European Journal of Medicinal Chemistry Reports最新文献

{"title":"Discovery and pharmacological evaluation of a novel series of chromenopyrazole-based GPR55 modulators in an androgen-driven model of female metabolic dysfunction","authors":"Francisco J. Ponce-Díaz,&nbsp;Francisco Ruiz-Pino,&nbsp;Aitor Herraiz,&nbsp;Beatriz Romero,&nbsp;Laura Cerero-Tejero,&nbsp;Adela García-Martín,&nbsp;Simon Porzio-Gonzalez,&nbsp;Paula Morales,&nbsp;Miguel A. Sánchez-Garrido,&nbsp;Marina Pulido,&nbsp;Nadine Jagerovic,&nbsp;Manuel Tena-Sempere,&nbsp;Eduardo Muñoz","doi":"10.1016/j.ejmcr.2026.100363","DOIUrl":"10.1016/j.ejmcr.2026.100363","url":null,"abstract":"<div><div>GPR55 is a lipid-responsive G-protein-coupled receptor implicated in metabolic regulation, but its characterization has been limited by the poor selectivity and pathway bias of classical ligands. To obtain more reliable chemical tools, we revisited the chromenopyrazole scaffold and prepared a focused series of derivatives to refine GPR55 pharmacology. <em>In vitro</em> profiling identified compound <strong>A</strong> as a selective lysophosphatidylinositol (LPI)-dependent positive allosteric modulator, whereas compounds <strong>16</strong> and <strong>23</strong> displayed dual orthosteric/allosteric activity. All derivatives showed clean GPR55 engagement with no detectable cannabinoid receptor type 2 activity, highlighting the improved selectivity of this scaffold.</div><div>The biological relevance of these pharmacological profiles was assessed in a preclinical model of androgen-driven metabolic dysfunction reproducing key features of the metabolic phenotype observed in women with polycystic ovary syndrome (PCOS). In this model, compound <strong>A</strong> improved body weight regulation, glucose tolerance, and insulin sensitivity, while lowering serum cholesterol and triglycerides. Hepatic parameters followed a similar pattern, with reduced steatosis, macrophage infiltration, and early fibrotic remodeling. Compounds <strong>16</strong> and <strong>23</strong> produced broadly comparable benefits despite their distinct modes of GPR55 engagement, suggesting convergence on shared downstream pathways buffering metabolic stress. Hepatic GPR55 expression increased under steatotic and inflammatory conditions but normalized after treatment, supporting the potential advantage of allosteric enhancement of endogenous LPI signaling.</div><div>Overall, these findings identify chromenopyrazoles as a selective GPR55-modulating scaffold with the potential to mitigate metabolic and hepatic dysfunction in models reflecting key features of PCOS.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"17 ","pages":"Article 100363"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New C-30 secondary and tertiary amines of betulin with selective antiproliferative activity toward hematological malignancies - Synthesis and biological evaluation","authors":"Jan Bachořík,&nbsp;Ivo Frydrych,&nbsp;Soňa Gurská,&nbsp;Štěpán Dostál,&nbsp;Jan Pokorný,&nbsp;Adam Přibylka,&nbsp;Martina Medvedíková,&nbsp;Petr Džubák,&nbsp;Marián Hajdúch,&nbsp;Milan Urban","doi":"10.1016/j.ejmcr.2026.100360","DOIUrl":"10.1016/j.ejmcr.2026.100360","url":null,"abstract":"<div><div>A novel synthetic approach for preparation of secondary and tertiary amine derivatives of betulin was developed. The synthesis starts from commercially available betulin diacetate (<strong>1</strong>). The final step of the sequence relied on a Tsuji–Trost reaction. To explore the scope of this procedure, we prepared a variety of substituted secondary and tertiary amines. The reaction successfully afforded 31 out of 32 target products, with only one example failing to react.