European Journal of Pharmaceutical Sciences最新文献

{"title":"Glycyrrhizic acid alters [^99mTc]Tc-PSMA biodistribution and tumour progression in a DMBA-induced breast cancer model.","authors":"Fatma J Al-Saeedi, Fahad F Almutairi, Mohammed Jaseem, Aisha W Alqadeeri, Dalal H Alwazzan, Moudhi M Alenezi","doi":"10.1016/j.ejps.2026.107689","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107689","url":null,"abstract":"<p><p>Breast cancer remains a major global health challenge, and understanding interactions between pharmacological agents and radiopharmaceuticals is important for interpreting molecular imaging findings. Glycyrrhizic acid (GA), a bioactive triterpenoid derived from Glycyrrhiza glabra, has reported anti-inflammatory and anticancer activities; however, its effects on PSMA-targeted radiotracer biodistribution remain poorly investigated. This study evaluated GA effects on tumour-related biological responses and [^99mTc]Tc-PSMA biodistribution in vitro and in vivo. Cytotoxicity, migration, and invasion were assessed in MDA-MB-231 breast cancer cells. Cell-free PSMA enzyme kinetics and a separate cellular [^99mTc]Tc-PSMA uptake assay were performed to distinguish effects on PSMA enzymatic activity from cell-associated radiotracer uptake. In vivo studies used a DMBA-induced mammary tumour model in female Sprague-Dawley rats, followed by SPECT/CT imaging and tissue biodistribution analysis. GA reduced cell viability concentration-dependently (IC₅₀ = 20 µM at 48 h) and suppressed migration and invasion. Cell-free kinetic analysis showed an apparent non-competitive PSMA inhibition pattern (Ki = 12.4 ± 1.5 µM), although this does not establish the molecular binding site. In vivo, GA reduced tumour uptake of [^99mTc]Tc-PSMA by 57% (P < 0.005) and altered non-target tissue distribution. Despite reduced absolute tumour uptake, the tumour-to-background ratio increased because background activity decreased proportionally more. GA was also associated with reduced tumour growth and metastatic burden and altered inflammatory, angiogenic, and apoptotic markers. Overall, GA alters tumour biology and [^99mTc]Tc-PSMA biodistribution, while the mechanism underlying radiotracer changes remains unresolved.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107689"},"PeriodicalIF":5.1,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational Evaluation of In Vitro-to-In Vivo Extrapolation Techniques for Brain Penetration Using Open Flow Microperfusion and Microdialysis in Rats.","authors":"Yukiko Murata, Janita Hogan, Zubida M Al-Majdoub, Jonathan Cheong, Jingjing Guo, Kunihiko Mizuno, Tom De Bruyn, Raymond Evers, Thomas Altendorfer-Kroath, Cornelis E C A Hop, Anne Kanta, Megan Turski, Michael A Zientek, Sibylle Neuhoff, Thomas Birngruber, Aleksandra Galetin, Amin Rostami-Hodjegan, Kayode Ogungbenro","doi":"10.1016/j.ejps.2026.107691","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107691","url":null,"abstract":"<p><p>There is a growing need to leverage mathematical models of the central nervous system (CNS) with translational approaches employing in vitro-in vivo extrapolation (IVIVE) approaches. As a benchmark of brain penetration, unbound brain partitioning (K_p,uu), and subsequently a combination of cerebral Open Flow Microperfusion (cOFM) and microdialysis (MD) were evaluated in rats. Additionally, a six-compartment physiologically-based pharmacokinetic (PBPK) model of the CNS was developed in rats using six drugs with varying affinities to the P-glycoprotein (P-gp) transporter to learn and verify the in vivo studies. Active and passive drug efflux and permeability parameters derived from two P-gp overexpressing cell lines (MDCK-I and LLC-PK₁) were scaled using proteomics-informed methods. Model predictions were evaluated with data obtained from terminal brain-to-plasma partition coefficient from both rat cOFM and MD experiments. In correcting for loss of drug in both the cOFM and MD equipment, a relative recovery (RR) showed significantly higher recovery in cOFM compared to MD experiments; for phenytoin, quinidine, and verapamil these were 0.53/0.063, 0.73/0.46, and 0.16/0.04 (cOFM/MD), respectively. Notably, higher P-gp efflux obtained from experiments with MDCK-I-transfected cells resulted in simulated lower drug concentrations in brain compartments. Overall, the CNS-IVIVE-PBPK model tended to overpredict brain drug concentrations, especially using data obtained from transfected LLC-PK₁ cells. However, there is better agreement between the model predictions and the observed data for whole-brain concentrations obtained from terminal studies. We also demonstrated the feasibility of an IVIVE framework that integrates cell line derived passive and active drug parameters to estimate brain concentrations.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107691"},"PeriodicalIF":5.1,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of PRG4 mRNA-Loaded Polymeric Nanoparticles in In Vitro and In Vivo Models of Osteoarthritis.","authors":"Katrin Agnes Muenzebrock, Kelly Warmink, Remei Escudero Franch, Daniela M J Koster, Mattie Rijker, Yeter Dilek, Jie Du, Adriano P Pontes, Niels Eijkelkamp, Joris Bekkers, Jaap Rip, Laura B Creemers, Jaqueline Lourdes Rios","doi":"10.1016/j.ejps.2026.107690","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107690","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is a highly prevalent degenerative joint disease for which no disease-modifying treatments are available. Proteoglycan 4 (PRG4) is a glycoprotein with lubricating and immunomodulatory properties, making it a promising therapeutic target for mRNA-based therapies. Therefore, this study evaluated the effects of PRG4 mRNA delivered via polymeric nanoparticles in both in vitro and in vivo OA models.