European Journal of Pharmaceutical Sciences最新文献

{"title":"Platinum-group metal half-sandwich complexes of sugar-isoxazol(in)e conjugates - synthesis and evaluation of their antineoplastic and antimicrobial activities.","authors":"Rahaf Akel, István Kacsir, Éva Kerekes, Csongor Freytag, Evelin Szoták, Dóra Boros-Pál, Eszter Anna Janka, Attila Bényei, Gábor Kardos, Éva Bokor, László Somsák, Péter Bai, Adrienn Sipos, Sándor Kun","doi":"10.1016/j.ejps.2025.107260","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107260","url":null,"abstract":"<p><p>Platinum-group metal half-sandwich complexes are considered to be potential replacements of the clinically widely used platins which have several side effects and tend to cause resistance to develop. In our previous works, we used a range of 2-pyridyl-substituted N- and C-glycosyl heterocycles as N,N-chelating ligands to prepare ruthenium(II), osmium(II), iridium(III) and rhodium(III) polyhapto arene/arenyl half-sandwich complexes. Some of these complexes, particularly with the C-glucopyranosyl isoxazole derived ligand in its O-perbenzoylated form, exhibited greater anticancer efficiency than cisplatin and had minimal or negligible effects on non-transformed fibroblasts. Additionally, these cytostatic compounds exhibited micromolar antibacterial activity against multiresistant Gram-positive bacteria. In the present work, novel modes of conjugation between the sugar and the isoxazole moieties have been studied. Specifically, glycosylidene-spiro-isoxazoline and polyhydroxyalkylisoxazole scaffolds were synthesised and utilised in complex formation reactions. The spiro-isoxazolines were obtained in 1,3-dipolar cycloadditions of exo-glycals and nitrile oxides generated from pyridine-2-carbaldoximes. Ring opening of the spiro-isoxazolines under basic or transition-metal-mediated conditions produced polyhydroxyalkylisoxazoles. These compounds were then transformed into their O-peracetylated, O-perbenzoylated and O-unprotected variants, which were used for complex formation with the above-mentioned platinum-group metal ions. The complexes induced cytostasis in cellular models of ovarian cancer and pancreatic adenocarcinoma; the best compounds had submicromolar IC₅₀ values (0.4-0.5 µM). A subset of the cytostatic complexes retained their activity on cisplatin resistant ovarian cancer cells. Furthermore, a reasonable therapeutic index was detected when complexes were assessed on primary human fibroblasts pointing towards a potential applicability of the complexes. Unexpectedly, none of the complexes induced bacteriostasis in Gram-positive bacteria as Staphylococcus aureus or Enterococcus species.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107260"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014213","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":"Diffusion of macromolecules in extracellular matrix mimetic hydrogels – effect of size and charge","authors":"Julia Parlow ,&nbsp;Eva Pet ,&nbsp;Anna Smirnova ,&nbsp;Enamul Mojumdar ,&nbsp;Helen Sjögren ,&nbsp;Per Hansson","doi":"10.1016/j.ejps.2025.107257","DOIUrl":"10.1016/j.ejps.2025.107257","url":null,"abstract":"<div><div>Subcutaneous (SC) injection is the primary alternative to oral administration for therapeutic proteins and peptides. However, bioavailability and absorption rate are often variable and difficult to predict. Therefore, there is a need for new biorelevant and predictive SC in vitro methods. In this study we systematically investigate the effect of size and charge of a macromolecule on its partitioning and diffusion within extracellular matrix (ECM) mimetic hydrogels in order to gain insight on interactions with the components of the ECM affecting the absorption of a drug after SC injection. Hydrogels consisting of either agarose, cross-linked collagen and hyaluronic acid (HA) or cross-linked HA, were made and equilibrated in solutions of FITC-dextrans of varying sizes (4 to 150 kDa) and model peptides of varying net charge (+2 to +9). Partitioning and diffusion coefficients within gel and solution were determined using confocal laser scanning microscopy and fluorescence recovery after photo bleaching (FRAP), and compared to theoretical models. Generally, the partitioning and diffusivities within the gels decreased with increasing molecular weight, which was in good agreement with models describing the effect of obstruction of the gel network corrected for heterogeneity in the gel structure. The cationic peptides were enriched in the oppositely charged gels and their diffusivities decreased with increasing peptide charge. The experimental results were in semi quantitative agreement with an electrostatic model presented in this work.