Pub Date : 2025-04-18DOI: 10.1016/j.bmc.2025.118203
Qiwen Shi , Tao Zhou , Yuqi Zhou , Zhi-Hao Wang , Yao-Jie Xue , Ya-Jing Chen
A series of tetracyclic 1,2,4-triazoline-fused dibenzo[b,f][1,4]oxazepines were evaluated as novel anti-tumor agents. MTT assay conducted in four human cancer cell lines (SW620, A549, MCF-7, HepG2) showed that 1,2,4-triazoline-fused dibenzo[b,f][1,4]oxazepine decorated by a methyl group on the benzene ring of 1,2,4-triazoline moiety exhibited a superior antiproliferative activity against SW620 cells with a IC50 value of 0.86 μM. The above compound was thus chosen for further investigation on its anti-colorectal cancer (CRC) effect, and displayed inhibitory effects on the proliferation of HCT116 and CT26 cells with IC50 values of 0.96 μM and 1.71 μM, respectively. Furthermore, this compound could effectively suppress colony formation and induce cell cycle arrest and apoptosis in SW620 cells. Western blot analysis demonstrated that it exerted the anti-tumor activity through blocking the PI3K-AKT signaling pathway. Next, we examined its in vivo anti-tumor activity by establishing a subcutaneous CT26 xenograft model, and found that it significantly reduced the tumor sizes with limited toxicity. Collectively, these findings suggest that this compound could be utilized as a promising candidate against CRC.
{"title":"Discovery of tetracyclic 1,2,4-triazoline-fused dibenzo[b,f][1,4]oxazepine as a potent anti-colorectal cancer agent with good efficacy and low toxicity","authors":"Qiwen Shi , Tao Zhou , Yuqi Zhou , Zhi-Hao Wang , Yao-Jie Xue , Ya-Jing Chen","doi":"10.1016/j.bmc.2025.118203","DOIUrl":"10.1016/j.bmc.2025.118203","url":null,"abstract":"<div><div>A series of tetracyclic 1,2,4-triazoline-fused dibenzo[<em>b,f</em>][1,4]oxazepines were evaluated as novel anti-tumor agents. MTT assay conducted in four human cancer cell lines (SW620, A549, MCF-7, HepG2) showed that 1,2,4-triazoline-fused dibenzo[<em>b,f</em>][1,4]oxazepine decorated by a methyl group on the benzene ring of 1,2,4-triazoline moiety exhibited a superior antiproliferative activity against SW620 cells with a IC<sub>50</sub> value of 0.86 μM. The above compound was thus chosen for further investigation on its anti-colorectal cancer (CRC) effect, and displayed inhibitory effects on the proliferation of HCT116 and CT26 cells with IC<sub>50</sub> values of 0.96 μM and 1.71 μM, respectively. Furthermore, this compound could effectively suppress colony formation and induce cell cycle arrest and apoptosis in SW620 cells. Western blot analysis demonstrated that it exerted the anti-tumor activity through blocking the PI3K-AKT signaling pathway. Next, we examined its <em>in vivo</em> anti-tumor activity by establishing a subcutaneous CT26 xenograft model, and found that it significantly reduced the tumor sizes with limited toxicity. Collectively, these findings suggest that this compound could be utilized as a promising candidate against CRC.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"125 ","pages":"Article 118203"},"PeriodicalIF":3.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859596","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}
Pub Date : 2025-04-16DOI: 10.1016/j.bmc.2025.118201
Qiuyu Guo , Chunxia Yang , Xuyuan Liu , Jian Liu , Wei Zhang , Xiuhong Lu , Ning Ding
While there have been advancements in the development of innovative PROTACs with sophisticated linkers designed to meet specific requirements, studies on the structure–activity relationships (SAR) of linker length remain a fundamental priority. Although several reliable chemistries for connecting the two ligands—one targeting the protein and the other for E3 ubiquitin ligase—have been established, the potential for utilizing various other methods still needs exploration. In this work, we introduced a concept that employs the SuFEx reaction, a novel family of click chemistry, to quickly construct a small PROTAC library for protein degradation. This was achieved by amidating a sulfonyl fluoride or fluorosulfate precursor (modified with the p300/CBP ligand CPI644) with CRBN ligands that possess amino-carbon chains of varying lengths. The protein degradation effects of the PROTACs created through this strategy were further validated using the p300/CBP overexpressed MDA-MB-468 cell line.