</p><p><strong>Methods: </strong>Human chondrocytes from OA patients were cultured in 3D pellet models and transfected with PRG4 mRNA-loaded polymeric nanoparticles at low or high dose, once or twice, respectively. Viability, pellet growth, glycosaminoglycan (GAG) production and mRNA expression were assessed, with EGFP mRNA transfection as a negative control. In vivo, an osteoarthritis rat model was used to evaluate PRG4 mRNA effects on pain behavior, cartilage degeneration, and synovial inflammation.</p><p><strong>Results: </strong>In vitro, nanoparticle treatment induced an increase in pellet size and overall GAG production, independent of their cargo. PRG4 mRNA nanoparticle treatment at lower doses increased total pellet GAG content and early GAG release. Higher doses showed no additional benefit, and repeated transfection of the high dose significantly decreased cell viability. Double transfection of either dose showed increased relative expression of PRG4 mRNA, indicating uptake of the nanoparticles into the pellet. In vivo, PRG4 mRNA nanoparticles did not alleviate pain, reduce OA severity, or mitigate synovial inflammation. Sham-operated joints injected with mRNA-loaded nanoparticles showed increased OA and inflammation scores compared to healthy joints.</p><p><strong>Conclusions: </strong>MRNA-loaded nanoparticles increased extracellular matrix production in vitro independent of mRNA sequence. A minor effect of delivering PRG4 mRNA compared to control mRNA was found in matrix production normalized to cell content, but this was not reproduced in vivo. An intrinsic effect of nanoparticles on matrix production is suggested. Further research into the biodistribution of the presented nanoparticles and their cellular uptake into the different joint tissues is necessary for the advancement of mRNA-based treatments of OA.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107690"},"PeriodicalIF":5.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compatibility of PVC after irradiation: spectroscopic evaluation.","authors":"Samuel Dorey, Fabien Girard, Nathalie Dupuy, Celine Huart, Sylvain R A Marque, Blanche Krieguer","doi":"10.1016/j.ejps.2026.107687","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107687","url":null,"abstract":"<p><p>Polyvinyl chloride (PVC) is extensively used in advanced therapies due to its flexibility, chemical resistance, and biocompatibility. This study investigates the equivalency of three ionizing radiation sterilization technologies (gamma rays, X-rays, and electron beam) at 50 and 100 kGy on three medical-grade PVC formulations. A comprehensive analytical approach combining Electron Spin Resonance (ESR), Fourier Transform Infrared Spectroscopy (FTIR), colorimetry, and High-Performance Liquid Chromatography (HPLC) was employed. ESR revealed persistent polyenyl radicals (up to 60 days) influenced by ageing rather than irradiation technology or dose. FTIR-PCA demonstrated dose-dependent carbonyl growth (1708 cm⁻¹) from additive oxidation whereas PVC backbone signatures remained stable. Statistical analysis established that differences among technologies remain within acceptable equivalence margins. These findings confirm that gamma, X-ray, and e-beam irradiation preserve the chemical integrity of PVC formulations for medical device applications.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107687"},"PeriodicalIF":5.1,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the spectral information acquired by an in-line high-speed near-infrared reflection sensor in a tableting environment.","authors":"Cristian Kulcițki, Anna Novikova, Claudia S Leopold","doi":"10.1016/j.ejps.2026.107683","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107683","url":null,"abstract":"<p><p>Near-infrared (NIR) spectroscopy is widely used in process analytical technology during manufacturing of tablets. Therefore, the aim of the present study was to investigate an NIR sensor capable of in-line monitoring of tablets during manufacturing regarding the influence of the tablet temperature on the spectral data and the relevance of the effective penetration depth of the NIR radiation. The influence of the temperature was assessed by subjecting two tablet formulations to a temperature program while simultaneously recording NIR spectra. Whereas chemometric methods, such as differentiation techniques and variable selection merely suppressed the temperature influence, a novel correction method based on the linearity between temperature and NIR spectra showed promising results in reducing this influence, while maintaining the relevant spectral features. To determine the effective NIR penetration depth of the tablets, bilayer tablets with a bottom layer consisting of polytetrafluoroethylene and a top layer with variable thickness consisting of a common immediate-release tablet formulation were used. The effective NIR penetration depth profiles showed a wavelength dependence and strongly correlated with the reflection spectra of the top layers. In conclusion, the temperature dependence of the spectral data and the effective NIR penetration depth are useful for the design of NIR calibration models.