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107257"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008126","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":"Dual-action nanotherapy: Temozolomide-loaded, anti-PD-L1 scFv-functionalized lipid nanocarriers for targeted glioblastoma therapy","authors":"Eren Aytekin ,&nbsp;Semer Maksoud ,&nbsp;Bakhos A. Tannous ,&nbsp;Sibel Bozdağ Pehlivan ,&nbsp;Christian E. Badr","doi":"10.1016/j.ejps.2025.107255","DOIUrl":"10.1016/j.ejps.2025.107255","url":null,"abstract":"<div><div>Glioblastoma (GBM) is a highly malignant brain tumor with limited treatment options and poor prognosis.</div><div>GBM exhibits resistance to conventional therapies, including temozolomide (TMZ), radiotherapy, and immunotherapy, partly due to immunosuppressive mechanisms such as programmed death-ligand 1 (PD-L1) overexpression. To address these challenges, we developed TMZ-loaded nanostructured lipid carriers (NLCs) conjugated with anti-PD-L1 single-chain variable fragments (scFv) for dual chemo-immunotherapy.</div><div>The anti-PD-L1 scFv enabled active targeting of PD-L1-expressing tumor cells while mitigating immune evasion, and the NLCs efficiently crossed the blood-brain barrier (BBB), delivering TMZ to the tumor site. In vitro studies confirmed nanoparticle internalization by GL261 glioma cells and specific binding of the conjugated scFv to PD-L1. In vivo studies using the GL261/C57BL/6 mouse model demonstrated that TMZ-NLCs conjugated with anti-PD-L1 scFv (TMZ-NP-scFv) stabilized tumor growth by the third week, unlike other treatment groups. While all therapeutic groups (TMZ solution, TMZ-NP, and anti-PD-L1 scFv alone) significantly improved survival compared to controls, the TMZ-NP-scFv group exhibited the most pronounced survival benefit.</div><div>These results highlight the potential of TMZ-loaded, PD-L1-targeted NLCs as a synergistic strategy to enhance GBM treatment by combining chemotherapy and immune checkpoint blockade.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107255"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008192","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":"Impact of the mucin barrier on the in vitro membrane permeability of cyclic peptides","authors":"Yuji Sakurai,&nbsp;Kazuhisa Ozeki,&nbsp;Haruka Tsutsui,&nbsp;Terushige Muraoka,&nbsp;Kimio Terao","doi":"10.1016/j.ejps.2025.107254","DOIUrl":"10.1016/j.ejps.2025.107254","url":null,"abstract":"<div><div>This study investigated the role of the mucin layer in cyclic peptide permeability using an <em>in vitro</em> assay system. We evaluated the membrane permeability of 18 cyclic peptides and reference compounds using biosimilar mucin and Caco-2/HT29 cells. The permeability of paracellular markers (FD4 and LY) and digoxin (a low molecular weight compound) remained unaffected by mucin presence when using biosimilar mucin. Conversely, cyclosporin A, a commercially available cyclic peptide drug, showed reduced permeability. In Caco-2/HT29 co-cultured cells compared with Caco-2 cells only, most compounds exhibited increased permeability due to enhanced interstitial permeability, except for cyclosporin A, which showed decreased permeability in the presence of mucin. Similarly, the permeability of LUNA18, a cyclic peptide under development, was reduced by 54.1 and 26.0 % in both Caco-2/HT29 co-cultured and HT29 cells. Furthermore, 12 of 18 cyclic peptides exhibited ≥ 2-fold decrease in membrane permeability in Caco-2/HT29 co-cultured cells. These findings suggest that current permeability evaluation methods, which do not account for the mucin layer, may overestimate the permeability of highly lipophilic cyclic peptides. The mucin layer may serve as a rate-limiting factor in cyclic peptide membrane permeability, highlighting the importance of including mucin layer permeability in cyclic peptide evaluation protocols.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107254"},"PeriodicalIF":4.