</div><div>All the prepared compounds were tested for <em>in vitro</em> cytotoxic activity against 6 cancer cell lines and 2 non-cancer cell lines. Several derivatives exhibited pronounced and selective antiproliferative activity toward hematological malignancies, with compounds <strong>5q</strong>, <strong>5s</strong>, and <strong>5t</strong> showing the most potent effects in CCRF-CEM and K562 cells while maintaining favorable selectivity over non-cancer fibroblasts. Mechanistic studies revealed that these compounds induce replication stress, leading to S-phase cell-cycle arrest and suppression of DNA synthesis. This was accompanied by activation of DNA damage response signaling, as indicated by increased γH2AX levels and upregulation of Cyclin E1 and p21. Further analysis demonstrated involvement of the intrinsic apoptotic pathway, as evidenced by mitochondrial membrane depolarization and increased expression of the pro-apoptotic protein BAX. In contrast, limited caspase activation and minimal PARP cleavage at equitoxic concentrations indicate that cells predominantly undergo early apoptotic commitment rather than full apoptotic execution. Collectively, these findings identify replication stress-mediated cell death as a key mechanism of action and highlight aminoderivatives of betulin diacetate as promising candidates for targeting proliferation-associated vulnerabilities in leukemia cells.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"17 ","pages":"Article 100360"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148640828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to “Exploring the antimicrobial potential of novel 2-oxo-2-H-chromene conjugates with guanine, thiazole, and imidazole: Synthesis, characterization, and biological evaluation” [Europ. J. Med. Chem. Rep. 14 (2024) 100179]","authors":"Suman Lata,&nbsp;Ramandeep Kaur,&nbsp;Gurinder Singh,&nbsp;Divya Dhawal Bhandari,&nbsp;Vikrant Abbot","doi":"10.1016/j.ejmcr.2026.100350","DOIUrl":"10.1016/j.ejmcr.2026.100350","url":null,"abstract":"","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"17 ","pages":"Article 100350"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational design of 3,4,5-trimethoxyphenyl-phenoxy-triazole derivatives as highly potent α-glucosidase inhibitors","authors":"Shahab Kermaninia,&nbsp;Morteza Farina,&nbsp;Mohammad Mahdavi,&nbsp;Aida iraji","doi":"10.1016/j.ejmcr.2026.100362","DOIUrl":"10.1016/j.ejmcr.2026.100362","url":null,"abstract":"<div><div>α-Glucosidase inhibitors are essential for better management of postprandial hyperglycemia in patients with type 2 diabetes mellitus. In this context, a novel series of fifteen 3,4,5-trimethoxyphenyl-phenoxy-1,2,3-triazole acetamide hybrids (<strong>11a-o</strong>) was designed, synthesized, and evaluated for α-glucosidase inhibitory activity. These compounds exhibited strong enzyme inhibition, with IC₅₀ values ranging from 0.15 to 60.41 μM, compared with the positive control, acarbose. Structure-activity relationship (SAR) analysis indicated that the type and position of substituents on the phenyl ring significantly affect potency, with 3-methyl, 2,4-dimethyl and 2,4-dimethoxy groups being the optimal substitutions to improve potency. Compound <strong>11c</strong> was the most active analog (IC₅₀ = 0.15 ± 0.01 μM) and exhibits competitive inhibition kinetics. Molecular docking showed that <strong>11c</strong> forms multiple stabilizing hydrogen bonds, π-π interactions, and π-cation interactions within the enzyme active site, while molecular dynamics simulations confirmed a stable protein-ligand complex over 100 ns. <em>In silico</em> ADME/T profiling showed good drug likeness, good intestinal absorption, low toxicity prediction, and acceptable pharmacokinetic parameters. Cytotoxicity studies in HEK-293 showed that all derivatives were minimally toxic at the cellular level. In summary, the results show that 3,4,5-trimethoxyphenyl-phenoxy-triazole acetamide hybrids, particularly <strong>11c</strong>, are ideal candidates for the future development of potent α-glucosidase inhibitors with a safety profile and oral bioavailability.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"17 ","pages":"Article 100362"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative in silico and experimental identification of non-covalent UBE2N inhibitors enhancing PARP inhibitor sensitivity","authors":"Côme Ghadi,&nbsp;Shafi Ullah Khan,&nbsp;Léonie Ibazizene,&nbsp;Florian Schwalen,&nbsp;Charline Kieffer,&nbsp;Peggy Suzanne,&nbsp;Julie Jaouen,&nbsp;Hassiba Bouafia,&nbsp;Xavier Thuru,&nbsp;Marie Cornu,&nbsp;Cedric Lecoutey,&nbsp;Matthieu Meryet-Figuiere,&nbsp;Anne Sophie Voisin-Chiret,&nbsp;Louis-Bastien Weiswald,&nbsp;Jana Sopkova-de Oliveira Santos","doi":"10.1016/j.ejmcr.2026.100361","DOIUrl":"10.1016/j.ejmcr.2026.100361","url":null,"abstract":"<div><div>UBE2N, an