Pub Date : 2025-04-10DOI: 10.1016/j.bmc.2025.118194
Ping Li , Jiacheng Wang , Mengjiao Wang , Xin Chen , Hongyu Zhu , Mingxin Dong
N-methyl-d-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 N-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.
{"title":"Development of GluN2A NMDA receptor positive allosteric modulators: Recent advances and perspectives","authors":"Ping Li , Jiacheng Wang , Mengjiao Wang , Xin Chen , Hongyu Zhu , 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 Ca<sup>2+</sup> 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}
Pub Date : 2025-04-09DOI: 10.1016/j.bmc.2025.118192
Sheng-Hong Li , Feng-Yi Lu , Muralikrishna Katta, Yun-Yun Liu, Danling Huang, Yong-Xian Cheng
A novel phosphine-catalyzed [4 + 1] cyclization reaction was developed to construct the 3-oxo-3H-spiro[benzofuran-2,1′-cyclopentane] scaffold. Utilizing this innovative method, twenty diverse 3-oxo-3H-spiro[benzofuran-2,1′-cyclopentane] carboxylic acid derivatives were synthesized and evaluated for their anti-fibrotic activities. Compound L10-P1 possessed potential anti-fibrotic activity by inhibiting the expression of fibronectin, collagen I, and α-SMA. This study presents a new synthetic route for 3H-spiro[benzofuran-2,1′-cyclopentan]-3-one derivatives, contributing valuable insights into the chemical and biological diversity of these compounds.
{"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 , Feng-Yi Lu , Muralikrishna Katta, Yun-Yun Liu, Danling Huang, 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}
Pub Date : 2025-04-07DOI: 10.1016/j.bmc.2025.118181
Nicolas Desroy , Razvan Borza , Jörg Heiermann , Nicolas Triballeau , Agnès Joncour , Natacha Bienvenu , Willem Jan Hengeveld , Jasper Springer , René Galien , Robbie P. Joosten , Anastassis Perrakis , Bertrand Heckmann
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, 4 and 41, displayed increased inhibitory activity (∼40-fold) compared to the type IV close analog 3. Type VI inhibitors 4 and 41 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.
{"title":"Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode","authors":"Nicolas Desroy , Razvan Borza , Jörg Heiermann , Nicolas Triballeau , Agnès Joncour , Natacha Bienvenu , Willem Jan Hengeveld , Jasper Springer , René Galien , Robbie P. Joosten , Anastassis Perrakis , 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}
Pub Date : 2025-04-05DOI: 10.1016/j.bmc.2025.118182
Yoshiteru Ito , Eiji Kimura , Izumi Nomura , Etsurou Watanabe , Jason Yano , Robert Skene , Maki Miyamoto , Tsuyoshi Ishii , Toshiya Nishi , Tatsuki Koike
Azole-, pyridine-, and pyrimidine-based cytochrome P450 (CYP) inhibitors strongly bind to CYP enzymes through the coordination between the heme iron of CYP and the sp2-nitrogen atoms of heteroaromatic rings, providing potent pharmacological effects by inhibiting the initiation of the catalytic cycles of target CYP enzymes. Although imidazole-, 1,2,4-triazole-, pyridine-, and pyrimidine-based CYP inhibitors have been widely explored, 1,3-oxazole-based CYP inhibitors have received little attention. In this study, we designed and identified novel 1,3-oxazole-based inhibitors of cholesterol 24- hydroxylase (CH24H; CYP46A1), a brain-specific enzyme involved in cholesterol catabolism, to form 24S-hydroxycholesterol. Detailed insights into the CH24H–ligand interactions were provided by the crystal structures of 1,3-oxazole compounds, including high-throughput screening hit 2 and rationally designed inhibitor 3f. Optimization of 3f led to the identification of 1,3-oxazole derivative 4 l as a potent, selective, and brain-penetrable CH24H inhibitor that significantly reduced 24HC levels in the mouse brain. The design of 1,3-oxazole-based CYP inhibitors holds the potential for the discovery of novel inhibitors with significant potency against a broad spectrum of CYP enzymes.
