Drug Development Research最新文献

{"title":"Tricin Inhibits Human Osteosarcoma Cell Metastasis via Suppression of ZNF503 and the PI3K–PIP3–Akt Pathway","authors":"Chia-Hsuan Chou,&nbsp;Jia-Sin Yang,&nbsp;Pei-Ni Chen,&nbsp;Yi-Hsien Hsieh,&nbsp;Chih-Hsin Tang,&nbsp;Ya-Chiu Lin,&nbsp;Shun-Fa Yang,&nbsp;Ko-Hsiu Lu","doi":"10.1002/ddr.70374","DOIUrl":"10.1002/ddr.70374","url":null,"abstract":"<p>Osteosarcoma is the most common primary malignant bone tumor and is associated with a high mortality rate due to its pronounced metastatic potential. Although tricin has been proposed as a chemosensitizer in various malignancies, its anti-metastatic effect in osteosarcoma remains poorly characterized. This study investigated whether tricin suppresses metastasis in human osteosarcoma cells and explored the underlying molecular mechanisms. Our results revealed that tricin significantly inhibited the migration and invasion of U2OS and Saos-2 osteosarcoma cells and downregulated ZNF503 expression at both the mRNA and protein levels. Similarly, siRNA-mediated knockdown of ZNF503 suppressed cell migration, as confirmed by immunofluorescence analysis. Tricin treatment also reduced phosphorylation of PI3K and Akt, without affecting the activation of ERK1/2, JNK1/2, or p38. Additionally, intracellular levels of PIP3 were diminished following tricin exposure. Notably, the Akt activator SC-79 significantly reversed tricin-induced suppression of both ZNF503 expression and cell migration in U2OS and Saos-2 cells. In conclusion, these findings suggest that ZNF503 inhibits osteosarcoma cell motility via the PI3K–PIP3–Akt signaling axis and that tricin exerts anti-metastatic effects by targeting this pathway. Tricin may therefore represent a promising therapeutic agent for inhibiting osteosarcoma metastasis.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfonamide-Based 2-Amino-1,3,4-Oxadiazole Derivatives as Dual Cholinesterase and Carbonic Anhydrase Inhibitors: Design, Synthesis, Kinetic Characterization, Molecular Modeling, and ADMET Evaluation","authors":"Gülnur Arslan Karahan,&nbsp;Başak Gökçe,&nbsp;Muhammed Tilahun Muhammed,&nbsp;Emre Kadir Ayan,&nbsp;Azime Berna Özçelik","doi":"10.1002/ddr.70375","DOIUrl":"10.1002/ddr.70375","url":null,"abstract":"<p>In this study, 12 novel sulfonamide derivatives incorporating 2-amino-1,3,4-oxadiazole and 1,3-benzazol-2(3<i>H</i>)-one scaffolds were synthesized and structurally characterized using ¹H NMR, ¹³C NMR, and LC–MS analyses. Their inhibitory activities were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase I and II (CA I and CA II), and α-glucosidase. Owing to their potent inhibitory profiles, enzyme kinetic studies were performed to determine inhibition constants (<i>Ki</i>) and inhibition mechanisms. The synthesized compounds exhibited potent nanomolar cholinesterase inhibition. Compound <b>5b</b> was identified as the most active AChE inhibitor (IC₅₀ = 32.6 ± 2.6 nM; <i>Kᵢ</i> = 7.1 ± 0.6 nM), acting through a competitive inhibition mechanism, whereas compound <b>5g</b> showed the strongest BChE inhibition (IC₅₀ = 34.6 ± 2.8 nM; <i>Kᵢ</i> = 8.4 ± 0.8 nM) with a mixed-type inhibition profile. The derivatives also displayed significant carbonic anhydrase inhibition, with compound <b>6d</b> emerging as the most potent inhibitor, particularly against CA II (IC₅₀ = 0.9 ± 0.06 μM; <i>Kᵢ</i> = 0.43 ± 0.037 μM), while exhibiting competitive inhibition and strong activity against both CA isoforms. In contrast, α-glucosidase inhibition was generally weak, with compound <b>5d</b> showing the highest activity (IC₅₀ = 250.5 ± 21.32 μM). Molecular docking studies revealed favorable binding interactions within the catalytic sites of cholinesterase and carbonic anhydrase enzymes, while 200 ns length