E2 ubiquitin-conjugating enzyme, has emerged as a promising therapeutic target in oncology due to its critical roles in DNA damage repair and NF-κB signalling. While covalent inhibitors have shown promising preclinical results, non-covalent inhibitors display increased selectivity and reduced off-target effects. However, structural and mechanistic data for non-covalent UBE2N inhibitors remain scarce. To address this gap, we implemented a dual <em>in silico</em> strategy combining structure-based molecular docking and ligand-based 3D pharmacophore modelling. Screening of a library of ∼19,000 compounds to identify molecules targeting the ubiquitin-binding or cofactor-interacting interfaces of UBE2N, led to the identification of 22 candidates suitable for biological evaluation.</div><div>Among these, compounds CERMN-2 and CERMN-16 emerged primarily as promising non-covalent inhibitors. CERMN-16, structurally related to the natural compound Variabine B (identified through 3D pharmacophore screening), significantly reduced SKOV-3 ovarian cancer cell viability and enhanced their sensitivity to the PARP inhibitor Olaparib, a phenotype observed upon effective UBE2N inhibition. CERMN-2, identified through our docking strategy, also demonstrated a synergistic effect with Olaparib and showed low toxicity in normal ovarian epithelial cells. Molecular dynamics simulations indicated distinct binding modes for each compound, consistent with their targeted binding sites. Biophysical experiments revealed weak binding of CERMN-16 to UBE2N, whereas CERMN-2 bound UBE2N in two orthogonal assays (Microscale thermophoresis and Nano differential scanning fluorimetry). CERMN-16, and more importantly CERMN-2, therefore represent promising hits for the future development of selective, non-natural, non-covalent UBE2N inhibitors. These results provide new insights into UBE2N inhibition and support further investigation of its therapeutic potential to sensitize ovarian cancer to approved therapeutics.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"17 ","pages":"Article 100361"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide-mediated modulation of miRNAs: A novel therapeutic strategy for cancer","authors":"Rony Abdi Syahputra ,&nbsp;Asriadi ,&nbsp;Arnika Gloria Br Sitorus ,&nbsp;Sintia Karina Putri ,&nbsp;Ana Gabriela Silva Olivera ,&nbsp;Livia Ramos Santiago ,&nbsp;Princella Halim ,&nbsp;Amer Ahmed ,&nbsp;Aasia Bibi ,&nbsp;Aminah Dalimunthe ,&nbsp;Poppy Anjelisa Zaitun Hasibuan ,&nbsp;Moon Nyeo Park ,&nbsp;Rosy Iara Maciel de Azambuja Ribeiro ,&nbsp;Bonglee Kim ,&nbsp;Pornphimon Meesakul ,&nbsp;Shugeng Cao","doi":"10.1016/j.ejmcr.2025.100313","DOIUrl":"10.1016/j.ejmcr.2025.100313","url":null,"abstract":"<div><div>MicroRNAs are essential post-transcriptional regulators of gene expression, playing dual roles in oncogenesis as either oncogenes or tumour suppressors. Aberrant miRNA expression is a critical factor in cancer progression, influencing tumour development, metastasis, resistance to apoptosis, and therapy evasion. Concurrently, therapeutic peptides have emerged as promising modulators of miRNA activity due to their specificity, low toxicity, and ability to interact with nucleic acids. This review provides of peptide-mediated modulation of miRNA pathways in cancer, emphasising strategies such as degradation of oncogenic miRNAs, stabilization of tumour-suppressive miRNAs, and the targeted delivery of miRNA therapeutics. These methodologies demonstrate the potential to reverse malignant phenotypes by reducing cell proliferation, suppressing metastasis, restoring normal cellular functions, and promoting apoptosis. The integration of peptide-based delivery systems with miRNA-targeted therapies represents a novel paradigm in precision oncology, addressing key challenges related to therapeutic specificity and systemic delivery.