Pub Date : 2025-02-01DOI: 10.1016/j.bmc.2024.118045
Joseph E. Quinlan , Joseph M. Salamoun , Christopher J. Garcia , Stefan Hargett , Martina Beretta , Riya Shrestha , Catherine Li , Kyle L. Hoehn , Webster L. Santos
Chemical mitochondrial uncouplers are protonophoric, lipophilic small molecules that transport protons from the mitochondrial intermembrane space into the matrix independent of ATP synthase, thus uncoupling nutrient oxidation from ATP production. Our previous work identified BAM15 (IC50 0.27 μM) as a potent and efficacious mitochondrial uncoupler with potential for obesity treatment. In this paper, we investigate in vitro and in vivo properties of hydroxylamine and hydrazine BAM15 derivatives and reveal the high uncoupling nature of these compounds. Our structure–activity relationship studies revealed that the hydroxylamine BAM15 analogs are more potent than hydrazine ones. For example, the most potent of the hydrazine series was 5a with an EC50 value of 4.6 μM and 103 % activity of BAM15 while compound 4e was the best among the hydroxylamine series with EC50 value of 340 nM and 118 % BAM15 mitochondrial uncoupling activity in rat L6 myoblasts. Pharmacokinetic profiling of 5a and 4e revealed low exposure (2–220 nM) and short half-life (15–27 min) in mice.
{"title":"Unsymmetric hydroxylamine and hydrazine BAM15 derivatives as potent mitochondrial uncouplers","authors":"Joseph E. Quinlan , Joseph M. Salamoun , Christopher J. Garcia , Stefan Hargett , Martina Beretta , Riya Shrestha , Catherine Li , Kyle L. Hoehn , Webster L. Santos","doi":"10.1016/j.bmc.2024.118045","DOIUrl":"10.1016/j.bmc.2024.118045","url":null,"abstract":"<div><div>Chemical mitochondrial uncouplers are protonophoric, lipophilic small molecules that transport protons from the mitochondrial intermembrane space into the matrix independent of ATP synthase, thus uncoupling nutrient oxidation from ATP production. Our previous work identified <strong>BAM15</strong> (IC<sub>50</sub> 0.27 μM) as a potent and efficacious mitochondrial uncoupler with potential for obesity treatment. In this paper, we investigate <em>in vitro</em> and <em>in vivo</em> properties of hydroxylamine and hydrazine <strong>BAM15</strong> derivatives and reveal the high uncoupling nature of these compounds. Our structure–activity relationship studies revealed that the hydroxylamine BAM15 analogs are more potent than hydrazine ones. For example, the most potent of the hydrazine series was <strong>5a</strong> with an EC<sub>50</sub> value of 4.6 μM and 103 % activity of <strong>BAM15</strong> while compound <strong>4e</strong> was the best among the hydroxylamine series with EC<sub>50</sub> value of 340 nM and 118 % <strong>BAM15</strong> mitochondrial uncoupling activity in rat L6 myoblasts. Pharmacokinetic profiling of <strong>5a</strong> and <strong>4e</strong> revealed low exposure (2–220 nM) and short half-life (15–27 min) in mice.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118045"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908828","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 : 2025-02-01DOI: 10.1016/j.bmc.2024.117988
Alexandra Serhouni , Francesco Calzaferri , Yannick Bessina , Arie van der Lee , Paola B. Arimondo , Maxime Louet , Jean-Yves Winum , Marie Lopez
Flavonoid derivatives are natural product analogues that have shown great interest for therapeutic applications as modulators of DNA methylation. In this article we report new synthesis pathways to access ten novel flavonoid derivatives (i.e. 3-halo-3-nitro-aza/thioflavanones) to be used as potential DNA methyltransferase inhibitors. These compounds have a micromolar inhibition against human DNA methyltransferase 3A in our in vitro fluorescence-based assay. Importantly, a docking study of representative compounds of this series in the enzyme pocket highlights a mode of interaction in the catalytic pocket of hDNMT3A that has never been described.