molecular dynamics simulations confirmed the stability of representative protein–ligand complexes. In silico ADMET and drug-likeness predictions using SwissADME and pkCSM indicated generally acceptable oral drug-likeness. Compound <b>6c</b> exhibited the most balanced predicted pharmacokinetic profile, whereas <b>6d</b>, despite its excellent enzyme inhibition, showed potential limitations associated with higher polarity, limited predicted blood–brain barrier penetration, and predicted toxicity risks. Overall, these findings identify the synthesized sulfonamide derivatives as promising scaffolds for the further development of multifunctional cholinesterase and carbonic anhydrase inhibitors.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quality by Design-Guided Transethosomal Gel of Donepezil Hydrochloride and Quercetin for Potential Alzheimer's Management: Stability-Indicating Eco-Compatible RP-HPLC Method","authors":"Abhishek Kumar,&nbsp;Aditi Kaushik,&nbsp;Arti Devi,&nbsp;Amar Deep Ankalgi,&nbsp;M. S. Ashawat,&nbsp;Hanan M. Alharbi,&nbsp;Manna Amin,&nbsp;Alaa A. Khojah,&nbsp;Shoeb Ahmad,&nbsp;Magdi E. A. Zaki","doi":"10.1002/ddr.70371","DOIUrl":"10.1002/ddr.70371","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease requires innovative therapeutic strategies that not only alleviate symptoms but also protect neurons. Donepezil hydrochloride, a cholinesterase inhibitor, and quercetin, a potent antioxidant, were co-formulated into a transethosomal gel to enhance brain delivery and therapeutic efficacy. To design and optimize a Quality by Design (QbD)-based transethosomal gel containing Donepezil hydrochloride and Quercetin, and to establish a stability-indicating, eco-compatible RP-HPLC method for their simultaneous estimation. Chromatographic separation was achieved on a C18 ODS column using an eco-friendly mobile phase of acetonitrile–phosphate buffer (45:55, pH 3.4). Detection was performed at 240 nm, the isoabsorptive wavelength for both drugs. Method validation followed ICH guidelines, and forced degradation studies (acidic, basic, oxidative, thermal, photolytic) were conducted to achieve controlled degradation (5%–20%) while minimizing the use of hazardous solvents. The transethosomal gel was developed using QbD algorithms, optimizing critical parameters including particle size distribution (PDI), zeta potential, entrapment efficiency, and drug release profile. The optimized gel exhibited a vesicle size of 128.4 ± 2.1 nm, PDI of 0.135, zeta potential of +29.52 mV, and 89% and 85% entrapment efficiency of Quercetin and Donepezil HCl. Drug content exceeded 97% for both drugs, while cumulative drug release reached approximately 85%–95% over 10 h. The RP-HPLC method demonstrated excellent linearity (R² &gt; 0.995), recovery (98−102%), precision (%RSD &lt; 2%), accuracy, robustness, and an Eco-Scale score of 83.18, confirming excellent analytical greeness. Forced degradation studies confirmed its stability-indicating capability. The study successfully integrates QbD-driven formulation design with a validated eco-friendly RP-HPLC method, providing a robust platform for simultaneous drug delivery in Alzheimer's therapy. This work underscores the synergistic potential of advanced formulation strategies and sustainable analytical validation in translational pharmaceutical research.