{"title":"Design and identification of brain-penetrant, potent, and selective 1,3-oxazole-based cholesterol 24-hydroxylase (CH24H) inhibitors","authors":"Yoshiteru Ito , Eiji Kimura , Izumi Nomura , Etsurou Watanabe , Jason Yano , Robert Skene , Maki Miyamoto , Tsuyoshi Ishii , Toshiya Nishi , Tatsuki Koike","doi":"10.1016/j.bmc.2025.118182","DOIUrl":"10.1016/j.bmc.2025.118182","url":null,"abstract":"<div><div>Azole-, pyridine-, and pyrimidine-based cytochrome P450 (CYP) inhibitors strongly bind to CYP enzymes through the coordination between the heme iron of CYP and the sp2-nitrogen atoms of heteroaromatic rings, providing potent pharmacological effects by inhibiting the initiation of the catalytic cycles of target CYP enzymes. Although imidazole-, 1,2,4-triazole-, pyridine-, and pyrimidine-based CYP inhibitors have been widely explored, 1,3-oxazole-based CYP inhibitors have received little attention. In this study, we designed and identified novel 1,3-oxazole-based inhibitors of cholesterol 24- hydroxylase (CH24H; CYP46A1), a brain-specific enzyme involved in cholesterol catabolism, to form 24S-hydroxycholesterol. Detailed insights into the CH24H–ligand interactions were provided by the crystal structures of 1,3-oxazole compounds, including high-throughput screening hit 2 and rationally designed inhibitor 3f. Optimization of 3f led to the identification of 1,3-oxazole derivative 4 l as a potent, selective, and brain-penetrable CH24H inhibitor that significantly reduced 24HC levels in the mouse brain. The design of 1,3-oxazole-based CYP inhibitors holds the potential for the discovery of novel inhibitors with significant potency against a broad spectrum of CYP enzymes.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118182"},"PeriodicalIF":3.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815273","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 : 2025-04-02DOI: 10.1016/j.bmc.2025.118179
U. Martínez-Ortega , R. Aguayo-Ortiz , D. Aguilar-Cazares , E.D. Guerrero-Molina , V. Aguilar-Martínez , A. Moreno-Rodríguez , J.S. López-González , J.M. Vázquez-Ramos , F. Hernández-Luis
Gefitinib (GFB) is a well-established EGFR inhibitor used in the treatment of non-small cell lung cancer (NSCLC) that has shown resistance in certain cases of this cancer. In this work, we aimed to enhance GFB’s inhibitory activity using alchemical free energy calculations, leading to the design of five new quinazoline derivatives. Among these, compound 8a was the most potent, inhibiting EGFR at 10 µM and showing significant antiproliferative effects at 25 µM. Further optimization identified two new compounds, NCU00 and NCU01, with improved EGFR inhibition and superior cytotoxicity in four NSCLC cell lines compared to GFB. Molecular dynamics simulations revealed crucial interactions that contribute to the enhanced inhibitory activity of NCU00 and NCU01. Toxicological assessments in mice showed no adverse effects on kidney or liver function, and NCU01 exhibited no developmental toxicity in zebrafish embryos. This study highlights the effectiveness of alchemical free energy methods in optimizing quinazoline-bearing EGFR inhibitors.
{"title":"Alchemical free energy-based optimization of quinazoline derivatives as potent EGFR inhibitors with cytotoxic activity","authors":"U. Martínez-Ortega , R. Aguayo-Ortiz , D. Aguilar-Cazares , E.D. Guerrero-Molina , V. Aguilar-Martínez , A. Moreno-Rodríguez , J.S. López-González , J.M. Vázquez-Ramos , F. Hernández-Luis","doi":"10.1016/j.bmc.2025.118179","DOIUrl":"10.1016/j.bmc.2025.118179","url":null,"abstract":"<div><div>Gefitinib (GFB) is a well-established EGFR inhibitor used in the treatment of non-small cell lung cancer (NSCLC) that has shown resistance in certain cases of this cancer. In this work, we aimed to enhance GFB’s inhibitory activity using alchemical free energy calculations, leading to the design of five new quinazoline derivatives. Among these, compound <strong>8a</strong> was the most potent, inhibiting EGFR at 10 µM and showing significant antiproliferative effects at 25 µM. Further optimization identified two new compounds, <strong>NCU00</strong> and <strong>NCU01</strong>, with improved EGFR inhibition and superior cytotoxicity in four NSCLC cell lines compared to GFB. Molecular dynamics simulations revealed crucial interactions that contribute to the enhanced inhibitory activity of <strong>NCU00</strong> and <strong>NCU01</strong>. Toxicological assessments in mice showed no adverse effects on kidney or liver function, and <strong>NCU01</strong> exhibited no developmental toxicity in zebrafish embryos. This study highlights the effectiveness of alchemical free energy methods in optimizing quinazoline-bearing EGFR inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118179"},"PeriodicalIF":3.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-30DOI: 10.1016/j.bmc.2025.118177
Michał Sulik , Eyob A. Workneh , Sofia Santana , Bárbara Teixeira , Miguel Prudêncio , Jan Janczak , Adam Huczyński
Malaria remains a significant public health issue and one of the leading causes of child mortality worldwide. Due to the growing problem of drug resistance, new modes of fighting the disease are searched for. In this context, ionophore antibiotics, natural compounds with high potential for combating parasitic diseases, deserve special attention. The primary representative of such compounds, monensin (MON), demonstrates exceptionally high antiplasmodial activity. In this work, the C26-amino derivative of MON was used as a convenient substrate for the synthesis of its acyl analogues, such as amides and urea. All derivatives exhibited strong activity against the hepatic stage of Plasmodium berghei infection in vitro, which exceeded that shown by the reference drug primaquine. The IC50 value for MONO-phenyl urethane (8) was less than 1 nM.
