Chemico-Biological Interactions最新文献

{"title":"HIF-1α/BNIP3L–mediated mitophagy is involved in T-2 toxin–induced myocardial injury","authors":"Qian Li ,&nbsp;Miao Wang ,&nbsp;Juan Zuo ,&nbsp;Zaichao Dong ,&nbsp;Tongtong Sha ,&nbsp;Kangting Luo ,&nbsp;Huanxia Zhang ,&nbsp;Yanjie Dou ,&nbsp;Guoyu Zhou ,&nbsp;Yue Ba ,&nbsp;Fang-fang Yu","doi":"10.1016/j.cbi.2025.111844","DOIUrl":"10.1016/j.cbi.2025.111844","url":null,"abstract":"<div><div>T-2 toxin, the most toxic type A mycotoxin, induces cardiotoxicity and impairs cardiac function. Herein, we investigated the regulatory role of mitophagy in T-2 toxin–induced myocardial injury. Using the Comparative Toxicogenomics Database, we identified 288 rat genes associated with T-2 toxin–induced myocardial injury. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that mitophagy was significantly associated with myocardial injury. Protein–protein interaction network analysis revealed <em>HIF-1α</em> as the core regulatory gene. Rats were exposed to T-2 toxin and assigned to control, low-dose (100 ng/g·bw/day), and high-dose (200 ng/g·bw/day) groups. H9C2 cardiomyocytes were divided into control, low-dose (3 ng/mL), medium-dose (6 ng/mL), and high-dose (12 ng/mL) groups. High-dose T-2 toxin exposure caused significant myocardial damage, increased lactate dehydrogenase and creatine kinase–myocardial band levels, elevated reactive oxygen species (ROS) accumulation, and upregulated HIF-1α expression in the nucleus. Flow cytometry showed that T-2 toxin significantly decreased mitochondrial membrane potential. Transmission electron microscopy revealed mitochondrial swelling, vacuolation, and cristae disruption. Molecular docking and immunofluorescence confirmed direct binding between BNIP3L and LC3. T-2 toxin significantly upregulated HIF-1α, BNIP3L, and LC3 mRNA and protein levels, promoted LC3-I to LC3-II conversion, and suppressed P62 expression in tissues and cells. Immunohistochemistry further confirmed these protein expression trends. Myocardial injury was ameliorated by 2-ME2 by suppressing HIF-1α accumulation and BNIP3L-mediated mitophagy. In summary, T-2 toxin–induced ROS accumulation activated HIF-1α in cardiomyocytes, which regulated BNIP3L–LC3 binding, mediated mitophagy, and ultimately caused myocardial injury.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111844"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575061","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":"Per- and polyfluoroalkyl substances trigger autoimmune diseases through inflammatory cytokines-IL-17/Th17 signaling axis","authors":"Qi Cheng ,&nbsp;Yifan Xie ,&nbsp;Yingying Hou ,&nbsp;Yan Du ,&nbsp;Huaxiang Wu","doi":"10.1016/j.cbi.2025.111837","DOIUrl":"10.1016/j.cbi.2025.111837","url":null,"abstract":"<div><div>This study systematically investigates the mechanisms by which per- and polyfluoroalkyl substances (PFAS) promote immune dysregulation and trigger autoimmune diseases (ADs). Using an integrated network toxicology and bioinformatics approach, we identified core molecular interactions between PFAS and five ADs—rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), ankylosing spondylitis (AS), and vasculitis. By combining data from STITCH, SwissTargetPrediction, Comparative Toxicogenomics Database, GeneCards, and OMIM, we identified shared targets linked to both PFAS exposure and AD pathogenesis. Functional enrichment analysis was performed using DAVID, and protein-protein interaction networks were constructed with STRING and visualized in Cytoscape to highlight core targets. Gene expression data from the GEO database revealed the upregulation or downregulation of these targets across these ADs. Molecular docking performed with CB-Dock2 confirmed robust binding between six PFAS and core targets, notably IL1B, TNF, IL6 and ALB. Importantly, we identified a common pathological mechanism involving PFAS-mediated disruption of the inflammatory cytokine axis (IL1B, TNF, IL6) and IL-17/Th17 signaling pathway, which triggers ADs. Furthermore, compared to PFOS, its alternative 6:2 Cl-PFESA showed higher binding affinity to core targets, suggesting greater environmental and health risks that warrant re-evaluation. In conclusion, our research has provided novel and important insights into environmental health and ADs by clarifying core targets and potential mechanisms, and has expanded the evidence into the molecular mechanism of PFAS-induced immunotoxicity and linking PFAS exposure to ADs.