{"title":"3-Halo-3-nitro-aza/thioflavanones: DNMT inhibitors with a two-site binding mode in the hDNMT3A catalytic pocket","authors":"Alexandra Serhouni , Francesco Calzaferri , Yannick Bessina , Arie van der Lee , Paola B. Arimondo , Maxime Louet , Jean-Yves Winum , Marie Lopez","doi":"10.1016/j.bmc.2024.117988","DOIUrl":"10.1016/j.bmc.2024.117988","url":null,"abstract":"<div><div>Flavonoid derivatives are natural product analogues that have shown great interest for therapeutic applications as modulators of DNA methylation. In this article we report new synthesis pathways to access ten novel flavonoid derivatives (<em>i.e.</em> 3-halo-3-nitro-aza/thioflavanones) to be used as potential DNA methyltransferase inhibitors. These compounds have a micromolar inhibition against human DNA methyltransferase 3A in our <em>in vitro</em> fluorescence-based assay. Importantly, a docking study of representative compounds of this series in the enzyme pocket highlights a mode of interaction in the catalytic pocket of <em>h</em>DNMT3A that has never been described.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 117988"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845410","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 : 2025-02-01DOI: 10.1016/j.bmc.2024.118056
Ying Meng, Rong Huang
Protein methylation regulates diverse cellular processes including gene expression and DNA repair. This review discusses the methods of identifying and validating substrates for protein methyltransferases (MTases), as well as the biological roles of methylation. Meanwhile, we outline continued efforts necessary to fully map MTase-substrate pairs and uncover the complex regulatory roles of protein methylation in cellular function.
{"title":"Decoding the protein methylome: Identification, validation, and functional insights","authors":"Ying Meng, Rong Huang","doi":"10.1016/j.bmc.2024.118056","DOIUrl":"10.1016/j.bmc.2024.118056","url":null,"abstract":"<div><div>Protein methylation regulates diverse cellular processes including gene expression and DNA repair. This review discusses the methods of identifying and validating substrates for protein methyltransferases (MTases), as well as the biological roles of methylation. Meanwhile, we outline continued efforts necessary to fully map MTase-substrate pairs and uncover the complex regulatory roles of protein methylation in cellular function.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118056"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925864","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 : 2025-02-01DOI: 10.1016/j.bmc.2024.118053
Hadeer M. Ali , Mohamed A. Said , Shady Allam , Hatem A. Abdel-Aziz , Sahar M. Abou-Seri
This study investigates a series of newly synthesized compounds, including pyridopyrimidine derivatives (9a-g), tricyclic pyridotriazolopyrimidine analogs (18a-d), and dihydropyrimidinones (22a-i), as apoptotic inducers and inhibitors of phosphatidylinositol-3-kinase α (PI3Kα), with potential anticancer activity. An initial in vitro screening of 60 cancer cell lines identified pyridopyrimidine derivatives 9a-g as promising broad-spectrum anticancer agents, with compound 9e demonstrating the strongest inhibitory activity, particularly against T-47D breast cancer cells. Notably, the antitumor potency of compound 9e surpassed that of Pictilisib, inducing G2-M phase cell cycle arrest and initiating apoptosis through the intrinsic apoptotic pathway. Molecular docking studies further indicated that compound 9e binds to PI3Kα in a similar fashion to the co-crystallized ligand. Moreover, compound 9e exhibited favorable drug-like properties, including compliance with Lipinski’s rule and Veber’s rule, good solubility, acceptable TPSA, and high gastrointestinal absorption reinforcing its potential as a highly effective anticancer agent.