{"title":"Construction of PROTAC molecules by the SuFEx reaction for inducing p300/CBP protein degradation","authors":"Qiuyu Guo , Chunxia Yang , Xuyuan Liu , Jian Liu , Wei Zhang , Xiuhong Lu , Ning Ding","doi":"10.1016/j.bmc.2025.118201","DOIUrl":"10.1016/j.bmc.2025.118201","url":null,"abstract":"<div><div>While there have been advancements in the development of innovative PROTACs with sophisticated linkers designed to meet specific requirements, studies on the structure–activity relationships (SAR) of linker length remain a fundamental priority. Although several reliable chemistries for connecting the two ligands—one targeting the protein and the other for E3 ubiquitin ligase—have been established, the potential for utilizing various other methods still needs exploration. In this work, we introduced a concept that employs the SuFEx reaction, a novel family of click chemistry, to quickly construct a small PROTAC library for protein degradation. This was achieved by amidating a sulfonyl fluoride or fluorosulfate precursor (modified with the p300/CBP ligand <strong>CPI644</strong>) with CRBN ligands that possess amino-carbon chains of varying lengths. The protein degradation effects of the PROTACs created through this strategy were further validated using the p300/CBP overexpressed MDA-MB-468 cell line.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"125 ","pages":"Article 118201"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859593","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}
Pub Date : 2025-04-16DOI: 10.1016/j.bmc.2025.118202
Yidan Wu , Li Tang , Qiang Liu
Poly (ADP-ribose) (PAR), a dynamic and reversible post-translational modification, is a structurally complex biopolymer synthesized via ADP-ribosylation, utilizing NAD+ as a substrate and catalyzed by ADP-ribosyltransferases (ARTs). PAR exists as linear or branched chains of up to 200 ADP-ribose units, playing pivotal roles in DNA repair, chromatin remodeling, transcriptional regulation, and cell death. The structural intricacy of PAR—marked by labile pyrophosphate linkages, stereochemical diversity, and branching architectures—poses significant synthetic challenges, necessitating innovative strategies integrating carbohydrate chemistry, enzymatic engineering, and phosphate coupling. Recent advances over the past decade have enabled the chemical and chemoenzymatic synthesis of well-defined PAR fragments, oligomers, and probes, facilitating breakthroughs in structural biology, interactome mapping, and therapeutic discovery. This review highlights key methodologies, including phosphoramidite-based assembly, development of photoaffinity probes and chemoenzymatic elongation with engineered ARTs, which collectively advance our understanding of PAR’s biological functions and therapeutic potential.