{"title":"Chemical modification of monensin as a source of potent antiplasmodial agents","authors":"Michał Sulik , Eyob A. Workneh , Sofia Santana , Bárbara Teixeira , Miguel Prudêncio , Jan Janczak , Adam Huczyński","doi":"10.1016/j.bmc.2025.118177","DOIUrl":"10.1016/j.bmc.2025.118177","url":null,"abstract":"<div><div>Malaria remains a significant public health issue and one of the leading causes of child mortality worldwide. Due to the growing problem of drug resistance, new modes of fighting the disease are searched for. In this context, ionophore antibiotics, natural compounds with high potential for combating parasitic diseases, deserve special attention. The primary representative of such compounds, monensin (<strong>MON</strong>), demonstrates exceptionally high antiplasmodial activity. In this work, the C26-amino derivative of <strong>MON</strong> was used as a convenient substrate for the synthesis of its acyl analogues, such as amides and urea. All derivatives exhibited strong activity against the hepatic stage of <em>Plasmodium berghei</em> infection <em>in vitro</em>, which exceeded that shown by the reference drug primaquine. The IC<sub>50</sub> value for <strong>MON</strong> <em>O</em>-phenyl urethane (<strong>8</strong>) was less than 1 nM.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118177"},"PeriodicalIF":3.3,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769013","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 : 2025-03-29DOI: 10.1016/j.bmc.2025.118178
Mingyang Liu , Muyan Ke , Hongchen Lu , Ziyu Feng , Kaixuan Wang , Danyang Wang , Kun Wang , Yueping Bai , Song Yang , Lu Miao , Qiang Chen , Mingming Sun , Changliang Shan , Jiancheng Hu , Lingyu Jiang , Hongzhen Jin , Jinfang Hu , Changjiang Huang , Rui Wang , Wei Zhao , Fan Yu
The RNA methyltransferase methyltransferaselike protein 16 (METTL16) is upregulated in a large proportion of hepatocellular carcinoma (HCC), and its high expression is associated with poor clinical outcomes. METTL16 deletion inhibits HCC growth in vitro and in vivo. Referencing the structure of cinnamic acid, here we designed and synthesized a novel series of small molecular compounds, and found through bioactivity screening that compound 15a effectively reduced METTL16 level and modulated oncogenic PI3K/AKT pathway signaling. Compound 15a inhibited the proliferation and migration of HepG2 cells, and induced apoptosis in vitro. Furthermore, compound 15a significantly inhibited the growth of patient-derived HCC xenografts in nude mice with greater efficacy than the multi-kinase inhibitor lenvatinib. The promising efficacy and good biosafety profile of compound 15a enables us to further develop this compound for treating patients with HCC and possibly other cancers in clinic.