{"title":"Exploring the antiproliferative and proapoptotic activities of new pyridopyrimidine derivatives and their analogs","authors":"Hadeer M. Ali , Mohamed A. Said , Shady Allam , Hatem A. Abdel-Aziz , Sahar M. Abou-Seri","doi":"10.1016/j.bmc.2024.118053","DOIUrl":"10.1016/j.bmc.2024.118053","url":null,"abstract":"<div><div>This study investigates a series of newly synthesized compounds, including pyridopyrimidine derivatives (<strong>9a-g</strong>), tricyclic pyridotriazolopyrimidine analogs (<strong>18a-d</strong>), and dihydropyrimidinones (<strong>22a-i</strong>), as apoptotic inducers and inhibitors of phosphatidylinositol-3-kinase α (PI3Kα), with potential anticancer activity. An initial in vitro screening of 60 cancer cell lines identified pyridopyrimidine derivatives <strong>9a-g</strong> as promising broad-spectrum anticancer agents, with compound <strong>9e</strong> demonstrating the strongest inhibitory activity, particularly against T-47D breast cancer cells. Notably, the antitumor potency of compound <strong>9e</strong> surpassed that of Pictilisib, inducing G2-M phase cell cycle arrest and initiating apoptosis through the intrinsic apoptotic pathway. Molecular docking studies further indicated that compound <strong>9e</strong> binds to PI3Kα in a similar fashion to the co-crystallized ligand. Moreover, compound <strong>9e</strong> exhibited favorable drug-like properties, including compliance with Lipinski’s rule and Veber’s rule, good solubility, acceptable TPSA, and high gastrointestinal absorption reinforcing its potential as a highly effective anticancer agent.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118053"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918731","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 : 2025-02-01DOI: 10.1016/j.bmc.2024.118050
Yuanpei Li , Yuan Liu , Chu Wang
Protein post-translational modification (PTM) serves as an important mechanism for regulating protein function. Accurate assay of PTM stoichiometry, or PTM occupancy, which refers to the proportion of proteins that contain specific modifications, is important for understanding the function of PTMs. We previously developed a novel chemoproteomic strategy “STO-MS” to quantify the PTM stoichiometry in complex biological samples, which employs a resolvable polymer mass tag to differentiate modified proteins and utilizes liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) techniques to measure PTM stoichiometry. However, the resolution of STO-MS is constrained by the relatively low molecular weight of the mass tag, and the incorporation of isotopic labels not only complicates the sample preparation but also restricts the measurement throughput. To address these challenges, we herein developed “STO-MS+”, an enhanced workflow, that incorporates an optimized DNA mass tag and employs a label-free quantitative data analysis approach. We applied STO-MS+ to measure stoichiometry of three distinct PTMs, including endogenous carbonylation induced by arachidonic acid (AA), itaconation, and endogenous O-GlcNAcylation. Our work marks a notable improvement in chemoproteomic methodologies for quantifying post-translational modifications and provides a powerful analytical tool for PTM research.
{"title":"Quantitative profiling of PTM stoichiometry by DNA mass tags","authors":"Yuanpei Li , Yuan Liu , Chu Wang","doi":"10.1016/j.bmc.2024.118050","DOIUrl":"10.1016/j.bmc.2024.118050","url":null,"abstract":"<div><div>Protein post-translational modification (PTM) serves as an important mechanism for regulating protein function. Accurate assay of PTM stoichiometry, or PTM occupancy, which refers to the proportion of proteins that contain specific modifications, is important for understanding the function of PTMs. We previously developed a novel chemoproteomic strategy “STO-MS” to quantify the PTM stoichiometry in complex biological samples, which employs a resolvable polymer mass tag to differentiate modified proteins and utilizes liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) techniques to measure PTM stoichiometry. However, the resolution of STO-MS is constrained by the relatively low molecular weight of the mass tag, and the incorporation of isotopic labels not only complicates the sample preparation but also restricts the measurement throughput. To address these challenges, we herein developed “STO-MS+”, an enhanced workflow, that incorporates an optimized DNA mass tag and employs a label-free quantitative data analysis approach. We applied STO-MS+ to measure stoichiometry of three distinct PTMs, including endogenous carbonylation induced by arachidonic acid (AA), itaconation, and endogenous O-GlcNAcylation. Our work marks a notable improvement in chemoproteomic methodologies for quantifying post-translational modifications and provides a powerful analytical tool for PTM research.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118050"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890850","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 : 2025-01-31DOI: 10.1016/j.bmc.2025.118094
