B action would be advantageous for tumor-specific fluorescence labelling, fluorescence-guided surgery and targeted treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117661"},"PeriodicalIF":6.0,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849913","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":"A new short pH-responsive anticancer peptide derived by intramolecular charge shielding strategy","authors":"Linlin Chang ,&nbsp;Kaixin Ran ,&nbsp;Fengzhan Wu ,&nbsp;Yali Tian ,&nbsp;Yuxia Wang ,&nbsp;Linfeng Liu ,&nbsp;Xiaoyan Wu ,&nbsp;Xu Ouyang ,&nbsp;Beibei Li ,&nbsp;Zufang Ba ,&nbsp;Sanhu Gou ,&nbsp;Chao Zhong ,&nbsp;Hui Liu ,&nbsp;Yun Zhang ,&nbsp;Jingman Ni","doi":"10.1016/j.ejmech.2025.117662","DOIUrl":"10.1016/j.ejmech.2025.117662","url":null,"abstract":"<div><div>The pH-responsive anticancer peptides (ACPs) have been regarded as a new generation of prospective antitumor candidates due to their selectivity. However, the successful utilizations have been hampered by their narrow therapeutic index, poor stability and long sequence. Here, a new type of short pH-responsive ACPs was constructed by smart intramolecular charge shielding in histidine-rich peptide LH. This design would not depend on the introduction of additional anionic binding peptide, which might be an effective method for appreciably shortening the sequence of pH-responsive ACPs while improving their safety and stability. As expected, 2E-K stood out from the acquired peptides as it exhibited a considerable pH-dependent antitumor activity concomitant with remarkably improved therapeutic selectivity (14.5-fold increase) and extended serum half-life (3.6-fold enhancement) compared to LH. Experimental results showed that acid-activated 2E-K could efficiently induce tumor cell death by rapid membrane damage. Notably, the <em>in vivo</em> experiments further confirmed its excellent antitumor efficacy and low toxicity when compared with PTX, which demonstrating its superiority for <em>in vivo</em> application. In conclusion, our work opened a new avenue for developing short pH-responsive ACPs as promising alternative drugs in cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117662"},"PeriodicalIF":6.0,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849915","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":"Discovery of novel 4-azaindole derivatives as selective Nav1.2 Inhibitor with potent antiepileptic activity and low neurotoxicity","authors":"Bin Lou ,&nbsp;Wenhui Liang ,&nbsp;Nan Jiang ,&nbsp;Yuhan Guo ,&nbsp;Tianhao Zhang ,&nbsp;Chuanlong Guo ,&nbsp;Tongtong Du ,&nbsp;Longjiang Huang ,&nbsp;Haibo Yu","doi":"10.1016/j.ejmech.2025.117664","DOIUrl":"10.1016/j.ejmech.2025.117664","url":null,"abstract":"<div><div>Developing novel structural compounds with high efficacy, low neurotoxicity, and well-defined molecular targets remains a paramount objective in antiepileptic drug discovery. In this study, we designed and synthesized a series of 3-(1,2,3,6-tetrahydropyridine)-4-azaindole derivatives and evaluated their antiepileptic activity using subcutaneous pentetrazole (sc-PTZ) and maximum electric shock (MES) tests. In the sc-PTZ model, the most active compounds, <strong>4w</strong> and <strong>5i,</strong> exhibited median effective dose (ED₅₀) values of 22.01 mg/kg and 25.26 mg/kg, respectively. Notably, these compounds exhibited superior safety profiles compared to standard antiepileptic drugs (AEDs) such as valproate and ethosuximide, both compounds demonstrated lower neurotoxicity and higher protective indexes (PI = TD₅₀/ED₅₀) with PI values exceeding 27.26 and 23.75, respectively. Detailed structure-activity relationship (SAR) studies indicated that the N-atom at the 4-position and the H-atom of the NH unit in the 4-azaindole skeleton, and the double bond in 1,2,3,6-tetrahydropyridine are critical for their antiepileptic activities. Mechanistic results revealed that both compounds <strong>4w</strong> and <strong>5i</strong> primarily target voltage-gated sodium channels, rather than GABA_A or NMDA receptors. Further studies indicated that compounds <strong>4w</strong> and <strong>5i</strong> effectively block sodium ion channels and significantly inhibit Nav1.2 at the cellular level, which was further supported by molecular docking of compound <strong>4w</strong> and <strong>5i</strong> with Nav1.2 (PDB ID: 6J8E) receptor <em>in silico</em>.