{"title":"A novel cinnamic acid derivative for hepatocellular carcinoma therapy by degrading METTL16 protein","authors":"Mingyang Liu , Muyan Ke , Hongchen Lu , Ziyu Feng , Kaixuan Wang , Danyang Wang , Kun Wang , Yueping Bai , Song Yang , Lu Miao , Qiang Chen , Mingming Sun , Changliang Shan , Jiancheng Hu , Lingyu Jiang , Hongzhen Jin , Jinfang Hu , Changjiang Huang , Rui Wang , Wei Zhao , Fan Yu","doi":"10.1016/j.bmc.2025.118178","DOIUrl":"10.1016/j.bmc.2025.118178","url":null,"abstract":"<div><div>The RNA methyltransferase methyltransferaselike protein 16 (METTL16) is upregulated in a large proportion of hepatocellular carcinoma (HCC), and its high expression is associated with poor clinical outcomes. METTL16 deletion inhibits HCC growth <em>in vitro</em> and <em>in vivo</em>. Referencing the structure of cinnamic acid, here we designed and synthesized a novel series of small molecular compounds, and found through bioactivity screening that compound <strong>15a</strong> effectively reduced METTL16 level and modulated oncogenic PI3K/AKT pathway signaling. Compound <strong>15a</strong> inhibited the proliferation and migration of HepG2 cells, and induced apoptosis <em>in vitro</em>. Furthermore, compound <strong>15a</strong> significantly inhibited the growth of patient-derived HCC xenografts in nude mice with greater efficacy than the multi-kinase inhibitor lenvatinib. The promising efficacy and good biosafety profile of compound <strong>15a</strong> enables us to further develop this compound for treating patients with HCC and possibly other cancers in clinic.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118178"},"PeriodicalIF":3.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769137","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}
In this study, the mechanism of the plasmid DNA (pDNA) delivery system using Magainin 2-derived stapled peptides (st7-5 and st7-5_R) was analysed. The effect of different cationic residues (Lys and Arg) on the stability and intracellular transport efficiency of the peptide/pDNA complex was assessed, with both peptides forming stable α-helical structures under neutral conditions and st7-5_R showing higher helical strength under acidic conditions. Agarose gel shift assays and PicoGreen staining showed that both peptides formed complete complexes at N/P ratios of 1.5–2 and protected pDNA from nucleases. However, in the presence of heparin sulfate, the st7-5_R/pDNA complex maintained higher stability than the st7-5/pDNA complex. Interaction analysis with lipid membranes indicated that st7-5 with Lys residues interacted strongly at pH 7.4 and st7-5_R with Arg residues at pH 5.5, suggesting that st7-5_R was highly capable of facilitating its escape from endosomes. The Förster resonance energy transfer (FRET) signal observed by confocal laser scanning microscopy (CLSM) indicated that the st7-5_R/pDNA complex disintegrated over time after intracellular introduction, releasing the encapsulated pDNA into the cell. These results indicate that Magainin 2-derived stapled peptides are promising carriers for efficient intracellular nucleic acid delivery, especially st7-5_R with its excellent stability and delivery efficiency. The findings of this study will contribute to the design of drug delivery system carrier peptides and the improvement of nucleic acid therapeutics.
{"title":"Mechanistic study of plasmid DNA delivery by Magainin 2-derived stapled peptides","authors":"Motoharu Hirano , Yuki Takechi-Haraya , Yasuhiro Abe , Takashi Misawa , Norihito Shibata , Yoji Sato , Yosuke Demizu","doi":"10.1016/j.bmc.2025.118176","DOIUrl":"10.1016/j.bmc.2025.118176","url":null,"abstract":"<div><div>In this study, the mechanism of the plasmid DNA (pDNA) delivery system using Magainin 2-derived stapled peptides (<strong>st7-5</strong> and <strong>st7-5_R</strong>) was analysed. The effect of different cationic residues (Lys and Arg) on the stability and intracellular transport efficiency of the peptide/pDNA complex was assessed, with both peptides forming stable α-helical structures under neutral conditions and <strong>st7-5_R</strong> showing higher helical strength under acidic conditions. Agarose gel shift assays and PicoGreen staining showed that both peptides formed complete complexes at N/P ratios of 1.5–2 and protected pDNA from nucleases. However, in the presence of heparin sulfate, the <strong>st7-5_R</strong>/pDNA complex maintained higher stability than the <strong>st7-5</strong>/pDNA complex. Interaction analysis with lipid membranes indicated that <strong>st7-5</strong> with Lys residues interacted strongly at pH 7.4 and <strong>st7-5_R</strong> with Arg residues at pH 5.5, suggesting that <strong>st7-5_R</strong> was highly capable of facilitating its escape from endosomes. The Förster resonance energy transfer (FRET) signal observed by confocal laser scanning microscopy (CLSM) indicated that the <strong>st7-5_R</strong>/pDNA complex disintegrated over time after intracellular introduction, releasing the encapsulated pDNA into the cell. These results indicate that Magainin 2-derived stapled peptides are promising carriers for efficient intracellular nucleic acid delivery, especially <strong>st7-5_R</strong> with its excellent stability and delivery efficiency. The findings of this study will contribute to the design of drug delivery system carrier peptides and the improvement of nucleic acid therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118176"},"PeriodicalIF":3.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734767","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 : 2025-03-26DOI: 10.1016/j.bmc.2025.118175
Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang
The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a pivotal role in the tumor microenvironment, making it an attractive target for therapeutic intervention. Small-molecule inhibitors of TGFβR1 offer a promising approach for the treatment of malignant tumors. In this study, a series of 1H-pyrrolo[2,3-b]pyridine derivatives were identified as novel TGFβR1 inhibitors. The most potent candidate, compound 7w, demonstrated inhibition of SMAD2/3 phosphorylation and Hep3B cell viability, with IC50 values of 160.3 nM and 228 μM, respectively. Compound 7w showed a synergistic anti-proliferation and pro-apoptotic effect when combined with sorafenib, highlighting its potential as a promising lead for the development of potential anticancer therapies.