Mingli Hu , Lang Zheng , Ailing Li , Xiao Li , Wengxue Liang , Yuanhao Zhu , Aoxue Wang , Ling He , Xiuxiu Liu , Qiu Sun
Breast cancer is one of the most prevalent malignant tumors in women, but the side effects and drug resistance limit the long-term effectiveness of existing drugs. To address these issues, we designed and synthesized a series of novel mono- and bis-indole-substituted 3-indolylbenzoquinone derivatives and evaluated their inhibitory activity against breast cancer. Among them, compound 1b demonstrated the most potent inhibitory activity against the MDA-MB-231 breast cancer cell line (IC50 = 3.2 µM) as well as the drug-resistant variant, MCF-7/ADR (IC50 = 8.36 µM). It demonstrated minimal toxicity and superior tumor suppression in a Balb/c mouse model of 4 T1 breast cancer. Mechanistically, compound 1b induced apoptosis and cell cycle arrest at the G2/M phase. Through computational study and CESTA assay, we implicated phosphoinositide 3-kinase α (PI3Kα) as a potential target. Thus, we present compound 1b as a lead candidate for the development of novel, safe, and effective small-molecule therapies against breast cancer.
{"title":"Discovery of 3-indolylbenzoquinone derivatives with therapeutic potential for breast cancer","authors":"Mingli Hu , Lang Zheng , Ailing Li , Xiao Li , Wengxue Liang , Yuanhao Zhu , Aoxue Wang , Ling He , Xiuxiu Liu , Qiu Sun","doi":"10.1016/j.bmc.2025.118094","DOIUrl":"10.1016/j.bmc.2025.118094","url":null,"abstract":"<div><div>Breast cancer is one of the most prevalent malignant tumors in women, but the side effects and drug resistance limit the long-term effectiveness of existing drugs. To address these issues, we designed and synthesized a series of novel mono- and bis-indole-substituted 3-indolylbenzoquinone derivatives and evaluated their inhibitory activity against breast cancer. Among them, compound <strong>1b</strong> demonstrated the most potent inhibitory activity against the MDA-MB-231 breast cancer cell line (IC<sub>50</sub> = 3.2 µM) as well as the drug-resistant variant, MCF-7/ADR (IC<sub>50</sub> = 8.36 µM). It demonstrated minimal toxicity and superior tumor suppression in a Balb/c mouse model of 4 T1 breast cancer. Mechanistically, compound <strong>1b</strong> induced apoptosis and cell cycle arrest at the G2/M phase. Through computational study and CESTA assay, we implicated phosphoinositide 3-kinase α (PI3Kα) as a potential target. Thus, we present compound <strong>1b</strong> as a lead candidate for the development of novel, safe, and effective small-molecule therapies against breast cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118094"},"PeriodicalIF":3.3,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378487","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 : 2025-01-31DOI: 10.1016/j.bmc.2025.118092
Wen Lu , Xiaoxiao Yang , Binghe Wang
Inflammation is a pathology implicated in a wide range of human diseases. Recent years have seen tremendous progress in developing new types of anti-inflammatory agents for the treatment of inflammation of various origins. However, each has its own strengths and weaknesses. The very fact that there needs to have multiple types of anti-inflammatory agents underlines the complexity of inflammatory diseases and conditions, their molecular origins, and their treatment. Such complexity dictates the need to search for new approaches with improved potency and efficacy as well as reduced side effects. For these reasons, we are interested in exploring the possibility of generating synergy between carbon monoxide (CO), an endogenously produced cytoprotective agent, and known anti-inflammatory agents. Herein, we report the potentiating actions of CO on the anti-inflammatory effects of cortisone and dexamethasone as demonstrated in their ability to suppress the expression of TNF-α and IL-6 induced by either LPS or the S protein of SARS-CoV-2. Such effects are reflected in the substantially increased potency as well efficacy, when the efficacy of the corticosteroid alone does not allow for complete suppression of the expression of these cytokines. Further, increased attenuation of p65 phosphorylation is at least part of the molecular mechanism for the observed potentiating effects. We hope our work will stimulate a high level of activity along the same direction, leading to anti-inflammatory strategies with improved potency and efficacy and reduced side effects.