{"title":"Recent advances in the synthesis of poly (ADP-ribose)","authors":"Yidan Wu , Li Tang , Qiang Liu","doi":"10.1016/j.bmc.2025.118202","DOIUrl":"10.1016/j.bmc.2025.118202","url":null,"abstract":"<div><div>Poly (ADP-ribose) (PAR), a dynamic and reversible post-translational modification, is a structurally complex biopolymer synthesized via ADP-ribosylation, utilizing NAD<sup>+</sup> as a substrate and catalyzed by ADP-ribosyltransferases (ARTs). PAR exists as linear or branched chains of up to 200 ADP-ribose units, playing pivotal roles in DNA repair, chromatin remodeling, transcriptional regulation, and cell death. The structural intricacy of PAR—marked by labile pyrophosphate linkages, stereochemical diversity, and branching architectures—poses significant synthetic challenges, necessitating innovative strategies integrating carbohydrate chemistry, enzymatic engineering, and phosphate coupling. Recent advances over the past decade have enabled the chemical and chemoenzymatic synthesis of well-defined PAR fragments, oligomers, and probes, facilitating breakthroughs in structural biology, interactome mapping, and therapeutic discovery. This review highlights key methodologies, including phosphoramidite-based assembly, development of photoaffinity probes and chemoenzymatic elongation with engineered ARTs, which collectively advance our understanding of PAR’s biological functions and therapeutic potential.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"125 ","pages":"Article 118202"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863316","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}
Tricyclic and tetracyclic genipin derivatives were investigated with variety of oxidized agents to give the corresponding oxidized genipin products with α,β-unsaturated aldehyde moiety. Based on the experimental results, Collins reagent (complex of chromium(VI) oxide with pyridine in CH2Cl2) was examined as the better favorable oxidized selective agent. On the other hand, the oxidized tricyclic and tetracyclic genipins were also evaluated for stability using UV–visible spectroscopy and tested for their effects on NO production in LPS-induced RAW 264.7 cells. Most of oxidized tricyclic and tetracyclic genipin aldehyde derivatives were substantially improved ≥4.0-fold inhibiting activity than allyl alcoholic genipin starting materials. On the other hand, SAR study indicated oxidized compound 3g possessed the best inhibitory activity (IC50 = 2.60 μM) in comparison with reference standard Celecoxib (IC50 = 22.6 μM) and Indomethacin (IC50 = 156 μM). Furthermore, potential compounds (IC50 ≤ 10 μM) were also chosen for safety profile study and oxidized compounds 3a–j showed significant safety, except for compound 3f possessed the cell toxicity (12.5 μM). The mechanism of compound 3g in reducing cyclooxygenase-2 (COX-2) during inflammation was further demonstrated through Western blot analysis. To sum-up, the potential drug candidate 3g, significantly exhibited better anti-inflammatory effect than Indomethacin.
{"title":"Oxidization synthesis and bioactivity study of tricyclic and tetracyclic genipin derivatives with collins reagent as anti-inflammatory agents","authors":"Wei-Zheng Zeng , Chun-Han Cha , Cheng-Yen Chung , Guan-Jhong Huang , Naoto Uramaru , Ichiro Arai , Fung Fuh Wong","doi":"10.1016/j.bmc.2025.118198","DOIUrl":"10.1016/j.bmc.2025.118198","url":null,"abstract":"<div><div>Tricyclic and tetracyclic genipin derivatives were investigated with variety of oxidized agents to give the corresponding oxidized genipin products with α,β-unsaturated aldehyde moiety. Based on the experimental results, Collins reagent (complex of chromium(VI) oxide with<!--> <!-->pyridine in CH<sub>2</sub>Cl<sub>2</sub>) was examined as the better favorable oxidized selective agent. On the other hand, the oxidized tricyclic and tetracyclic genipins were also evaluated for stability using UV–visible spectroscopy and tested for their effects on NO production in LPS-induced RAW 264.7 cells. Most of oxidized tricyclic and tetracyclic genipin aldehyde derivatives were substantially<!--> <!-->improved ≥4.0-fold inhibiting activity than allyl alcoholic genipin starting materials. On the other hand, SAR study indicated oxidized compound <strong>3g</strong> possessed the best inhibitory activity (IC<sub>50</sub> = 2.60 μM) in comparison with reference standard Celecoxib (IC<sub>50</sub> = 22.6 μM) and Indomethacin (IC<sub>50</sub> = 156 μM). Furthermore, potential compounds (IC<sub>50</sub> ≤ 10 μM) were also chosen for safety profile study and oxidized compounds <strong>3a</strong>–<strong>j</strong> showed significant safety, except for compound <strong>3f</strong> possessed the cell toxicity (12.5 μM). The mechanism of compound <strong>3g</strong> in reducing cyclooxygenase-2 (COX-2) during inflammation was further demonstrated through Western blot analysis. To sum-up, the potential drug candidate <strong>3g</strong>, significantly exhibited better anti-inflammatory effect than Indomethacin.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118198"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850588","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}
Pub Date : 2025-04-16DOI: 10.1016/j.bmc.2025.118199
Qing Ma, Zhiwei Liu, Dan Wang, Chi Liu, Xinyue Liu, Enbo Cai, Fengyan Su
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.