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"16 ","pages":"Article 100313"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145787390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitrofuranyl derivatives as promising antitubercular agents: Structural insights and drug discovery perspectives","authors":"Afreen N ,&nbsp;Smriti Sharma","doi":"10.1016/j.ejmcr.2025.100314","DOIUrl":"10.1016/j.ejmcr.2025.100314","url":null,"abstract":"<div><div>The emergence of MDR (multidrug-resistant) and XDR (extensively drug-resistant) variants of <em>Mycobacterium tuberculosis</em> has contributed to the universal resurgence of tuberculosis (TB). Nitrofuran-based compounds, traditionally used as antibacterial agents, have recently gained attention for their potential antitubercular properties. This review presents a comprehensive overview of structural classes of nitrofuran derivatives—including nitrofuranylamides, hydrazides, triazoles, spirocyclic hybrids, and prodrugs—and their corresponding structure–activity relationships, efficacy profiles, and safety evaluations. Several lead compounds exhibit potent <em>in vitro</em> as well as <em>in vivo</em> activity, often surpassing the effectiveness of existing TB drugs while maintaining favorable cytotoxicity and selectivity indices. Repurposing strategies and chemical modifications have significantly improved their pharmacological profiles, offering promising avenues for TB drug discovery. While current findings are encouraging, further mechanistic studies, pharmacokinetic optimization, and translational research are essential to advance nitrofuran derivatives toward clinical application. This review underscores the therapeutic value of nitrofuran scaffolds and supports their continued exploration as viable candidates in the global effort to combat TB.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"16 ","pages":"Article 100314"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the hepatoprotective properties of Vitex Altissima bark extracts and isolated bioactive: In-vitro and In-vivo approach","authors":"I.A. Chethan ,&nbsp;Jaishree Vaijanathappa","doi":"10.1016/j.ejmcr.2025.100312","DOIUrl":"10.1016/j.ejmcr.2025.100312","url":null,"abstract":"<div><div><em>Vitex altissima</em> (<em>V. altissima</em>), an ethnopharmacologically valuable plant, is explicitly used as traditional medicine by local folks to cure liver-related disorders in Coorg. Hence, the present study aimed to evaluate the bark extract's hepatoprotective and antioxidant mechanisms and its isolated potent compound against CCl₄-induced toxicity. Ethanolic bark extracts underwent phytochemical screening, LC-MS profiling and bioactivity-guided antioxidant assays, including DPPH and hydroxyl radical scavenging methods. Preparative HPLC enabled the isolation of three compounds, among which Isolate-1 demonstrated the most potent bioactivity and was structurally characterized as Albafuran C via FTIR, NMR, and LC-MS/MS analyses. <em>In vitro</em> hepatoprotection studies using HepG2 cells revealed that pretreatment with Isolate-1 significantly enhanced cell viability, suppressed CCl₄-induced oxidative stress, and restored antioxidant enzyme levels (SOD, CAT). Flow cytometry confirmed reduced intracellular ROS and iNOS expression, supporting its antioxidative and anti-inflammatory potential. <em>In vivo</em> experiments in CCl₄-induced Wistar rats demonstrated significant amelioration of hepatic markers (ALT, AST, ALP, bilirubin, and albumin) and restoration of liver histoarchitecture upon treatment with Isolate-1. Molecular analysis by RT-PCR and Western blotting revealed downregulation of NF-κB signaling and inflammatory mediators. These findings confirm the hepatoprotective mechanism of <em>V. altissima</em>, substantiating its traditional use and identifying Albafuran C as a promising phytotherapeutic agent. This study establishes a scientific rationale for further development of Albafuran C as a natural hepatoprotective compound targeting oxidative and inflammatory liver injury.