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 Evaluation of Benzimidazol-2-One Hybrids as Potential Anti-Alzheimer's Disease Agents","authors":"Fatih Yılmaz,&nbsp;Emre Menteşe,&nbsp;Ozan Emre Eyüpoğlu,&nbsp;Bahittin Kahveci,&nbsp;Mustafa Emirik","doi":"10.1002/ddr.70369","DOIUrl":"https://doi.org/10.1002/ddr.70369","url":null,"abstract":"<p>Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which single-target therapies often provide insufficient benefit, motivating the development of multi-target-directed ligands (MTDLs). In this study, a novel series of benzimidazolone-based hybrids incorporating piperazine, coumarin, and triazole moieties was designed, synthesized, and evaluated for inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase-B (MAO-B), as well as antioxidant potential via on-line HPLC-based assays. Structures were confirmed by ¹H-NMR, ¹³C-NMR (APT), and elemental analysis. Several compounds showed notable, micromolar-range inhibitory activity, though less potent than the reference drugs. Kinetic analysis showed that the leading compounds inhibited their respective enzymes via a mixed-type mechanism. Compound <b>1</b> showed the strongest AChE inhibition (IC₅₀ = 0.777 ± 0.014 µM), compound <b>9b</b> the highest BChE inhibition (IC₅₀ = 0.659 ± 0.005 µM), and compound <b>9c</b> the most potent MAO-B inhibition (IC₅₀ = 2.431 ± 0.003 µM). Compound <b>8a</b> showed the highest CUPRAC copper-reducing capacity, while <b>7c</b> displayed the strongest DPPH radical-scavenging activity. Liposomal formulations of <b>4c</b>, <b>7c</b>, and <b>8a</b> exhibited enhanced antioxidant responses relative to their free forms. In silico ADME predictions (SwissADME) indicated favorable drug-likeness and blood–brain barrier permeation for the compact scaffold (compound <b>1</b>) and the piperazine-based hybrids, whereas the larger bis-conjugated derivatives were limited by high polarity and molecular weight. Overall, these benzimidazolone-based hybrids represent promising multi-target candidates for AD drug development.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70369","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiadiazolo-Triazolo-Pyrimidine Hybrids as Dual Aurora A/ERK Inhibitors: Design, Synthesis, and Apoptotic Activity","authors":"Mai A. E. Mourad,&nbsp;Amal Hofni,&nbsp;Ahmed A. E. Mourad","doi":"10.1002/ddr.70364","DOIUrl":"https://doi.org/10.1002/ddr.70364","url":null,"abstract":"<div>\u0000 \u0000 <p>Aberrant activation of Aurora A kinase causes mitotic spindle assembly, chromosome segregation, and cell cycle progression, leading to genomic instability as well as disruption of several tumor suppressors. Furthermore, ERK has largely emerged as a survival signaling pathway controlling cell proliferation, differentiation, and metastasis. Unfortunately, this pathway is overexpressed in most of the human malignancies. In efforts to develop innovative inhibitors targeting Aurora A/ERK signaling pathway, a novel series of thiadiazolo-, triazolo-pyrimidine hybrids have been designed, synthesized, and assessed for their ability to block Aurora A/ERK and induce apoptosis. Cytotoxicity of the synthesized hybrids was examined against MCF-7, HCT-116 and A549 cell lines. Among the synthesized hybrids, <b>9a</b>, <b>9c</b>, and <b>14b</b> demonstrated higher cytotoxic action than alisertib and GDC-0994 against the MCF-7 and A549 cancer cell lines. IC₅₀ values for these hybrids were 2.59 ± 0.13, 4.63 ± 0.25, and 5.77 ± 0.38, respectively, against MCF-7 cell line and were 3.61 ± 0.19, 3.85 ± 0.21, and 4.23 ± 0.15, respectively, against A549. The selected hybrids significantly suppressed p-Aurora A kinase level as well as p-ERK1/2 level and its upstream regulators p-SRC, p-c-RAF, p-MEK1/2; meanwhile, ERK downstream effectors FOXO3a level was upregulated, and c-Myc was downregulated, in a dose-dependent manner. The selected hybrids significantly decreased the expression of Bcl-2 protein while increasing the levels of <i>p53</i>, caspase-7, caspase-9, and Bax. They effectively induced pre-G1 phase, G0/G1 phase apoptosis, and G2/M phase arrest. The synthesized hybrids possessed favorable binding interactions in the molecular docking investigations as well as appropriate drug-like characteristics.