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000081","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/in vivo evaluation of 3D bioprinted silk fibroin hydrogels for IBD: A dual mesalazine and TNF-α siRNA approach","authors":"Ayşegül Yıldız ,&nbsp;N.Başaran Mutlu-Ağardan ,&nbsp;Özge Özgenç Çınar ,&nbsp;Ahmet Ceylan ,&nbsp;Recep Uyar ,&nbsp;Begüm Yurdakök Dikmen ,&nbsp;Füsun Acartürk","doi":"10.1016/j.ejps.2025.107252","DOIUrl":"10.1016/j.ejps.2025.107252","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is a chronic, relapsing disease that poses significant challenges in treatment. This study aimed to develop silk fibroin-based mesalazine and chitosan:TNF-α siRNA polyplex-loaded, 3D bioprinted hydrogels for the oral treatment of IBD. For this purpose, bioink formulations composed of silk fibroin, hyaluronic acid, and sodium alginate were optimized. A chitosan:TNF-α siRNA polyplex was also formulated at a 40:1 chitosan-to-siRNA ratio. Hydrogel formulations were fabricated using 3D bioprinting and characterized in terms of compatibility, thermal stability, swelling behavior, degradation, mechanical properties, and mucoadhesion to both healthy and IBD-induced colon tissues. The optimized oral hydrogel (H-M-P12) demonstrated a swelling index of 366±67 % and underwent 31.2 % degradation after 24 h in vitro. Mesalazine and TNF-α siRNA exhibited a sustained release profile from the hydrogels. Cytotoxicity studies confirmed the biocompatibility of the hydrogels and a TNF-α gene silencing efficiency of 46.53 % was obtained. In vivo studies in a Balb/c mouse model of IBD revealed significant improvements in physiological parameters, macroscopic and microscopic morphology, and biochemical markers following treatment with the developed hydrogels. These findings suggest that silk fibroin-based hydrogels incorporating mesalazine and chitosan/TNF-α siRNA polyplex, produced via 3D bioprinting, hold promise as an effective therapeutic approach for IBD.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107252"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000086","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":"Predicting the adsorption behavior of olaparib on zinc oxide nanoparticles for improved pH-responsive drug delivery: experimental and DFT insights","authors":"Arwa Sultan Alqahtani ,&nbsp;Mahboubeh Pishnamazi","doi":"10.1016/j.ejps.2025.107253","DOIUrl":"10.1016/j.ejps.2025.107253","url":null,"abstract":"<div><div>The development of efficient drug delivery systems for hydrophobic anticancer drugs like Olaparib (OLA) remains a critical challenge in cancer therapy. This study presents a comprehensive investigation of OLA-loaded zinc oxide nanoparticles (OLA@ZnO) through integrated experimental and computational approaches to optimize pH-responsive drug delivery. ZnO nanoparticles were synthesized via a sol-gel method and characterized using SEM, XRD, FTIR, and UV–Vis spectroscopy, revealing successful OLA loading through Zn²⁺-carbonyl coordination and π-stacking interactions. The nanocomposites exhibited excellent colloidal stability (zeta potential = 11 mV at pH 7.4) and pH-triggered drug release, with 100 % release in 20 h (physiological pH) versus 90 % in 24 h (acidic pH). Korsmeyer-Peppas modeling confirmed diffusion-dominated release (<em>n</em> = 0.52) at neutral pH and erosion-controlled release (<em>n</em> = 0.69) in acidic conditions. Density functional theory (DFT) calculations revealed strong charge transfer, evidenced by a narrowed HOMO-LUMO gap (4.89 → 3.21 eV) and increased dipole moment (5.7 → 9.13 D). Molecular descriptors highlighted enhanced reactivity (softness = 0.621 eV⁻¹) and pH sensitivity (electrophilicity = 4.54 eV), while reduced density gradient (RDG) analysis visualized key binding interactions (−0.9 eV for Zn²⁺-<em>C</em> = <em>O</em> coordination). Thermodynamic analysis demonstrated spontaneous adsorption (ΔG = −0.77 to −0.89 eV) with exothermic behavior (ΔH = −0.87 to −1.00 eV) and entropy-driven release (ΔS = −0.00034 to −0.00037 eV/K). Size-dependent trends showed that smaller nanoparticles (0.9 nm) enabled rapid release (τ = 1.05 s) for acute therapy, while larger nanoparticles (2.0 nm) provided sustained delivery (τ = 152 s) for chronic treatment. These findings establish a robust structure-property relationship for designing tunable ZnO-based nanocarriers, offering a promising strategy to improve the therapeutic efficacy of OLA and other hydrophobic drugs in targeted cancer therapy.