{"title":"Discovery of novel transforming growth factor β type 1 receptor inhibitors through structure-based virtual screening, preliminary structure–activity relationship study, and biological evaluation in hepatocellular carcinoma","authors":"Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang","doi":"10.1016/j.bmc.2025.118175","DOIUrl":"10.1016/j.bmc.2025.118175","url":null,"abstract":"<div><div>The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a pivotal role in the tumor microenvironment, making it an attractive target for therapeutic intervention. Small-molecule inhibitors of TGFβR1 offer a promising approach for the treatment of malignant tumors. In this study, a series of 1<em>H</em>-pyrrolo[2,3-<em>b</em>]pyridine derivatives were identified as novel TGFβR1 inhibitors. The most potent candidate, compound <strong>7w</strong>, demonstrated inhibition of SMAD2/3 phosphorylation and Hep3B cell viability, with IC<sub>50</sub> values of 160.3 nM and 228 μM, respectively. Compound <strong>7w</strong> showed a synergistic anti-proliferation and pro-apoptotic effect when combined with sorafenib, highlighting its potential as a promising lead for the development of potential anticancer therapies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118175"},"PeriodicalIF":3.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734766","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 : 2025-03-23DOI: 10.1016/j.bmc.2025.118173
Alaa Ahmed Kadry , Mai Adel , Samar A. Abubshait , Galal Yahya , Marwa Sharaky , Rabah A.T. Serya , Khaled A.M. Abouzid
Poly(ADP-ribose) polymerase-1 (PARP-1) plays a crucial role in DNA repair, mediating approximately 90 % of ADP-ribosylation processes associated with DNA damage response. Consequently, inhibiting PARP-1 with small molecules represents a promising strategy for cancer therapy. Utilizing a structure-based design and molecular hybridization approach, we developed three novel series of spirobenzoxazinone-piperdine/salicylamide-based derivatives. These compounds were evaluated for their in vitro PARP-1 inhibitory activity, and their structure–activity relationships were analyzed. At 10 µM concentration, derivatives (18a-d) demonstrated nearly complete inhibition, and the spirocyclic derivative (7c) also achieved a considerable inhibitory effect, with IC50 values in the low micromolar range. The most promising compounds (7c, 18a-d) were tested for their antiproliferative activity against six cancer cell lines. Notably, compounds (7c) and (18d) exhibited significant antiproliferative effects against H1299 and FaDu cells, which correlated with their calculated logP values. These compounds were also tested against normal human skin fibroblasts (HSF), revealing a favorable safety profile compared to cancer cells. Basal anti-PARP-1 activity of the most promising compounds was validated in the HCT116 colorectal cancer cell line. Western blot analysis confirmed robust cleavage of PARP-1, indicating enzymatic inhibition and loss of PARP-1 activity. Combining these inhibitors with doxorubicin showed synergistic lethality in colony-formation assay. Finally, a molecular docking study was conducted to examine the binding modes of these compounds within the PARP-1 active site. The results demonstrated binding modes comparable to those of olaparib and other approved PARP-1 inhibitors, maintaining the key interactions necessary for activity. Based on these findings, compounds (7c) and (18d) emerge as promising candidates for further development in targeting anti-cancer drug resistance through PARP-1 inhibition.
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