Bioorganic & Medicinal Chemistry最新文献

{"title":"Scaffold hopping and sidechain modification from a flavone scaffold lead to discovery of potent, selective CK2A2 inhibitors with favorable properties for CNS activity","authors":"James K. Tucker,&nbsp;Ioana I.N. Da Silva,&nbsp;Fred H. Gage","doi":"10.1016/j.bmc.2025.118196","DOIUrl":"10.1016/j.bmc.2025.118196","url":null,"abstract":"<div><div>The human protein kinase CK2 has long been of interest as a target in oncology, but new evidence is emerging of its role in central nervous system (CNS) disorders. The CK2 catalytic subunit paralog CK2A2 is enriched in the CNS relative to other tissues; however, the catalytic subunit paralog CK2A1 is expressed at similar levels across most tissues. Current treatment modalities centered on CK2 inhibition under clinical study lack evidence of CNS activity, kinome-wide selectivity, or CK2A2 paralog selectivity. Therefore, a brain-penetrant inhibitor selective for CK2A2 over CK2A1 may enable the further elucidation of the role of this paralog in CNS pathologies. In this work, we describe a series of flavone-inspired inhibitors of CK2A1 and CK2A2 designed and synthesized in a structure-based drug-design campaign. Multiple candidates demonstrating promising CK2A2 potency, kinome-wide selectivity, and CNS permeability/activity were identified, with compound <strong>65</strong> representing the best confluence of these properties. Although these lead candidates exhibited only up to three-fold preferential inhibition of CK2A2, they represent a starting point for the study of CK2A2 and the disorders it may mediate in the CNS.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"127 ","pages":"Article 118196"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935458","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":"Verification of the mechanism of action of isoliquiritigenin derivatives on LPS-induced FLS cells in rheumatoid arthritis based on network pharmacology","authors":"Qing Ma,&nbsp;Zhiwei Liu,&nbsp;Dan Wang,&nbsp;Chi Liu,&nbsp;Xinyue Liu,&nbsp;Enbo Cai,&nbsp;Fengyan Su","doi":"10.1016/j.bmc.2025.118199","DOIUrl":"10.1016/j.bmc.2025.118199","url":null,"abstract":"<div><div>Isoliquiritigenin (ISL), which has a chalcone parent structure, has a variety of pharmacological effects. In this study, ISL was structurally modified to create 16 bromate derivatives of ISL. The structures of these derivatives were determined using ¹H NMR and ¹³C NMR. An in vitro rheumatoid arthritis inflammation model was established using LPS-induced fibroblast-like synoviocytes (FLS). The survival, NO content and viability of derivatives bound to LPS were determined by Elisa assay of the expression of the relevant inflammatory factors TNF-α, IL-1 and IL-1β. Network pharmacology predicted the relevant targets and pathways of action of ISL in rheumatoid arthritis, which were experimentally validated by RT-PCR method and Western Blot method. The results showed that ISL-6 exerted anti-rheumatoid arthritis effects by reducing the expression of inflammatory factors TNF-α, IL-1 and IL-1β, activating the PI3K/AKT pathway, promoting AKT phosphorylation, and then affecting the expression of the downstream signaling molecule FOXO1, which is associated with inflammation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118199"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850589","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":"Discovery of structurally diverse diazatricyclododecenes as lysosomotropic autophagy inhibitors","authors":"Kazuki Miura ,&nbsp;Kohei Umedera ,&nbsp;Tomoya Doi ,&nbsp;Hiroyuki Nakamura","doi":"10.1016/j.bmc.2025.118200","DOIUrl":"10.1016/j.bmc.2025.118200","url":null,"abstract":"<div><div>Lysosomotropic autophagy inhibitors were identified from a structurally diverse library of diazatricycloundecanes. Structure activity relationship (SAR) studies on the three side chain substituents (R¹-R³) of diazatricycloundecane identified compound <strong>1e</strong> as the most potent inducer of LC3-II protein accumulation. Mechanistic analysis revealed that compound <strong>1e</strong> functions as a lysosomotropic agent, increasing lysosomal pH and inhibiting autophagy through lysosomal dysfunction. Furthermore, compound <strong>1e</strong> was less cytotoxic compared to previously reported lysosomotropic agents and exhibited excellent drug-like physicochemical properties, surpassing those of classical lysosomotropic agents such as chloroquine and hydroxychloroquine.