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis and NMDA Receptor Activity in Alzheimer's Disease: Implications for Amyloid Pathology and P-Glycoprotein Regulation","authors":"Jotiram Salunkhe,&nbsp;Vinod Ugale","doi":"10.1002/ddr.70367","DOIUrl":"https://doi.org/10.1002/ddr.70367","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and excitotoxicity. Ferroptosis and N-methyl-D-aspartate (NMDA) receptor activity,may be interconnected in the pathogenesis of Aβ accumulation and associated neurodegeneration in AD. However, the interplay between these pathways remains poorly understood and underexplored for therapeutic intervention against the AD. The review aims to explore the shared molecular triggers of ferroptosis and NMDA receptor overactivation, including the roles of iron, glutamate overload, calcium dysregulation, and reactive oxygen species (ROS) accumulation. We further highlighted the convergent consequences of these processes on mitochondrial dysfunction, lipid peroxidation, and their impact on Aβ pathology. Particular attention is given to P-glycoprotein (P-gp), an efflux transporter involved in the Aβ clearance at the blood–brain barrier, whose expression and function may be modulated by oxidative stress, iron homeostasis, and NMDA receptor signaling. Emerging evidence indicated that ferroptosis and NMDA receptor activity may disrupt P-gp function, thereby impairing Aβ clearance and promoting its accumulation in the AD. Overall, the review elucidates the molecular mechanisms linking ferroptosis and NMDA receptor overactivation and their impact on P-gp-mediated Aβ transport in the AD, providing integrated mechanisms and harnessing their potential for AD therapeutics.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TEAD1 Knockdown Ameliorates Diabetic Erectile Dysfunction in Rats and Is Associated With Modulation of Calcium Signaling-Mediated Contractile Machinery","authors":"Tao Zhang,&nbsp;Chenxiao Wu,&nbsp;Youlong Lu,&nbsp;Weili Li,&nbsp;Huaru Zhang,&nbsp;Cheng Li","doi":"10.1002/ddr.70365","DOIUrl":"https://doi.org/10.1002/ddr.70365","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetes mellitus (DM) related erectile dysfunction (ED) is a common complication in males. We aim to explore the specific regulatory mechanisms of TEA domain family member 1 (TEAD1) in DMED rats. Diabetic ED in rats was induced by streptozotocin and evaluated by the intracavernosal pressure response to electrical stimulation and the apomorphine test. Corpus cavernosum smooth muscle cells (CCSMCs) were isolated to explore the role of TEAD1 in phenotypic transformation. TEAD1 knockdown was performed in DMED rats and CCSMCs using the CRISPR/Cas9 technology. Hematoxylin–Eosin and Masson staining were applied to observe the penile tissue pathology. The CCSMC function was evaluated by detecting viability and apoptosis. Protein and gene expression levels were examined by Western blot and real-time quantitative polymerase chain reaction. The TEAD1 gene knockdown ameliorated erectile function in DMED rats. Knockdown of TEAD1 in CCSMCs of DMED rats enhanced their viability and inhibited their apoptosis, promoting the transformation of CCSMCs from a synthetic to a contractile phenotype. Furthermore, bioinformatics analysis identified the calcium signaling pathway as a candidate pathway warranting further experimental investigation. TEAD1 knockdown was associated with altered expression of calcium-related proteins and elevated intracellular Ca²⁺ levels. The calcium channel blocker Nimodipine could reverse the improvement of erectile function in DMED rats and the transformation of CCSMC phenotype caused by TEAD1 knockdown. TEAD1 knockdown promotes the transformation of CCSMCs from a synthetic to a contractile phenotype and is associated with modulation of calcium signaling-mediated contractile machinery, contributing to the relief of DMED.