{"title":"Carbon monoxide potentiates the effect of corticosteroids in suppressing inflammatory responses in cell culture","authors":"Wen Lu , Xiaoxiao Yang , Binghe Wang","doi":"10.1016/j.bmc.2025.118092","DOIUrl":"10.1016/j.bmc.2025.118092","url":null,"abstract":"<div><div>Inflammation is a pathology implicated in a wide range of human diseases. Recent years have seen tremendous progress in developing new types of anti-inflammatory agents for the treatment of inflammation of various origins. However, each has its own strengths and weaknesses. The very fact that there needs to have multiple types of anti-inflammatory agents underlines the complexity of inflammatory diseases and conditions, their molecular origins, and their treatment. Such complexity dictates the need to search for new approaches with improved potency and efficacy as well as reduced side effects. For these reasons, we are interested in exploring the possibility of generating synergy between carbon monoxide (CO), an endogenously produced cytoprotective agent, and known anti-inflammatory agents. Herein, we report the potentiating actions of CO on the anti-inflammatory effects of cortisone and dexamethasone as demonstrated in their ability to suppress the expression of TNF-α and IL-6 induced by either LPS or the S protein of SARS-CoV-2. Such effects are reflected in the substantially increased potency as well efficacy, when the efficacy of the corticosteroid alone does not allow for complete suppression of the expression of these cytokines. Further, increased attenuation of p65 phosphorylation is at least part of the molecular mechanism for the observed potentiating effects. We hope our work will stimulate a high level of activity along the same direction, leading to anti-inflammatory strategies with improved potency and efficacy and reduced side effects.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118092"},"PeriodicalIF":3.3,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147961","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}
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the loss of upper and lower motor neurons. Cu/Zn superoxide dismutase (SOD1) is one of the genes associated with the familial form of the disease (fALS). The mechanism of neuron degeneration by SOD1 is not clear, it is hypothesised that there is a toxic gain of function in the protein which leads to the downstream effects. In the present study, carbazole-based molecules have been rationally designed and synthesised as potential inhibitors of mutant hSOD1 protein aggregation. SG-9 and SG-10 prevented the aggregation of all three purified mutant hSOD1 proteins. Transmission electron microscopy and dynamic light scattering experiments also revealed that co-incubation of SG-9 and SG-10 with mutant hSOD1 protein resulted in smaller and slender fibril forming. Molecules SG-9 and SG-10 did not display toxicity and prevented Neuro-2a cells expressing hSOD1 G85R protein from its associated cytotoxicity. SG-9 and SG-10 were also able to prevent the transfected cells from apoptosis and were also able to reduce ROS levels associated with hSOD1 G85R protein aggregation significantly. Therefore, novel carbazole derivatives SG-9 and SG-10 proved to be effective inhibitors of mutant hSOD1 protein aggregation and can be further utilised as lead molecules for the amelioration of mutant hSOD1 aggregation-associated ALS.