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118200"},"PeriodicalIF":3.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847580","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":"Antitumor and immunomodulatory activities of diphyllin and its derivatives","authors":"Yulin Ren ,&nbsp;Judith C. Gallucci ,&nbsp;Jianhua Yu ,&nbsp;Joanna E. Burdette ,&nbsp;James R. Fuchs ,&nbsp;A. Douglas Kinghorn","doi":"10.1016/j.bmc.2025.118197","DOIUrl":"10.1016/j.bmc.2025.118197","url":null,"abstract":"<div><div>Immune surveillance plays a key role in controlling tumor formation and development, and immune cell-based therapies, such as chimeric antigen receptor (CAR)-T cells and CAR-natural killer (NK) cells, have become important for the treatment of cancer. The proton pump (PP), vacuolar H⁺-ATPase (V-ATPase), acidifies intracellular organelles, pumps protons across the cell plasma membranes, and regulates the activity of various signaling pathways, and thus has been regarded as a potential target for cancer treatment. In addition, V-ATPase plays an important role in cytotoxic T lymphocytes, extracellular vesicle (EV) endocytosis, innate immune responses (IIR), and phagocytosis and hence has the potential to function as a target for the enhancement of immunotherapy. As potent V-ATPase inhibitors, the arylnaphthalene lignans, diphyllin and its derivatives, have exhibited potent antitumor and immunomodulatory activities. The structurally related aryltetralin lignan, podophyllotoxin, has served as a lead compound for both etoposide and teniposide, which have been developed as effective anticancer agents. In the present review, the role of V-ATPase in cancer immunotherapy and the structure–activity relationships (SARs) of diphyllin and its cytotoxic and V-ATPase inhibitory activities and the mechanisms of action are discussed. Also, the promise of diphyllin and its derivatives in the development of new adjuvants for cancer immunotherapies has been proposed.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118197"},"PeriodicalIF":3.3,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850587","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":"A novel integrated diagnostic and therapeutic ferroptosis inhibitor based on a phenothiazine scaffold with ROS-Responsive strategy","authors":"Jiangye Zhang ,&nbsp;Rui Cai ,&nbsp;Changxu Ning ,&nbsp;Zhongxiang Zhou ,&nbsp;Yibo Zhang ,&nbsp;Shisheng Wang ,&nbsp;Yueqing Li ,&nbsp;Xiuhan Guo","doi":"10.1016/j.bmc.2025.118195","DOIUrl":"10.1016/j.bmc.2025.118195","url":null,"abstract":"<div><div>Ferroptosis is a newly discovered form of cell death that is closely related to the occurrence of various diseases, such as neurodegenerative diseases, cardiovascular and cerebrovascular ischemic damage, and organ fibrosis. Therefore, the discovery of new active compounds with ferroptosis inhibitory activity is regarded as a new strategy for the clinical treatment of these diseases. In this study, a multifunctional prodrug molecule PNX-B2 with a phenoxazine structure was designed based on the oxidative microenvironment characteristic of ferroptosis. PNX-B2 can recognize the ferroptosis-associated oxidative conditions and simultaneously release compounds with ferroptosis-inhibitory activity. Moreover, it integrates diagnostic and therapeutic functions and offers a fluorescent indication of the ferroptosis microenvironment. PNX-B2 has demonstrated excellent ferroptosis-inhibitory activity with an EC₅₀ value of 1.7 nM. This intelligent multifunctional compound shows great potential as a novel clinical agent for ferroptosis inhibition and presents broad prospects for future development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118195"},"PeriodicalIF":3.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143845055","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":"Quantitative and site-specific chemoproteomic profiling of O-GlcNAcylation in Drosophila","authors":"Cong Lei ,&nbsp;Zihan Chen ,&nbsp;Yi Hao ,&nbsp;Wanping Huang ,&nbsp;Tianyu Chu ,&nbsp;Kangming Xiao ,&nbsp;Che Zhang ,&nbsp;Wen Zhou ,&nbsp;Chenjian Li ,&nbsp;Xing Chen","doi":"10.1016/j.bmc.2025.118191","DOIUrl":"10.1016/j.bmc.2025.118191","url":null,"abstract":"<div><div>Protein O-GlcNAcylation plays a crucial role in <em>Drosophila melanogaster</em> development. Dysregulation of O-GlcNAc transferase (<em>sxc</em>/<em>Ogt</em>) and O-GlcNAcase (<em>Oga</em>) disrupts early embryogenesis and locomotor behavior. It is therefore of great interest to identify