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111837"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566748","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":"Selective cytotoxicity of anhydroicaritin in ER-positive breast cancer via ESR1-mediated MAPK and apoptotic signaling","authors":"Huiyan Ying ,&nbsp;Jujia Zheng ,&nbsp;Mingxiang Jiang ,&nbsp;Wanlu Shi ,&nbsp;Xiangwei Xu ,&nbsp;Xiaofen Ni","doi":"10.1016/j.cbi.2025.111825","DOIUrl":"10.1016/j.cbi.2025.111825","url":null,"abstract":"<div><div>Anhydroicaritin (AHI), a chemically characterized prenylated flavonoid, exhibits strong and selective cytotoxicity against estrogen receptor-positive (ER+) breast cancer cells. In this study, we aimed to elucidate its molecular and cellular toxicological mechanisms using an integrated strategy consisting of chemoinformatics, machine learning-based target prioritization, Mendelian randomization (MR) causal inference, and in vitro mechanistic assays. Network pharmacology analysis revealed that ESR1 (estrogen receptor 1) was ranked as the top hit hub gene and was further supported as a functional mediator of AHI action by machine learning models and MR analysis. Molecular docking and 100-ns molecular dynamics simulations demonstrated that AHI could form a stable and energetically preferred interaction with estrogen receptor 1 (ESR1). Subsequent mechanistic experiments in MCF-7 and ZR-75-1 cells revealed that AHI could attenuate the activity of MAPK signaling pathway and induce apoptosis by downregulating ESR1 mRNA expression through reducing ERα phosphorylation. Notably, AHI exhibited weak cytotoxicity against normal mammary epithelial cells, suggesting that it might exhibit selective toxicity toward malignant phenotypes. Our findings offered mechanistic evidence for the dual-level (post-translational and transcriptional) regulation of ESR1 signaling by AHI in ER+ breast cancer and suggested that AHI might be a subtype-specific chemotherapeutic lead compound.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111825"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515250","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":"Expanding the reactive chemistry toolbox – warhead screening for covalent butyrylcholinesterase inhibitors","authors":"Anže Meden ,&nbsp;Xavier Brazzolotto ,&nbsp;José Dias ,&nbsp;Jure Stojan ,&nbsp;Damijan Knez ,&nbsp;Stanislav Gobec","doi":"10.1016/j.cbi.2025.111841","DOIUrl":"10.1016/j.cbi.2025.111841","url":null,"abstract":"<div><div>Many covalent inhibitors of butyryl- and acetylcholinesterase, typically featuring electrophilic carbamoyl, phosphonyl, and sulfonyl groups, were reported in the literature. In this study, we screened these and several other electrophilic moieties for covalent cholinesterase inhibition. The electrophilic warheads were either installed at different positions on a reversible, selective human butyrylcholinesterase inhibitor scaffold or featured as small molecular weight, fragment-sized compounds. Time-dependency of the enzyme inhibition served as an indicator of covalent binding. The 7-indolyl substitution pattern proved optimal for generating time-dependent inhibitors, and carbamate chemotype produced most of the time-dependent hit compounds. Interestingly, the carbamates' reactivity was strongly influenced by their leaving groups’ nucleofugality and not by steric hindrance, as sufficiently acidic leaving groups (pKa &lt;10) enabled carbamoylation of the catalytic serine. Notably, an exception to this rule of a thumb was found in a series of chalcogen carbachol analogues. The gathered insights highlight some key structure–reactivity relationships for covalent hBChE inhibitors and may assist in development of novel serine hydrolase inhibitors.