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"16 ","pages":"Article 100312"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating the mechanism of anti-ischemic stroke action of Irisflorentin:A combined approach using network pharmacology, molecular docking, and in vitro validation","authors":"Yue Zhang ,&nbsp;Tingting Lu ,&nbsp;Xuping Luo ,&nbsp;Chang Jin ,&nbsp;Meizhu Zheng ,&nbsp;Dongfang Shi ,&nbsp;Kai Song ,&nbsp;Qicheng Ying ,&nbsp;Yongxing Ai","doi":"10.1016/j.ejmcr.2025.100318","DOIUrl":"10.1016/j.ejmcr.2025.100318","url":null,"abstract":"<div><div>Irisflorentin, an isoflavonoid isolated from <em>Belamcanda chinensis</em> (L.) Redouté, serves as a key bioactive molecule in Sagittaria, exhibiting antioxidative, hypoglycemic, and anti-inflammatory properties. Despite these attributes, the precise roles and mechanisms of Irisflorentin in mitigating cerebral ischemia/reperfusion injury are not well elucidated. This study aims to clarify the therapeutic targets and pathways of irisflorentin in ischemic stroke utilizing network pharmacology, molecular docking, molecular dynamics simulation and experimental validation. The predictions generated by network pharmacology and molecular docking concerning potential targets and pathways. Irisflorentin influences numerous biological processes, such as signaling, protein phosphorylation, the suppression of neuronal apoptosis and the amplification of the MAPK cascade. Key targets identified via molecular docking include ESR1, EGFR, HIF1A, HSP90AB1, CCND1, ERBB2, MTOR, ESR2, MAPK8, and MAPK1. Molecular dynamics simulations indicate that the Irisflorentin small molecule exhibits favourable binding interactions with the HIF1A and MTOR target proteins.Cellular studies showed that irisflorentin improves cellular morphology, boosts cell viability and mitochondrial membrane potential, and decreases LDH release, ROS production, Ca²⁺ levels, and apoptosis rates. IFR enhances the expression of PI3K, AKT, mTOR, Bcl-2, BDNF, TRқB, ERK1, ERK2, p90RSK, and CREB, while suppressing FOXO1A, HIF1A, Bax, and Caspase-3.Ultimately, Irisflorentin promotes neuroprotection and lessens cerebral ischemia/reperfusion damage by activating the PI3K/AKT/FOXO1A, mTOR/HIF1A, and BDNF/TRқB/ERK1/2/p90RSK/CREB pathways, underscoring its potential as an adjunct therapy for ischemic stroke and providing a foundation for its further development and clinical utility.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"16 ","pages":"Article 100318"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145787345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sanguinarine alleviates cisplatin-induced apoptosis in AKI by upregulating BCL-2 through targeting the gene promoter i-motif","authors":"Xiaoya Li ,&nbsp;Wen-Li Fu ,&nbsp;Fenfen He ,&nbsp;Xiaoli Xu ,&nbsp;Bianxiang Hu ,&nbsp;Yuqing Wang ,&nbsp;Shuo-Bin Chen ,&nbsp;Jianmin Chen","doi":"10.1016/j.ejmcr.2025.100316","DOIUrl":"10.1016/j.ejmcr.2025.100316","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a severe clinical condition with high morbidity and mortality. Apoptosis of renal tubular epithelial cells is a key pathological driver, and upregulation of the anti-apoptotic protein <em>BCL-2</em> is a validated protective mechanism. The <em>BCL-2</em> promoter harbors a C-rich sequence capable of forming an i-motif, a non-canonical DNA secondary structure with regulatory functions. Previous studies have reported steroid-like molecules as potential ligands for the <em>BCL-2</em> i-motif, but their interactions were generally weak and lacked systematic pharmacophore insight. Here, we identify Sanguinarine (<strong>SG</strong>), a benzophenanthridine alkaloid, as a more potent ligand from a natural product library. Surface plasmon resonance (SPR) revealed broad-spectrum binding of <strong>SG</strong> to multiple promoter i-motifs, yet circular dichroism (CD) and melting assays suggested a relatively stronger stabilizing effect on the BCL-2 C-rich structure under our assay conditions. This apparent conformational preference, rather than strict binding selectivity, led to transcriptional activation of <em>BCL-2</em> and protection of HK-2 cells from cisplatin-induced apoptosis. While i-motifs have only rarely been explored in AKI, our study provides new mechanistic insight by defining an aromatic–cationic pharmacophore and suggesting that structure-dependent stabilization may serve as a plausible mechanism for promoter-specific modulation. These findings support the biological relevance of the <em>BCL-2</em> i-motif and highlight natural products as valuable scaffolds for nucleic-acid–interacting agents in renal injury models.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"16 ","pages":"Article 100316"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}