{"title":"Development of carbazole-based molecules for inhibition of mutant hSOD1 protein aggregation in Amyotrophic Lateral Sclerosis","authors":"Siddharth Gusain , Chandra Bhushan Mishra , Kajal Yadav , Meenakshi Sharma , Daman Saluja , Manisha Tiwari","doi":"10.1016/j.bmc.2025.118091","DOIUrl":"10.1016/j.bmc.2025.118091","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the loss of upper and lower motor neurons. Cu/Zn superoxide dismutase (SOD1) is one of the genes associated with the familial form of the disease (fALS). The mechanism of neuron degeneration by SOD1 is not clear, it is hypothesised that there is a toxic gain of function in the protein which leads to the downstream effects. In the present study, carbazole-based molecules have been rationally designed and synthesised as potential inhibitors of mutant hSOD1 protein aggregation. SG-9 and SG-10 prevented the aggregation of all three purified mutant hSOD1 proteins. Transmission electron microscopy and dynamic light scattering experiments also revealed that co-incubation of SG-9 and SG-10 with mutant hSOD1 protein resulted in smaller and slender fibril forming. Molecules SG-9 and SG-10 did not display toxicity and prevented Neuro-2a cells expressing hSOD1 G85R protein from its associated cytotoxicity. SG-9 and SG-10 were also able to prevent the transfected cells from apoptosis and were also able to reduce ROS levels associated with hSOD1 G85R protein aggregation significantly. Therefore, novel carbazole derivatives SG-9 and SG-10 proved to be effective inhibitors of mutant hSOD1 protein aggregation and can be further utilised as lead molecules for the amelioration of mutant hSOD1 aggregation-associated ALS.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118091"},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143287856","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 : 2025-01-30DOI: 10.1016/j.bmc.2025.118093
Lorenz Beckmann , Fabian Liessmann , Maik Icker , Dominic Rieger , Phillip Schlegel , Nicole Urban , Michael Schaefer , Jens Meiler , Clara T. Schoeder , Maik Tretbar
Crimean-Congo hemorrhagic fever (CCHF) is a viral tick-borne disease with fatality rates of up to 30 %. Currently, there are no vaccines or specific antivirals available. The genome of the CCHF virus (CCHFV) encodes an ovarian tumor (OTU) protease with a deubiquitinating activity that is responsible for the evasion of the innate immune response. Therefore, the inhibition of the OTU protease could provide a strategy for the treatment of CCHFV infections. In this study, we screened for small-molecule inhibitors of CCHFV OTU using a fluorescent ubiquitin rhodamine 110 assay. We identified and validated a 2-aminothiazole hit compound (IC50 = 42.3 μM) followed by structure–activity relationships (SAR) studies resulting in a new inhibitor of the CCHFV OTU protease. The most active derivative is a competitive CCHFV OTU inhibitor with an IC50 value of 10.7 μM. Selectivity studies revealed that the ubiquitin-specific peptidase 7 (USP7), ubiquitin C–terminal hydrolase 5 (UCHL5), OTU deubiquitinase 1 (OTUD1), and Cezanne are also inhibited by this newly developed inhibitor indicating binding to conserved regions of the ubiquitin-binding site within the deubiquitinase superfamilies. Molecular docking into the active site of CCHFV OTU proposes starting points for further structural modifications to improve activity and selectivity. These structure–activity relationships are the first to our knowledge to be reported for the CCHFV OTU protease and will help guide further drug discovery efforts.