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107683"},"PeriodicalIF":5.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drugs solubility parameter prediction using modified Cubic Plus Chain equation of state.","authors":"Arwa Sultan Alqahtani, Saeed Shirazian","doi":"10.1016/j.ejps.2026.107631","DOIUrl":"10.1016/j.ejps.2026.107631","url":null,"abstract":"<p><p>Accurate prediction of drug solubility parameter is essential for understanding drug-solvent interactions and guiding formulation design. Experimental determination is often limited by low solubility and measurement complexity; thus, reliable predictive methods are required. In this work, the main objective is to estimate drug solubility parameter using a modified Cubic-Plus-Chain (CPC) equation of state (EoS). This work emphasizes that a simple cubic-based EoS can effectively model complex pharmaceutical systems and can be readily implemented in commercial simulation software. Accordingly, the CPC EoS was coupled with the Two-State Theory (TST) to enhance the description of complex molecular interactions, such as association in drug systems. The primary motivation for employing the TST instead of Wertheim's theory lies in the difficulty of defining the number and types of association sites in large and complex drug molecules. In contrast to Wertheim's approach, TST does not require explicit specification of association sites, which greatly simplifies the modeling of associating components. Moreover, the proposed CPC-TST model retains analytical solvability comparable to conventional cubic EoS, further enhancing its practicality for implementation in commercial simulation tools. The model parameters were determined using available experimental solubility data for selected drug-solvent systems. The solubility of drugs in various pure and mixed solvents was then estimated with the CPC-TST model. The analysis shows that accounting for a binary interaction parameter that varies with temperature leads to a notable improvement in the model's capability, yielding the average RMSD of 0.034 and AAD% of 0.168. The CPC-TST model was employed to predict the solubility parameter of several drug compounds. The predicted values were compared with those obtained from regression-based, group-contribution methods, and PC-SAFT EoS. The CPC-TST model demonstrated good accuracy in predicting solubility parameter, particularly for strongly associating systems, while maintaining low computational complexity. These results highlight the potential of the CPC-TST model as a robust and efficient alternative for modeling solubility behavior in pharmaceutical systems.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107631"},"PeriodicalIF":5.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Evaluation of transduction properties and vaccine efficacy of a simian adenovirus type 25-based vector\" [European Journal of Pharmaceutical Sciences 225 (2026)107619].","authors":"Fuka Okumura, Sora Tokuoka, Naoya Nagata, Rika Onishi, Aoi Shiota, Fuminori Sakurai, Kahori Shimizu, Hiroyuki Mizuguchi","doi":"10.1016/j.ejps.2026.107658","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107658","url":null,"abstract":"","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107658"},"PeriodicalIF":5.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological Investigation of Novel Pyrazole-Based Anticancer Scaffolds: A Trinity of Synthetic Methodologies on Computational Assessment of IC₅₀ Against Human Cancer Cell Lines MCF-7, MDA-MB and HeLa.","authors":"Pooja Kumari, Anandkumar Tengli","doi":"10.1016/j.ejps.2026.107663","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107663","url":null,"abstract":"<p><p>Aurora kinase A (AURKA) is a key regulator of mitotic progression and is frequently overexpressed in human malignancies, making it an attractive therapeutic target for the development of targeted anticancer agents. The present study aimed to design and synthesize sixteen novel pyrazole derivatives (Pz-01 to Pz-16) as potential AURKA-targeted anticancer agents and to evaluate their anticancer activity, AURKA-binding potential, and SAR using integrated experimental and computational approaches. The synthesized compounds were screened for cytotoxic activity against human breast cancer (MCF-7 and MDA-MB-231) and cervical cancer (HeLa) cell lines. Among the evaluated derivatives, Pz-10 emerged as the most potent analogue, exhibiting significant antiproliferative activity against MCF-7 cells (IC₅₀ = 22.30 ± 2 μM), comparable to the reference drug doxorubicin, while demonstrating moderate activity against MDA-MB-231 cells (IC₅₀ = 27.60 ± 3 μM). Structure-based molecular docking revealed that Pz-10 adopted a favourable binding orientation within the ATP-binding pocket of AURKA, which was further supported by MM-GBSA binding free-energy calculations and favourable predicted pharmacokinetic properties, indicating excellent oral absorption and drug-like characteristics. To validate the