{"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, Zhiwei Liu, Dan Wang, Chi Liu, Xinyue Liu, Enbo Cai, 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 <sup>1</sup>H NMR and <sup>13</sup>C 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}
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 1e as the most potent inducer of LC3-II protein accumulation. Mechanistic analysis revealed that compound 1e functions as a lysosomotropic agent, increasing lysosomal pH and inhibiting autophagy through lysosomal dysfunction. Furthermore, compound 1e 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.
{"title":"Discovery of structurally diverse diazatricyclododecenes as lysosomotropic autophagy inhibitors","authors":"Kazuki Miura , Kohei Umedera , Tomoya Doi , 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 (R<sup>1</sup>-R<sup>3</sup>) 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}
Pub Date : 2025-04-14DOI: 10.1016/j.bmc.2025.118197
Yulin Ren , Judith C. Gallucci , Jianhua Yu , Joanna E. Burdette , James R. Fuchs , A. Douglas Kinghorn
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.
{"title":"Antitumor and immunomodulatory activities of diphyllin and its derivatives","authors":"Yulin Ren , Judith C. Gallucci , Jianhua Yu , Joanna E. Burdette , James R. Fuchs , 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<sup>+</sup>-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}
Pub Date : 2025-04-11DOI: 10.1016/j.bmc.2025.118195
Jiangye Zhang , Rui Cai , Changxu Ning , Zhongxiang Zhou , Yibo Zhang , Shisheng Wang , Yueqing Li , Xiuhan Guo
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.
{"title":"A novel integrated diagnostic and therapeutic ferroptosis inhibitor based on a phenothiazine scaffold with ROS-Responsive strategy","authors":"Jiangye Zhang , Rui Cai , Changxu Ning , Zhongxiang Zhou , Yibo Zhang , Shisheng Wang , Yueqing Li , 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 EC<sub>50</sub> 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}
Pub Date : 2025-04-10DOI: 10.1016/j.bmc.2025.118191
Cong Lei , Zihan Chen , Yi Hao , Wanping Huang , Tianyu Chu , Kangming Xiao , Che Zhang , Wen Zhou , Chenjian Li , Xing Chen
Protein O-GlcNAcylation plays a crucial role in Drosophila melanogaster development. Dysregulation of O-GlcNAc transferase (sxc/Ogt) and O-GlcNAcase (Oga) disrupts early embryogenesis and locomotor behavior. It is therefore of great interest to identify and quantitatively analyze O-GlcNAcylation sites in Drosophila. Here, we perform quantitative and site-specific profiling of O-GlcNAcylation in Drosophila 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 Drosophila with sxc/Ogt knockdown in GABAergic neurons reveals a reduction in O-GlcNAcylation of several proteins involved in muscle development, consistent with the phenotypic defects observed in sxc/Ogt RNAi Drosophila. 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 Drosophila.
{"title":"Quantitative and site-specific chemoproteomic profiling of O-GlcNAcylation in Drosophila","authors":"Cong Lei , Zihan Chen , Yi Hao , Wanping Huang , Tianyu Chu , Kangming Xiao , Che Zhang , Wen Zhou , Chenjian Li , 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}
Pub Date : 2025-04-10DOI: 10.1016/j.bmc.2025.118193
Dhananjayan Vasu , Ha T. Do , Huiying Li , Christine D. Hardy , Thomas L. Poulos , Richard B. Silverman
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 (18, 6-(2,3-difluoro-5-((methylamino)methyl)phenyl)-4-methylpyridin-2-amine dihydrochloride) exhibits excellent potency, with Ki 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 18 displays high permeability (Pe = 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.
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