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107253"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000037","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":"pH-stat versus pH-shift lipolysis model: Exploring in vitro-in vivo relationships for lipid-based formulations of nilotinib","authors":"Hannah S. Kirschbaum ,&nbsp;Niklas J. Koehl ,&nbsp;Johannes A. Blechar ,&nbsp;Christina Wiesinger ,&nbsp;Laura J. Koehl ,&nbsp;Patrick J. O´Dwyer ,&nbsp;Martin Kuentz ,&nbsp;René Holm ,&nbsp;Christian Jede ,&nbsp;Brendan T. Griffin","doi":"10.1016/j.ejps.2025.107250","DOIUrl":"10.1016/j.ejps.2025.107250","url":null,"abstract":"<div><div>The pH-stat <em>in vitro</em> lipolysis method is well established for evaluating lipid-based formulations (LBFs), however the absence of a simulated gastrointestinal transition may lead to an overestimation of drug precipitation particularly in the case of weakly basic drugs. This study aimed to compare the conventional pH-stat method with a pH-shift lipolysis approach by evaluating a diverse set of LBFs using nilotinib, a weakly basic model drug. Additionally, the study sought to assess <em>in vitro–in vivo</em> relationships (IVIVRs) and enhance understanding of the predictive capabilities of these models. Four nilotinib-containing LBFs were tested <em>in vitro</em>, and pharmacokinetic profiles were evaluated in Sprague Dawley rats. The formulations included a supersaturated Peceol® solution (sLBF), a Peceol® lipid suspension (type I according to the Lipid Formulation Classification System (LFCS)), a type III LFCS medium-chain suspension, and a type IV LFCS suspension. The highest bioavailability was achieved with the Peceol® sLBF and the type III LFCS formulation. Strong IVIVRs were established for both <em>in vitro</em> lipolysis models. In conclusion, utilizing both <em>in vitro</em> models offered distinct advantages depending on the stage of development and the specific questions being addressed. This approach contributes to more efficient formulation development and a reduced reliance on animal studies in early-stage drug development.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107250"},"PeriodicalIF":4.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947809","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":"Intranasal empagliflozin modulates synaptic plasticity in migraine: Insights into calcium signaling and epigenetic regulation","authors":"Nesrine S. El-Mezayen ,&nbsp;Ashraf A. Noah ,&nbsp;Samar O. El-Ganainy","doi":"10.1016/j.ejps.2025.107251","DOIUrl":"10.1016/j.ejps.2025.107251","url":null,"abstract":"<div><div>Migraine is a primary headache disorder without a definite pathophysiology or satisfactory managing strategies. Recently, migraine is primarily a disorder of brain plasticity coupled with altered Ca²⁺ dynamics regulating gene activity and protein expression. Further, epigenetics provided new insight into migraine pathogenesis and therapeutic response elucidation. Sodium-glucose co-transporter-2-inhibitors (e.g., empagliflozin (EMPA)), are a class of antihyperglycemic agents that can cross the blood-brain-barrier to maintain glucose homeostasis. EMPA possesses myriad pharmacological actions with potential beneficial effects for migraine management. Thus, the current study aimed at exploring EMPA efficacy and mechanisms for treating migraine headache, emphasizing its role in synaptic plasticity and epigenetic mechanisms.</div><div>Using an animal model of chronic migraine headache, the effect of oral (PO)/intranasal (IN) (brain-targeted)-EMPA versus Zolmitriptan (ZOL) on serum pain marker; Substance-P and migraine symptoms; pain, and photophobia were assessed biochemically and behaviorally. The influence on synaptic plasticity was evaluated by quantifying immunohistochemically stained synaptophysin in brain tissues and assessing calcium/calmodulin-activated-kinases (CaMKIIa)/ Camp-response-element-binding-protein (CREB)/calcitonin-gene-related-peptide (CGRP) or brain-derived-neurotrophic-factor (BDNF) pathways. Further, epigenetic modulation of migraine key genes was evaluated by determining HDAC6, CALCR, and MiR155–5p Moreover, serum glucose and amylin levels were appraised.</div><div>Both EMPA-PO/IN significantly decreased serum levels of substance-P and pain symptoms, increased brain serotonin levels, synaptophysin expression, and modulated the CaMKIIa/CREB/CGRP/or BDNF pathway. In addition, EMPA-IN, but not ZOL, down-regulated HDAC6, CALCR, and MiR155–5p expressions. Further, unlike EMPA-IN, ZOL, and EMPA-PO demonstrated significant hypoglycemic effects.</div><div>In conclusion, EMPA-IN shows potential as a novel therapeutic approach for managing migraine headaches by enhancing synaptic plasticity and modulating altered migraine-related epigenetic mechanisms.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107251"},"PeriodicalIF":4.