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117664"},"PeriodicalIF":6.0,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853800","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":"Discovery of a potent ornithine-modified gramicidin S analogue against drug-resistant Staphylococcus aureus and Enterococcus faecalis with minimal red blood cell toxicity","authors":"Harshita Dubkara ,&nbsp;Jhajan Lal ,&nbsp;Deepanshi Saxena ,&nbsp;Abdul Akhir ,&nbsp;Rahul Maitra ,&nbsp;Sidharth Chopra ,&nbsp;Damodara N. Reddy","doi":"10.1016/j.ejmech.2025.117654","DOIUrl":"10.1016/j.ejmech.2025.117654","url":null,"abstract":"<div><div>The high haemolytic toxicity of Gramicidin S restricts its therapeutic use to topical applications. Given the growing need for new antibiotics and drawing inspiration from the cyclic structure and druggable characteristics of Gramicidin S, we have synthesized 15 ornithine (Orn) modified analogous peptides systematically and investigated their antimicrobial activity and cytotoxicity. Results revealed that mono- ornithine residue replaced with tryptophan (<strong>11)</strong> and arginine (<strong>12)</strong> peptides showed improved activity against multidrug resistant bacterial strains of <em>Staphylococcus aureus</em> and <em>Enterococcus faecalis</em> (MIC 4–8 μg/mL) compared with comparators vancomycin (MIC &gt;64 μg/mL), levofloxacin (MIC 32–64 μg/mL) and meropenem (MIC 8–64 μg/mL). Cytotoxicity data demonstrated that peptide <strong>11</strong> (HC₅₀ = 112.1 μg/mL) and <strong>12</strong> (HC₅₀ = 186 μg/mL) exhibited greatly reduced haemolytic activity, as compared with Gramicidin S (HC₅₀ = 35.13 μg/mL). The concentration-dependent time-kill kinetic assay resulted the active peptide <strong>12</strong> represents better bactericidal effect compared with <strong>11</strong> and vancomycin. Scanning electron microscope analysis shows that <strong>GS</strong> and the modified peptide <strong>12</strong> disrupt the bacterial cell surface, causing damage and leading to bacterial cell death. 2D NOESY data of <strong>12</strong> showed that the arginine residue side-chain guanidinium ion and tryptophan indole form a cation-π interaction. This interaction between arginine and tryptophan stabilizes the <em>β</em>-sheet conformation, selectively targets bacterial membranes, hence exhibiting reduced red blood cell toxicity. The overall study suggests that the peptide <strong>12</strong> may be further developed as an antibiotic for systematic use against infections caused due to <em>S. aureus</em>.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117654"},"PeriodicalIF":6.0,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849917","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":"Enhancing the Activity of γ-Hydroxy Lactone Derivatives as Innovative Peroxisome Proliferator-Activated Receptor γ Non-Agonists Inhibiting Cyclin-Dependent Kinase 5-Mediated Phosphorylation","authors":"Giulia Cazzaniga, Davide Capelli, Roberta Montanari, Enrico Mario Alessandro Fassi, Giovanni Grazioso, Andrea Tresoldi, Francesca Rinaldi, Enrica Calleri, Ivan Bassanini, Sergio Romeo, Mariangela Garofalo, Matteo Mori, Fiorella Meneghetti, Stefania Villa","doi":"10.1016/j.ejmech.2025.117657","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117657","url":null,"abstract":"Insulin resistance (IR) is a pathological condition in which tissues exhibit a reduced response to normal or elevated levels of insulin. Type 2 diabetes mellitus (T2DM) and Metabolic Syndrome are the most prevalent disorders associated with IR. Most of the glitazones, traditional anti-diabetic drugs acting as Peroxisome Proliferator-Activated Receptor γ (PPARγ) agonists, have been withdrawn from the market. To mitigate the serious