and quantitatively analyze O-GlcNAcylation sites in <em>Drosophila</em>. Here, we perform quantitative and site-specific profiling of O-GlcNAcylation in <em>Drosophila</em> by employing a chemoenzymatic labeling strategy. A total of 2196 unambiguous O-GlcNAcylation sites and 1308 O-GlcNAcylated proteins are identified. Quantitative analysis of O-GlcNAcylation in the head of <em>Drosophila</em> with <em>sxc</em>/<em>Ogt</em> knockdown in GABAergic neurons reveals a reduction in O-GlcNAcylation of several proteins involved in muscle development, consistent with the phenotypic defects observed in <em>sxc</em>/<em>Ogt</em> RNAi <em>Drosophila</em>. Furthermore, quantitative analysis of O-GlcNAcylation under a high-sugar diet reveals altered O-GlcNAcylation of several proteins associated with obesity and neurological diseases, such as Hex-A and Ankyrin 2. Our study not only establishes an effective method for large-scale identification of O-GlcNAcylation sites, but also provides a valuable resource for studying O-GlcNAc biology in <em>Drosophila</em>.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118191"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834797","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":"Truncated pyridinylbenzylamines: Potent, selective, and highly membrane permeable inhibitors of human neuronal nitric oxide synthase","authors":"Dhananjayan Vasu ,&nbsp;Ha T. Do ,&nbsp;Huiying Li ,&nbsp;Christine D. Hardy ,&nbsp;Thomas L. Poulos ,&nbsp;Richard B. Silverman","doi":"10.1016/j.bmc.2025.118193","DOIUrl":"10.1016/j.bmc.2025.118193","url":null,"abstract":"<div><div>Neuronal nitric oxide synthase (nNOS) is a promising target for addressing various neurological disorders and melanoma. Our discovery of a series of truncated pyridinylbenzylamines has yielded potent, selective, and membrane permeable inhibitors of human neuronal nitric oxide synthase. By implementing an efficient synthetic procedure using the Suzuki–Miyaura cross-coupling reaction, we were able to rapidly identify a potent inhibitor. This new inhibitor (<strong>18</strong>, 6-(2,3-difluoro-5-((methylamino)methyl)phenyl)-4-methylpyridin-2-amine dihydrochloride) exhibits excellent potency, with <em>K</em>_i values of 30 nM for human nNOS and 40 nM for rat nNOS. It also demonstrates high isoform selectivity, showing an 821-fold preference for human nNOS over human endothelial NOS (eNOS) and a 75-fold selectivity over human inducible NOS (iNOS). Additionally, inhibitor <strong>18</strong> displays high permeability (<em>P</em>_e = 10.7 × 10⁻⁶ cm s⁻¹) in an artificial membrane permeability assay. The crystal structures of several NOS-inhibitor complexes provide valuable structural insights into the potency and selectivity of this series of novel inhibitors. A particularly notable finding is the unexpected role of a Cl⁻ anion bound to heNOS, which contributes to the high isoform selectivity of these inhibitors and explains why heNOS binds Cl⁻, while hnNOS does not. This unique Cl⁻ binding site could be important in future inhibitor design, opening new avenues for the development of more selective NOS inhibitors. Additionally, the presented crystal structures reveal the key factors required to maintain both high potency and selectivity in the simplified inhibitors discussed in this study.</div><div>Abbreviations: NO, nitric oxide; nNOS, neuronal nitric oxide synthase; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase; rnNOS, rat neuronal nitric oxide synthase; hnNOS, human neuronal nitric oxide synthase; hiNOS, human inducible nitric oxide synthase; heNOS, human endothelial nitric oxide synthase; <span>l</span>-Arg, <span>l</span>-arginine; NADPH, reduced nicotinamide adenine dinucleotide phosphate; CaM, calmodulin; H₄B, (6<em>R</em>)-5,6,7,8-tetrahydrobiopterin; FAD, flavin adenine dinucleotide; FMN, Flavin mononucleotide, BBB, blood–brain barrier; CNS, central nervous system; PAMPA, parallel artificial membrane permeability assay; P-gp, P-glycoprotein; ER, efflux ratio; <em>P</em>_e, effective permeability; <em>P</em>_app, apparent permeability; Caco-2, cancer coli-2; TLC, thin layer chromatography; TBAF, tetra-<em>n</em>-butylammonium fluoride; TFA, trifluoroacetic acid.