{"title":"Identification and optimization of a small molecule inhibitor of the ovarian tumor protease of the Crimean-Congo hemorrhagic fever virus","authors":"Lorenz Beckmann , Fabian Liessmann , Maik Icker , Dominic Rieger , Phillip Schlegel , Nicole Urban , Michael Schaefer , Jens Meiler , Clara T. Schoeder , Maik Tretbar","doi":"10.1016/j.bmc.2025.118093","DOIUrl":"10.1016/j.bmc.2025.118093","url":null,"abstract":"<div><div>Crimean-Congo hemorrhagic fever (CCHF) is a viral tick-borne disease with fatality rates of up to 30 %. Currently, there are no vaccines or specific antivirals available. The genome of the CCHF virus (CCHFV) encodes an ovarian tumor (OTU) protease with a deubiquitinating activity that is responsible for the evasion of the innate immune response. Therefore, the inhibition of the OTU protease could provide a strategy for the treatment of CCHFV infections. In this study, we screened for small-molecule inhibitors of CCHFV OTU using a fluorescent ubiquitin rhodamine 110 assay. We identified and validated a 2-aminothiazole hit compound (IC<sub>50</sub> = 42.3 <!--> <!-->μM) followed by structure–activity relationships (SAR) studies resulting in a new inhibitor of the CCHFV OTU protease. The most active derivative is a competitive CCHFV OTU inhibitor with an IC<sub>50</sub> value of 10.7 <!--> <!-->μM. Selectivity studies revealed that the ubiquitin-specific peptidase 7 (USP7), ubiquitin C–terminal hydrolase 5 (UCHL5), OTU deubiquitinase 1 (OTUD1), and Cezanne are also inhibited by this newly developed inhibitor indicating binding to conserved regions of the ubiquitin-binding site within the deubiquitinase superfamilies. Molecular docking into the active site of CCHFV OTU proposes starting points for further structural modifications to improve activity and selectivity. These structure–activity relationships are the first to our knowledge to be reported for the CCHFV OTU protease and will help guide further drug discovery efforts.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118093"},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349441","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 : 2025-01-29DOI: 10.1016/j.bmc.2025.118084
Mengyuan Ding , Ming Chen , Zhiyang Cheng , Jiyu Jin , Wei Lu , Shulei Zhu
Antibody–drug conjugates (ADCs) with camptothecin derivatives as payloads have been a hot topic of interest and research since the launch of DS-8201a. As an important component of ADCs, the adequate stability of the linker during circulation and its rapid release at the target site are crucial for the efficient efficacy of ADCs. Although traditional quaternary ammonium ADCs based on dipeptide linkers were highly stable and could be released by specific enzymes, their poor in vitro anti-tumor activity had limited their further exploration. We applied a methylsulfonylethylamine-modified MAC self-elimination system to a valine-alanine linker and constructed a quaternary ammonium ADC (HER2-11) that combines both stability and cleavability. The optimization of the linker effectively improved the in vitro cellular activity of conventional quaternary ammonium ADCs, but the complex intracellular cleavage mechanism of HER2-11 resulted in a weaker anti-tumor activity compared to HER2-GGFG-DXd, which provides great reference value for the continued research of this type of linker in the future.
{"title":"Comparison of quaternary ammonium-based linkers for antibody–drug conjugates based on camptothecin derivatives","authors":"Mengyuan Ding , Ming Chen , Zhiyang Cheng , Jiyu Jin , Wei Lu , Shulei Zhu","doi":"10.1016/j.bmc.2025.118084","DOIUrl":"10.1016/j.bmc.2025.118084","url":null,"abstract":"<div><div>Antibody–drug conjugates (ADCs) with camptothecin derivatives as payloads have been a hot topic of interest and research since the launch of DS-8201a. As an important component of ADCs, the adequate stability of the linker during circulation and its rapid release at the target site are crucial for the efficient efficacy of ADCs. Although traditional quaternary ammonium ADCs based on dipeptide linkers were highly stable and could be released by specific enzymes, their poor <em>in vitro</em> anti-tumor activity had limited their further exploration. We applied a methylsulfonylethylamine-modified MAC self-elimination system to a valine-alanine linker and constructed a quaternary ammonium ADC (<strong>HER2-11</strong>) that combines both stability and cleavability. The optimization of the linker effectively improved the <em>in vitro</em> cellular activity of conventional quaternary ammonium ADCs, but the complex intracellular cleavage mechanism of <strong>HER2-11</strong> resulted in a weaker anti-tumor activity compared to <strong>HER2-GGFG-DXd</strong>, which provides great reference value for the continued research of this type of linker in the future.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118084"},"PeriodicalIF":3.3,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077847","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}
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