adverse effects associated with PPARγ agonism, a new opportunity is represented by the inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser245. Recently, we identified 4-(4-bromophenyl)-3-hydroxy-5-(3-hydroxyphenyl)furan-2(5<em>H</em>)-one (<strong>I</strong>) as a PPARγ non-agonist, capable of blocking the phosphorylation of the enzyme without direct effects on either CDK5 or PPARγ.Here, we isolated the two enantiomers of <strong>I</strong>, unambiguously defined their absolute configuration through single crystal X-ray diffraction and demonstrated by Grating-Coupled Interferometry binding assays that both <strong>(<em>S</em>)-I</strong> and <strong>(<em>R</em>)-I</strong> exhibited comparable affinity for PPARγ. Then, a library of 12 analogs was designed through structure-based modifications, optimizing the interactions within the ligand-binding domain. GCI analysis identified derivative <strong>11</strong>, featuring an oxyacetic group in place of the initial hydroxyl function of the reference compound <strong>I</strong>, as the most promising candidate (K_D = 186 nM). The crystal structure of the PPARγ-LBD/<strong>11</strong> complex revealed a hydrogen bond interaction with Arg280, further stabilizing the binding conformation. These findings highlight the potential of γ-hydroxy lactone derivatives as PPARγ modulators and provide a foundation for future drug development targeting IR.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849918","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 activity of novel pyrimidine piperazine ureas as μ-opioid and TRPV1 dual-target ligands for pain management","authors":"Yusui Wang ,&nbsp;Shuyu Liu ,&nbsp;Zhikang Zhang ,&nbsp;Yunmeng Ma ,&nbsp;Kexin Qin ,&nbsp;Jiahao Du ,&nbsp;Yu Wang ,&nbsp;Bingxin Wang ,&nbsp;Hai Qian ,&nbsp;Xiaobin Pang ,&nbsp;Fenqin Zhao ,&nbsp;Guanhua Du ,&nbsp;Lin Yan","doi":"10.1016/j.ejmech.2025.117656","DOIUrl":"10.1016/j.ejmech.2025.117656","url":null,"abstract":"<div><div>The pathophysiology of pain involves multiple signaling pathways, making its management a persistent clinical challenge. Transient receptor potential vanilloid 1 (TRPV1) acts as a molecular integrator of nociceptive stimuli in primary C-fiber sensory neurons and plays a crucial role in nociception, as well as in neuropathic and inflammatory pain. Numerous TRPV1 antagonists have been evaluated in clinical trials for various pathologies, including pain. However, their clinical development has been hindered by side effects such as hyperthermia and impaired noxious heat sensation. Additionally, these antagonists have limited efficacy when used as standalone therapies. Furthermore, studies have demonstrated a complex interplay between TRPV1 and μ-opioid receptor (MOR). In this study, dual-acting compounds targeting both TRPV1 and MOR were designed and synthesized using a pharmacophore fusion strategy, aimed at enhancing pain treatment, overcoming drug resistance, and minimizing the adverse effects typically associated with single-target drugs. Among these, compound <strong>2ac</strong> demonstrated the highest <em>in vitro</em> potency, with an IC₅₀ of 29.3 nM for TRPV1 antagonism and a K_i of 60.3 nM for MOR binding affinity. <em>In vivo</em> analgesic experiments conducted using a formalin-induced pain model in mice showed that compound <strong>2ac</strong> exhibited a potent, dose-dependent anti-nociceptive effect. Target engagement studies confirmed that the analgesic effect of compound <strong>2ac</strong> was attributed to both TRPV1 antagonism and MOR activation. Notably, further testing indicated that compound <strong>2ac</strong> did not induce hyperthermia (a common side effect of TRPV1 antagonists) or lead to analgesic tolerance (a typical opioid-related adverse effect). Additionally, molecular docking studies showed strong compatibility of compound <strong>2ac</strong> with the active sites of hMOR and hTRPV1, supporting its potential as a promising lead compound for pain management.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117656"},"PeriodicalIF":6.