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two-Component System as Drug Target: Is It a Bandwagon or a Breakthrough?","authors":"Akanksha Haldiya,&nbsp;Himanshi Kain,&nbsp;Poonam Kumari,&nbsp;Vijay Kumar Srivastava,&nbsp;Vinay Sharma,&nbsp;S. L. Kothari,&nbsp;Sanket Kaushik","doi":"10.1002/ddr.70368","DOIUrl":"https://doi.org/10.1002/ddr.70368","url":null,"abstract":"<div>\u0000 \u0000 <p>MDR ESKAPE pathogens are the leading cause of hospital-acquired infections (HAIs) that resist most antibiotics and form biofilms. Biofilm formation is dependent on the two-component system (TCS), which regulates virulence traits including adhesion to host tissues, evasion of innate immunity, the synthesis of exopolysaccharides, and antibiotic resistance. TCS sense environmental stimuli such as pH, osmotic pressure and antimicrobial peptides. They regulate gene expression to promote bacterial survival and persistence during infection. TCS represents a contemporary and novel pathway for the advancement of targeted, adjuvant-based options to fend off infections caused by ESKAPE pathogens. Targeting TCS may improve drug penetration and reduce resistance pressure, although challenges remain due to their structural conservation, regulatory complexity, and mutation-driven resistance. However, there are several limitations in targeting TCS for drug development like TCS not always being essential for bacterial viability, structural homologies between TCS are not sufficient for broad-spectrum inhibitors, sometimes TCS can be involved in complex and essential regulatory networks and can evolve resistance mechanisms by mutations. To further investigate this paradox, we implemented comprehensive computational and phylogenetic analyses of selected ESKAPE TCS. The findings from this investigation form the basis for our in-depth review of the significance and challenges of TCS as emerging drug targets.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DSCAM-AS1 Facilitates Osteosarcoma Progression via Regulating miR-211-5p/PDCD6 Axis","authors":"Qi Wang,&nbsp;Yunzheng Zhao,&nbsp;Longyan Shi,&nbsp;Hongjian Liu,&nbsp;Qiuliang Liu","doi":"10.1002/ddr.70360","DOIUrl":"https://doi.org/10.1002/ddr.70360","url":null,"abstract":"<div>\u0000 \u0000 <p>Among adolescents worldwide, osteosarcoma (OS) is one of the most frequently occurring cancers. DSCAM-AS1, a recognized lncRNA, has been noted for its abnormal expression in the development of certain cancers, but its role in OS is still unclear. Quantification of DSCAM-AS1, miR-211-5p, and PDCD6 expression was carried out via qRT-PCR or western blotting in human osteosarcoma cell lines (HOS, MG63, U2OS, SaOS-2) and a normal osteoblastic cell line (hFOB 1.19) using quantitative real-time polymerase chain reaction (qRT-PCR) for RNA detection and western blotting for protein detection, respectively. Cellular proliferation, apoptosis, migration, and invasion in OS cell models were comprehensively evaluated through a combination of experimental approaches, including EdU incorporation assay, CFSE labeling coupled with flow cytometric analysis, as well as transwell invasion and migration assays. To shed light on the molecular mechanisms of interactions among pertinent RNA molecules, researchers conducted luciferase reporter assays, RNA pull-down experiments, and RIP assays. Expression of DSCAM-AS1, miR-211-5p, and PDCD6 was analyzed based on the GEO database, and their correlations were evaluated. The levels of DSCAM-AS1and PDCD6 were predominantly overexpressed, while miR-211-5p was apparently lowly expressed in OS cells. Functional loss-of-function experiments demonstrated that silencing (knockdown) of DSCAM-AS1 expression substantially diminished OS cell proliferation, migration, and invasion, while simultaneously promoting cellular apoptosis in vitro. Mechanistically. DSCAM-AS1 acted as an upstream factor for miR-211-5p and could increase the expression of miR-211-5p-targeted PDCD6. DSCAM-AS1 facilitated the advancement of OS by increasing PDCD6 levels through miR-211-5p sponging. This observation could shed light on a novel therapeutic target option for OS.