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111841"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145589561","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":"Cardiac glycosides toxicity: Mechanisms and mitigation strategies in recent studies","authors":"Shuyun Xiao ,&nbsp;Mengqi Tong ,&nbsp;Jiayi Ren ,&nbsp;Yidan Bai ,&nbsp;Jian Xu ,&nbsp;Kouharu Otsuki ,&nbsp;Wei Li ,&nbsp;Feng Feng ,&nbsp;Jie Zhang","doi":"10.1016/j.cbi.2025.111817","DOIUrl":"10.1016/j.cbi.2025.111817","url":null,"abstract":"<div><div>Cardiac glycosides, while renowned for their cardiotonic effects, present a significant challenge in drug development due to their narrow therapeutic window. Although their antitumor potential, exemplified by derivatives such as RX108 entering clinical trials, has renewed research interest, inherent cardiotoxicity remains a major safety concern. This review focuses on recent advances in understanding and mitigating cardiac glycoside toxicity. A central focus is placed on comprehensively summarizing the intricate molecular mechanisms underlying their cardiotoxicity, which extend beyond the canonical Na⁺/K⁺-ATPase inhibition. In addition, we examine their multi-organ toxicity profiles and corresponding clinical management strategies, with particular emphasis on digoxin-specific Fab antibodies. Another pivotal aspect of this review is a critical analysis of contemporary, rational structural modification strategies designed to decouple cardiotoxicity from therapeutic efficacy. By synthesizing these insights, this work aims to provide a foundational framework for overcoming the toxicity hurdles and advancing the repurposing of cardiac glycosides in precision oncology and other therapeutic areas.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111817"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145508518","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":"Dieckol induces vasodilation via endothelial–smooth muscle crosstalk in co-culture and in vivo zebrafish models","authors":"Seungjin Jeong ,&nbsp;Yu-An Lu ,&nbsp;Seokmin Lee ,&nbsp;Jae-Il Kim ,&nbsp;You-Jin Jeon ,&nbsp;Jimin Hyun ,&nbsp;Bomi Ryu","doi":"10.1016/j.cbi.2025.111815","DOIUrl":"10.1016/j.cbi.2025.111815","url":null,"abstract":"<div><div>Dieckol (DK), a phlorotannin isolated from <em>Ecklonia cava</em>, has been suggested to exert vasodilatory effects through endothelial signaling. In this study, the endothelial–smooth muscle signaling pathway involved in DK-mediated vasodilation was recapitulated using a multistep experimental system that integrates a co-culture of human coronary artery endothelial cells (HCAEC) and human coronary artery Smooth Muscle Cells (HCASMC) with an in vivo zebrafish model. DK activated calcium-dependent signaling pathways in HCAEC, notably via muscarinic acetylcholine receptor M3 (AChM3R) and voltage-dependent calcium channels (VDCC), resulting in increased intracellular calcium levels and nitric oxide (NO) production. These effects were confirmed using specific antagonists. NO produced by HCAEC was subsequently transferred to adjacent HCASMC, leading to reduced expression of contractile proteins such as phosphorylated myosin light chain (<em>p</em>-MLC) and calmodulin (CaM), thereby promoting smooth muscle relaxation. Moreover, DK counteracted phenylephrine-induced vasoconstriction in zebrafish by reinforcing vascular integrity and regulating blood flow dynamics, ultimately restoring vascular patency and hemodynamic homeostasis. Collectively, these results demonstrate that DK induces vasodilation by activating AChM3R– and VDCC–mediated calcium signaling and NO production in endothelial cells, with downstream effects on vascular smooth muscle cells. This study highlights the therapeutic potential of DK for improving vascular function through modulation of endothelial–smooth muscle signaling.