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849914","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":"Targeted vancomycin delivery via in situ albumin conjugation and acid-triggered drug release for reduced nephrotoxicity","authors":"Tao Li ,&nbsp;Ziyi Tang ,&nbsp;Ruixue Zhang ,&nbsp;Mahesh Challa ,&nbsp;Hongzhi Gong ,&nbsp;Zhi Gong ,&nbsp;Shao-Lin Zhang ,&nbsp;Jian Guo ,&nbsp;Yun He","doi":"10.1016/j.ejmech.2025.117652","DOIUrl":"10.1016/j.ejmech.2025.117652","url":null,"abstract":"<div><div>Vancomycin has long been considered as the last-resort antibiotic for tacking extremely severe infections caused by methicillin-resistant <em>Staphylococcus aureus</em> (MRSA). However, its clinical application is limited by dose-limiting nephrotoxicity. In this study, we report a novel <em>in situ</em> albumin conjugation and acid sensitive prodrug strategy to selectively release vancomycin at the infection site, thereby minimizing the accumulation of vancomycin in the kidney and thus reducing its nephrotoxicity. We synthesized and evaluated four vancomycin prodrugs <strong>13a-d</strong> and found that <strong>13c</strong> effectively bound to plasma albumin <em>in vitro,</em> and released vancomycin rapidly at the infection site. Its therapeutic effect against MRSA USA300 infection was comparable to that of free vancomycin at 10 mg/kg. <em>In vivo</em> safety assessments demonstrated that <strong>13c</strong> did not exhibit significant nephrotoxicity at 50 mg/kg, whereas vancomycin caused obvious nephrotoxicity at the same dose. This work represents the first example of utilizing albumin for targeted delivery of antibiotic to the bacterial infection site to mitigate the common dose-limiting nephrotoxicity of vancomycin, and this strategy may also be applicable to other aminoglycoside antibiotics with nephrotoxicity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117652"},"PeriodicalIF":6.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846901","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":"Challenging triple negative breast cancer through HDAC6 selective inhibition: Novel cap-group identification, structure-activity relationships, computational and biological studies","authors":"Simona Barone ,&nbsp;Ivana Bello ,&nbsp;Anna Guadagni ,&nbsp;Carmen Cerchia ,&nbsp;Gessica Filocamo ,&nbsp;Emilia Cassese ,&nbsp;Antonella Ilenia Alfano ,&nbsp;Camilla Esposito ,&nbsp;Álvaro Javier Feliz Morel ,&nbsp;Mirko Brunetti ,&nbsp;Antonio Lavecchia ,&nbsp;Vincenzo Summa ,&nbsp;Elisabetta Panza ,&nbsp;Margherita Brindisi","doi":"10.1016/j.ejmech.2025.117634","DOIUrl":"10.1016/j.ejmech.2025.117634","url":null,"abstract":"<div><div>Triple negative breast cancer (TNBC) stands out among breast cancers subtypes for its high aggressiveness and invasiveness. Compelling new evidence pointed out the role of epigenetic modifications in TNBC, with recent studies demonstrating that approximately 30 % of human breast cancers could potentially benefit from histone deacetylase 6 (HDAC6) inhibitor therapy. We herein disclose a novel class of spiro-fused compounds acting as potent and selective HDAC6 inhibitors. Structure-based optimization led to derivatives <strong>23c</strong> and <strong>24c</strong> with high potency and selectivity towards HDAC6 <em>in vitro</em> and in cell-based settings. Following our observation that mRNA expression level of HDAC6 was significantly higher in MDA-MB-231, we have evaluated the effect of the compounds on cell viability. Moreover, we have unveiled for compounds <strong>23c</strong> and <strong>24c</strong> the involvement of the autophagic machinery in cell death induction. Scratch assay revealed for the newly conceived compounds a very potent effect on inhibiting the migration process in MDA-MB-231 cells. Our results underscore the key role of HDAC6 in TNBC progression, providing a solid groundwork to reshape TNBC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117634"},"PeriodicalIF":6.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849920","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}