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of New Pyrazole-Linked Pyridine Derivatives as Multi-Target Anti-Inflammatory Agents With Immunomodulatory Potential","authors":"Mohamed A. Salem,&nbsp;Reham R. Raslan,&nbsp;Nirvana A. Gohar,&nbsp;Moustafa S. Abusaif,&nbsp;Yousry A. Ammar,&nbsp;Ahmed Ragab","doi":"10.1002/ddr.70362","DOIUrl":"https://doi.org/10.1002/ddr.70362","url":null,"abstract":"<div>\u0000 \u0000 <p>Cyclooxygenase (COX) plays a crucial role in the inflammatory response, making selective COX-2 inhibition a significant strategy for developing safer anti-inflammatory medications. Accordingly, developing new pharmacotherapies is a critical objective in anti-inflammatory drug discovery. In this study, a new pyrazole-linked pyridine derivatives <b>2-7</b> were synthesized through the reaction of the 4-(pyridin-1-yl)benzohydrazide derivative <b>1</b> with substituted-ketenes, activated olefinic dimers, and <i>α,β</i>-unsaturated carbonyl compounds. The synthesized derivatives were characterized and subsequently assessed in vitro for their inhibitory effects on COX-2. The results of the COX-2 inhibition assay revealed a broad range of activity, with IC₅₀ values ranging from 0.70 ± 0.02 to 63.49 ± 2.32 µM. Among the derivatives, <b>3</b> and <b>7b</b> demonstrated the most significant inhibitory effects, with IC₅₀ values of 1.11 ± 0.04 and 0.70 ± 0.02 µM, respectively, compared to celecoxib (IC₅₀ = 0.87 ± 0.03 µM). Furthermore, these promising derivatives exhibited COX-1 inhibitory activity, with IC₅₀ values of 16.08 ± 0.54 µM (SI_cox-2 = 14.48) and 2.77 ± 0.09 µM (SI_cox-2 = 3.95), respectively, compared to indomethacin (0.199 ± 0.01 µM) and celecoxib (21.62 ± 0.73 µM). Given the extensive COX activity of <b>7b</b>, further investigations were conducted, as it demonstrated immunomodulatory potential through the suppression of IL-6 (IC₅₀ = 167.65 ± 6.65 pg/mL) and TNF-α (IC₅₀ = 816.59 ± 28.01 pg/mL) compared to celecoxib's IC₅₀ (129.50 ± 4.44 pg/mL) and (399.7 ± 13.7 pg/mL), respectively. Additionally, pyrazole-linked pyridine derivative <b>7b</b> significantly reduced PGE2 levels to 539.49 ± 17.87 pg/mL and NO production to 4.230 ± 0.159 nM, compared to celecoxib 256.79 ± 8.50 pg/mL for PGE2 and 3.997 ± 0 nM for NO, respectively, suggesting that compound <b>7b</b> can attenuate both cytokine and eicosanoid signaling, exhibit extensive anti-inflammatory activity, and may serve as a potential multi-target therapeutic agent. The molecular docking simulation revealed that compound <b>7b</b> exhibited a significant binding affinity through various interactions. Finally, the DFT calculation indicated that <b>7b</b> has a low energy band gap, which suggests lower hardness and higher softness that implies a greater ability to redistribute electron density during binding, favoring the formation of stable polar interactions with protein residues. Overall, these findings demonstrate that compound <b>7b</b> is a promising multi-target anti-inflammatory lead drug with strong COX-2 inhibition and immunomodulatory properties. Moreover, further studies will concentrate on in vivo anti-inflammatory evaluation and pharmacokinetic profiling.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}