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118193"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143845057","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":"Development of GluN2A NMDA receptor positive allosteric modulators: Recent advances and perspectives","authors":"Ping Li ,&nbsp;Jiacheng Wang ,&nbsp;Mengjiao Wang ,&nbsp;Xin Chen ,&nbsp;Hongyu Zhu ,&nbsp;Mingxin Dong","doi":"10.1016/j.bmc.2025.118194","DOIUrl":"10.1016/j.bmc.2025.118194","url":null,"abstract":"<div><div><em>N</em>-methyl-<span>d</span>-aspartate (NMDA) receptors, functioning as glutamate-gated ion channels, mediate the permeation of Ca²⁺ and are essential for excitatory synaptic transmission and synaptic plasticity within the central nervous system (CNS). During brain development, there is a switch from an early dominance of GluN2B subunit expression to the incorporation of GluN2A subunits at mature synapses. NMDARs hypofunction is implicated in various psychiatric disorders, and activation of NMDARs containing GluN2A has recently attracted attention as a promising therapeutic approach for treating these diseases. This review focuses on the selective positive allosteric modulators (PAMs) that specifically target the ligand-binding domain (LBD) and <em>N</em>-terminal domain (NTD) regions of GluN2A subtype, as well as non-subunit selective PAMs, and discusses their implications in neuropsychiatric diseases such as stroke, depression, Alzheimer’s disease, and Huntington’s disease.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118194"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834861","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":"Construction of 3-oxo-3H-spiro[benzofuran-2,1′-cyclopentane] carboxylic acid derivatives via phosphine-catalyzed [4 + 1] annulations and their biological evaluation against fibrosis","authors":"Sheng-Hong Li ,&nbsp;Feng-Yi Lu ,&nbsp;Muralikrishna Katta,&nbsp;Yun-Yun Liu,&nbsp;Danling Huang,&nbsp;Yong-Xian Cheng","doi":"10.1016/j.bmc.2025.118192","DOIUrl":"10.1016/j.bmc.2025.118192","url":null,"abstract":"<div><div>A novel phosphine-catalyzed [4 + 1] cyclization reaction was developed to construct the 3-oxo-3<em>H</em>-spiro[benzofuran-2,1′-cyclopentane] scaffold. Utilizing this innovative method, twenty diverse 3-oxo-3<em>H</em>-spiro[benzofuran-2,1′-cyclopentane] carboxylic acid derivatives were synthesized and evaluated for their anti-fibrotic activities. Compound <strong>L10-P1</strong> possessed potential anti-fibrotic activity by inhibiting the expression of fibronectin, collagen I, and α-SMA. This study presents a new synthetic route for 3<em>H</em>-spiro[benzofuran-2,1′<em>-</em>cyclopentan]-3-one derivatives, contributing valuable insights into the chemical and biological diversity of these compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118192"},"PeriodicalIF":3.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143845077","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":"Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode","authors":"Nicolas Desroy ,&nbsp;Razvan Borza ,&nbsp;Jörg Heiermann ,&nbsp;Nicolas Triballeau ,&nbsp;Agnès Joncour ,&nbsp;Natacha Bienvenu ,&nbsp;Willem Jan Hengeveld ,&nbsp;Jasper Springer ,&nbsp;René Galien ,&nbsp;Robbie P. Joosten ,&nbsp;Anastassis Perrakis ,&nbsp;Bertrand Heckmann","doi":"10.1016/j.bmc.2025.118181","DOIUrl":"10.1016/j.bmc.2025.118181","url":null,"abstract":"<div><div>Autotaxin (ATX) is a circulating enzyme that plays a major role in the production of the signaling mediator lysophosphatidic acid (LPA). A role for ATX/LPA signaling has been described in multiple disease areas, including fibrosis and cancer. ATX inhibitors are classified in five types (I-V) depending on how they target parts of the tripartite site (active site, pocket and tunnel). We set to explore a “penultimate” type of inhibitors, targeting all these three parts at once. Designing new analogs extending on an ethyl group of the type IV GLPG1690 compound, yielded potent new molecules. Co-crystal structures confirmed compounds that utilize a three-point lock binding mode. The most potent “type VI” inhibitors, <strong>4</strong> and <strong>41</strong>, displayed increased inhibitory activity (∼40-fold) compared to the type IV close analog <strong>3</strong>. Type VI inhibitors <strong>4</strong> and <strong>41</strong> showed cellular and phenotypic activity similar to type IV inhibitor GLPG1690. Identification of this new binding mode completes this combinatorial puzzle in inhibitor design and calls for further investigation to characterize potential therapeutic benefit.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118181"},"PeriodicalIF":3.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826119","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}