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111815"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145544265","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":"Reactivation screening of A-234-inhibited human recombinant acetylcholinesterase in vitro","authors":"Jakub Opravil ,&nbsp;Jaroslav Pejchal ,&nbsp;Martina Hrabinova ,&nbsp;Lubica Muckova ,&nbsp;Lukas Prchal ,&nbsp;Jan Korabecny ,&nbsp;Tomas Rozsypal ,&nbsp;Lukas Gorecki ,&nbsp;Jakub Fibigar ,&nbsp;Ondrej Soukup ,&nbsp;Kamil Musilek ,&nbsp;Daniel Jun","doi":"10.1016/j.cbi.2025.111810","DOIUrl":"10.1016/j.cbi.2025.111810","url":null,"abstract":"<div><div>The nerve agent A-234, classified among the so-called A-series agents or “Novichoks”, represents a significant challenge in the treatment of nerve agent poisoning due to its potent and irreversible inhibition of human recombinant acetylcholinesterase (<em>Hss</em>AChE). In this study, we screened 22 structurally diverse oxime reactivators for their efficacy against A-234-inhibited <em>Hss</em>AChE <em>in vitro</em> after a 10-min incubation. The initial screening was extended to GB- and VX-inhibited enzymes under the same conditions for comparison. Then, the 22 oximes were tested against A-234-inhibited <em>Hss</em>AChE for up to 24 h. Finally, we evaluated the reactivation kinetics of the two most effective oximes over a 240-min period. While most reactivators demonstrated considerable reactivation against GB- and VX-inhibited enzymes within 10 min, none showed efficacy against A-234 in this time frame. Extended incubation over 24 h revealed that only HLö-7, MMB-4, HI-6, K027, K868, TMB-4, GM415, and LüH-6 achieved efficient reactivation (set at a 10 % threshold for a 24-h interval), with HLö-7 and methoxime (MMB-4) being the most effective. Kinetic analysis indicated that HLö-7 exhibited a superior second-order reactivation rate constant compared to MMB-4, highlighting differences in binding affinity and catalytic efficacy. In the case of A-234 poisonings, our findings indicate the most effective oxime antidotes and emphasize the need for prolonged therapy to improve clinical outcomes.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111810"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460854","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":"Dual cholinergic modulation in dementia: Quinuclidine carbamates targeting butyrylcholinesterase and α7 nicotinic receptor","authors":"Peter Mastnak-Sokolov ,&nbsp;Damijan Knez ,&nbsp;Anže Meden ,&nbsp;Nika Strašek Benedik ,&nbsp;Svit Ferjančič Benetik ,&nbsp;Martina Hrast Rambaher ,&nbsp;Maša Zorman ,&nbsp;Florian Nachon ,&nbsp;Xavier Brazzolotto ,&nbsp;Kent Jardemark ,&nbsp;Oscar Jungholm ,&nbsp;Joseph Bruton ,&nbsp;Emilia Strandback ,&nbsp;Tomas Nyman ,&nbsp;Mohammed Shahid ,&nbsp;Stanislav Gobec","doi":"10.1016/j.cbi.2025.111830","DOIUrl":"10.1016/j.cbi.2025.111830","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the leading cause of dementia worldwide, but current therapies provide only symptomatic relief. Multi-target directed ligands (MTDLs) represent a promising approach to address AD pathology by modulating multiple targets with a single molecule. Here we describe quinuclidine carbamates that act simultaneously on butyrylcholinesterase (BChE) and the cholinergic α7 nicotinic receptor (α7 nAChR), thereby approaching cholinergic dysfunction at two levels: by modulating acetylcholine degradation and by direct agonism at this receptor. Starting with the α7 nAChR agonist bradanicline, its amide group was replaced by a carbamate moiety to enhance BChE inhibition while retaining receptor agonism. These quinuclidine carbamates inhibited BChE in the