stability of the predicted binding mode, 200 ns molecular dynamics simulations were performed, demonstrating persistent protein-ligand interactions, stable hydrogen-bonding networks, and minimal structural fluctuations throughout the simulation trajectory, consistent with the behaviour of the reference inhibitor. SAR analysis identified hydroxyl substitution on the pyrazole scaffold as a critical determinant of antiproliferative activity and target engagement, whereas bulky halogenated and nitro substituents were associated with reduced biological activity. Collectively, these findings identify Pz-10, together with the structurally related Pz-11, as promising pyrazole-based lead molecules for the development of AURKA-targeted anticancer therapeutics and provide valuable structural insights for the future optimization of selective mitotic kinase inhibitors.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107663"},"PeriodicalIF":5.1,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Evaluation of Lornoxicam Liquitablets: Permeability, Anti-Inflammatory Action, Cytotoxicity, and Stability.","authors":"Alaa Gamiel, Dóra Paróczai, Katalin Burian, Gábor Katona, Maryana Salamah, Rita Ambrus, Mahwash Mukhtar","doi":"10.1016/j.ejps.2026.107630","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107630","url":null,"abstract":"<p><strong>Background: </strong>Lornoxicam (LXM) is a potent non-steroidal anti-inflammatory drug (NSAID), characterised by low aqueous solubility, which limits its oral bioavailability and is frequently associated with gastrointestinal adverse effects. The liquitablet, prepared by blister moulding combined with freeze-drying, was previously shown to significantly improve LXM dissolution. The present study extends that work by comprehensively evaluating biopharmaceutical and pharmacological performance through in vitro permeability testing, cytotoxicity, anti-inflammatory efficacy, and long-term physicochemical stability.</p><p><strong>Methods: </strong>Dissolution profiling was performed in a pH 1.2 medium. Drug release data were fitted to zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas and Weibull models. Apparent permeability coefficients (Papp) and flux ratios were determined using a horizontal diffusion cell system together with Parallel Artificial Permeability Assays (PAMPA). Cytotoxicity was evaluated using an MTT assay in Caco-2 cells in clinically relevant concentrations. Anti-inflammatory activity was evaluated in Caco-2 cells induced with lipopolysaccharide (LPS) by quantifying the expression of cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) mRNA using polymerase chain reaction (qRT-PCR). Stability was assessed over 12 months at (25°C/60% RH), the assessment focused on drug content, solid‑state characterisation, and dissolution profiling.</p><p><strong>Results: </strong>LXM liquitablets dissolution fitted both Weibull and Korsmeyer-Peppas models, and exhibited a statistically significant increase in Papp compared to pure LXM, with an efflux ratio below 2.0, and maintained Caco-2 cell viability above 70% cytotoxicity threshold at all therapeutic concentrations. It induced a marked downregulation of COX-2 and IL-6 mRNA expression, with high COX-2 attenuation relative to pure LXM, thereby confirming that the liquitablet retains anti-inflammatory activity. Stability data showed no significant changes in drug content (≥ 96%), solid-state characteristics, or dissolution profile.</p><p><strong>Conclusions: </strong>LXM liquitablets show improved diffusion, biocompatibility, anti-inflammatory action, and long-term stability, providing strong biopharmaceutical support for clinical and regulatory development.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107630"},"PeriodicalIF":5.1,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective Nanomolar Inhibitors of Carbonic Anhydrases IX and XII: Coumarin Aminophosphonates as Potential Anticancer Agents.","authors":"Manuela Voráčová, Elena Andreucci, Lucia Magnelli, Alessio Biagioni, Marija Skvorcova, Ashenafi Legehar, Henri Xhaard, Fabrizio Carta, Paula Kiuru","doi":"10.1016/j.ejps.2026.107590","DOIUrl":"https://doi.org/10.1016/j.ejps.2026.107590","url":null,"abstract":"<p><p>Tumor-associated carbonic anhydrases IX and XII are validated targets for cancer therapy. Here we report the first exploration of coumarin aminophosphonates as inhibitors of these isoforms. Using a straightforward Kabachnik-Fields approach followed by dealkylation, we synthesized 25 novel coumarin aminophosphonates (2a-p and water-soluble 3a-i) and evaluated their activity. The compounds were screened against four hCA isoforms (I, II, IX, XII) using a stopped-flow CO₂ hydration assay and displayed remarkable selectivity for IX and XII, with nanomolar K_I values (34.8-53.2 nM for IX; 15.8-37.3 nM for XII). Cellular assays of six selected derivatives revealed micromolar cytostatic effects toward seven CA IX/XII-expressing tumor cell lines while showing negligible toxicity toward normal cells. These results identify coumarin aminophosphonates as promising scaffolds for selective CA IX/XII inhibition and warrant further studies and evaluation.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107590"},"PeriodicalIF":5.1,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}