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931602","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":"Designing fluorescent estrogen mimetic 7-hydroxycoumarin probe substrates for human sulfotransferase enzymes","authors":"Risto O. Juvonen ,&nbsp;Pekka A. Postila ,&nbsp;Pankaj Kumar Singh ,&nbsp;Juhani Huuskonen ,&nbsp;Juri Timonen ,&nbsp;Muluneh Fashe ,&nbsp;Rasikh Hussain ,&nbsp;Zaeema Aqip ,&nbsp;Olli Kärkkäinen ,&nbsp;Hannu Raunio ,&nbsp;Olli T. Pentikäinen","doi":"10.1016/j.ejps.2025.107249","DOIUrl":"10.1016/j.ejps.2025.107249","url":null,"abstract":"<div><div>Sulfonation is one of drug metabolism reactions affecting homeostasis of estrogens. C-3 aryl substituted 7-hydroxycoumarins are fluorescent estrogen mimetics; i.e., the hydroxyl groups of both estrogens and 7-hydroxycoumarins are conjugated by human sulfotransferases (SULTs). Sulfonation of the 7‑hydroxyl group by SULTs decreases the fluorescence of 7-hydroxycoumarins. Sulfonation of a series of 7-hydroxycoumarins by human SULTs was determined based on this property. SULT subtype-specific binding interactions of 7-hydrocoumarins were assessed against the modelled optimal arrangement needed for sulfonation. 3-(4-Methoxyphenyl)-7-hydroxycoumarin (<strong>11</strong>) and 3-(4-hydroxyphenyl)-7-hydroxycoumarin (<strong>9</strong>) were selective substrates for SULT1E1, whereas 3-(1H-1,2,4-triazol-1-yl)-7-hydroxycoumarin (<strong>14</strong>) was a selective SULT1A1 substrate. Other tested 7-hydroxycoumarin were sulfonated by more than two SULTs. Sulfonation of most 7-hydroxycoumarins by SULT1A1 or SULT1C4 followed Michaelis-Menten kinetics, while substrate inhibition kinetics occurred in sulfonation of several derivatives by SULT1E1. Selective sulfonation of derivatives <strong>9</strong> and <strong>11</strong> by SULT1E1 was due to the enzyme’s long and cylindrical active site that assures optimal 7‑hydroxyl group placement in the precursory reaction state. SULT1A1 and SULT1C4 preferred smaller derivatives as substrates than the SULT1E. Estrogens potently inhibited the sulfonation of 3,4-dimethyl-7-hydroxycoumarin (<strong>4</strong>) by SULT1E1 (IC₅₀ below 1 µM). SULT1A1 and SULT1C4 were less potently inhibited by the estrogens. Several 7-hydroxycoumarin derivatives share common binding interaction patterns with the estrogens at SULT1E1 and SULT1A1 active sites. Fluorescent 7-hydroxycoumarins could serve as convenient probe substrates for SULTs to evaluate their inhibition by new chemical entities during drug development. 7-Hydroxycoumarins <strong>9</strong> or <strong>11</strong> could be used as selective probe substrates for SULT1E1 and <strong>14</strong> for SULT1A1.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107249"},"PeriodicalIF":4.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920028","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":"Cosolvent effects on the complexation of the antifungal propiconazole nitrate with β-cyclodextrin: A combined molecular dynamics and NMR study","authors":"Dragos L. Isac ,&nbsp;Petru Tîrnovan ,&nbsp;Alina Nicolescu ,&nbsp;Adrian Fifere ,&nbsp;Andrei Neamtu ,&nbsp;Mariana Pinteala","doi":"10.1016/j.ejps.2025.107248","DOIUrl":"10.1016/j.ejps.2025.107248","url":null,"abstract":"<div><div>Understanding the effects of cosolvents in cyclodextrin (CyD)-drug complexation is essential for optimizing drug formulations, as cosolvents influence solubility, stability, and binding affinity. In this study, the inclusion complexation of propiconazole nitrate (PCZH<img>NO₃) with β-cyclodextrin (β-CyD) in mixed dimethyl sulfoxide (DMSO)/water solvent systems was investigated using molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy. MD simulations revealed that DMSO exhibits a strong affinity for the β-CyD cavity, effectively displacing water molecules even at low concentrations highlighting the competitive nature of DMSO and PCZH<img>NO₃ for inclusion within the β-CyD cavity. Enhanced sampling simulation techniques and potential of mean force (PMF) calculations demonstrated that complexation is most favorable at low DMSO concentrations (∼5 % v/v), with a gradual decrease in binding affinity as DMSO levels increase, ultimately leading to complex destabilization at high DMSO ratios. ¹H-NMR and ROESY spectra confirmed these findings, with chemical shift variations and ROESY cross-peaks indicating a weakening of host-guest interactions with increasing DMSO concentration. The results provide molecular-level insights into the role of cosolvents in modulating drug-CyD interactions, highlighting the need to tailor solvent environments to enhance the stability and efficacy of β-CyD inclusion complexes for pharmaceutical applications.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107248"},"PeriodicalIF":4.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925239","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}