submicromolar range with the desired selectivity over acetylcholinesterase (AChE). In a calcium-flux assay on recombinant HEK293T cells expressing the α7 nAChR, all compounds were agonists of the α7 nAChR in the nanomolar range. Importantly, compound <strong>6b</strong> displayed balanced, submicromolar activity against both targets. The crystal structures confirmed non-covalent binding to the active site of human BChE, and the <strong>6b</strong>-hBChE complex also revealed an unprecedented flip of Tyr440, representing the first described example of backdoor opening for hBChE. Taken together, these results demonstrate that quinuclidine carbamates are promising dual modulators of hBChE and α7 nAChR, supporting their potential as MTDLs for AD therapy and highlighting this underexplored dual-target strategy as a promising approach in cholinergic drug discovery.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111830"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535206","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":"Reflection about articaine: in vitro studies and clinical data - RE: Schwann cells exposed to articaine display distinct toxic pathways compared to lidocaine by Rodrigues da Silva et al. - Chem Biol Interact. 2025 Jan 25; 406: 111315","authors":"Filipe Polese Branco ,&nbsp;Maria Cristina Leme Godoy dos Santos","doi":"10.1016/j.cbi.2025.111816","DOIUrl":"10.1016/j.cbi.2025.111816","url":null,"abstract":"","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111816"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491170","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":"Potent carbonic anhydrase inhibition by ruthenium(II)-acetazolamide conjugates uncoupled from antiproliferative activity in vitro","authors":"Alberto Gobbo ,&nbsp;Simone Giovannuzzi ,&nbsp;Maria Luisa Massardi ,&nbsp;Marta Turati ,&nbsp;Lorenzo Biancalana ,&nbsp;Stefano Zacchini ,&nbsp;Marco Bortoluzzi ,&nbsp;Claudiu T. Supuran ,&nbsp;Fabio Marchetti","doi":"10.1016/j.cbi.2025.111842","DOIUrl":"10.1016/j.cbi.2025.111842","url":null,"abstract":"<div><div>The novel ruthenium(II) complexes [RuCl(κ³<em>N</em>-tpm)(PPh₃)(κ¹<em>N</em>-AcmH₂)]Cl (<strong>5</strong>) and [Ru(κ³<em>N</em>-tpm)(PPh₃)(κ²<em>N,N′</em>-AcmH)]NO₃ (<strong>6</strong>) were synthesized in 46–57 % yields via thermal reactions of [RuCl(κ³<em>N</em>-tpm)(PPh₃)₂]Cl (<strong>4</strong>) with AcmH₂, conducted in THF and ethanol, respectively [tpm = tris(pyrazolyl)methane; AcmH₂ = acetazolamide]. Both complexes were fully characterized by single crystal X-ray diffraction, IR and NMR spectroscopy. Their solubility in D₂O, octanol/water partition coefficients (Log <em>P</em>_<em>ow</em>) and speciation in physiological-like solutions were assessed by ¹H NMR and UV–Vis methods. Additionally, DFT calculations provided insights into the structural and thermodynamic properties of <strong>5</strong>. Complexes <strong>5–6</strong>, together with the previously reported ruthenium(II) arene acetazolamide adducts [RuCl₂(κ¹<em>N</em>-AcmH₂)(η⁶-<em>p</em>-cymene)] (<strong>1</strong>)<strong>,</strong> [RuCl(κ²<em>N</em>,<em>N</em>′-AcmH)(η⁶-<em>p</em>-cymene)] (<strong>2</strong>) and [Ru(κ²<em>N</em>,<em>N</em>′-Acm)(κ<em>P</em>-PTA)(η⁶-<em>p</em>-cymene)] (<strong>3</strong>, PTA = 1,3,5-triaza-7-phosphaadamantane), exhibited potent inhibitory activity against human carbonic anhydrase isoforms I, II, IX and XII, with K_I values in the low to sub-nanomolar range. Under hypoxic conditions, complexes <strong>5</strong> and <strong>6</strong> showed a moderate antiproliferative activity against the human triple negative breast cancer cell line MDA-MB-231 (IC₅₀ = 143.3, 40.9 μM), while complexes <strong>2</strong> and <strong>3</strong> were inactive (IC₅₀ &gt; 200 μM).</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111842"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598199","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}