Pub Date : 2025-02-26DOI: 10.1016/j.bmc.2025.118135
Honglei Bao , Hui Meng , Shilin Gong , Yaguo Gong , Gao Tu , Zhenya Du , Yuwei Wang , Jianlin Wu , Chunhua Ma , Qinhai Ma , Xiaojun Yao
Since 2020, numerous compounds have been investigated for their potential use in treating SARS-CoV-2 infections. By identifying the molecular targets during the virus replication process, rationally designed anti-SARS-CoV-2 agents are developed. Among these targets, the main protease (Mpro) is a crucial enzyme required for virus replication, and its highly conserved characteristic make it an important drug target for the development of anti-SARS-CoV-2 drugs. Herein, we utilized warhead-based design strategy to conduct the structural optimization of M-1 developed through virtual screening, leading to a series of novel Mpro inhibitors with 4-(quinolin-2-yl)aniline scaffold. Among them, M-32 exhibited good SARS-CoV-2 Mpro inhibitory activity (IC50 = 5.2 μM) with a nearly 25-fold increase. Isothermal titration calorimetry (ITC) directly proved that M-32 binds directly to SARS-CoV-2 Mpro in an entropy-driven manner. Mass spectrometry (MS) further confirmed the covalent binding ability of M-32 to Mpro. Meanwhile, M-32 effectively inhibited the replication of SARS-CoV-2 in Vero E6 cells (EC50 = 5.29 μM).
{"title":"Design, synthesis and activity evaluation of 4-(quinoline-2-yl)aniline derivatives as SARS-CoV‑2 main protease inhibitors","authors":"Honglei Bao , Hui Meng , Shilin Gong , Yaguo Gong , Gao Tu , Zhenya Du , Yuwei Wang , Jianlin Wu , Chunhua Ma , Qinhai Ma , Xiaojun Yao","doi":"10.1016/j.bmc.2025.118135","DOIUrl":"10.1016/j.bmc.2025.118135","url":null,"abstract":"<div><div>Since 2020, numerous compounds have been investigated for their potential use in treating SARS-CoV-2 infections. By identifying the molecular targets during the virus replication process, rationally designed anti-SARS-CoV-2 agents are developed. Among these targets, the main protease (M<sup>pro</sup>) is a crucial enzyme required for virus replication, and its highly conserved characteristic make it an important drug target for the development of anti-SARS-CoV-2 drugs. Herein, we utilized warhead-based design strategy to conduct the structural optimization of <strong>M-1</strong> developed through virtual screening, leading to a series of novel M<sup>pro</sup> inhibitors with 4-(quinolin-2-yl)aniline scaffold. Among them, <strong>M-32</strong> exhibited good SARS-CoV-2 M<sup>pro</sup> inhibitory activity (IC<sub>50</sub> = 5.2 μM) with a nearly 25-fold increase. Isothermal titration calorimetry (ITC) directly proved that <strong>M-32</strong> binds directly to SARS-CoV-2 M<sup>pro</sup> in an entropy-driven manner. Mass spectrometry (MS) further confirmed the covalent binding ability of <strong>M-32</strong> to M<sup>pro</sup>. Meanwhile, <strong>M-32</strong> effectively inhibited the replication of SARS-CoV-2 in Vero E6 cells (EC<sub>50</sub> = 5.29 μM).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118135"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520614","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 : 2025-02-26DOI: 10.1016/j.bmc.2025.118140
Md. Ayub Ali , Mona A. Maalouf , Dan Feng , Mamunur Rashid , Nathaniel R. Gehrke , Yashpal S. Chhonker , Daryl J. Murry , David F. Wiemer , Sarah A. Holstein
Geranylgeranyl diphosphate synthase (GGDPS) produces the 20-carbon isoprenoid species used in protein geranylgeranylation reactions. Inhibition of GGDPS has emerged as a novel means of disrupting the activity of geranylgeranylated proteins in cancers such as myeloma and osteosarcoma. We have focused on developing a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, demonstrating a complex structure–activity relationship (SAR), not only at the enzymatic level, but also at the cellular and whole organism levels. To further investigate this SAR, we have prepared a family of novel derivatives that have a fixed phosphorus position by virtue of vinyl, epoxy or cyclopropyl groups that incorporate the α-carbon position. Additional modifications include compounds with homocitronellyl chains instead of homogeranyl or homoneryl chains. All new compounds were evaluated in GGDPS enzyme assays and in cellular assays involving a panel of human myeloma and osteosarcoma cell lines. The homocitronellyl derivatives displayed markedly reduced activity in both enzymatic and cellular assays. While all of the homogeranyl/homoneryl vinyl/epoxy/cyclopropyl compounds had relatively similar activity in the enzyme assay (IC50’s 0.37–2.87 μM), the cellular potencies varied more dramatically (ranging from 10 nM to no activity at 100 μM), depending on the olefin stereochemistry, the specific α-carbon modification and the tumor cell type. These findings, coupled with POM-prodrug and membrane permeability studies, support the hypothesis that there are specific membrane transporters mediating cellular uptake of these GGDPS inhibitors. Future studies focused on the identification of the membrane transporters responsible for the cellular uptake will enable further understanding of this complex SAR.
{"title":"Impact of fixed phosphorus position on activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors","authors":"Md. Ayub Ali , Mona A. Maalouf , Dan Feng , Mamunur Rashid , Nathaniel R. Gehrke , Yashpal S. Chhonker , Daryl J. Murry , David F. Wiemer , Sarah A. Holstein","doi":"10.1016/j.bmc.2025.118140","DOIUrl":"10.1016/j.bmc.2025.118140","url":null,"abstract":"<div><div>Geranylgeranyl diphosphate synthase (GGDPS) produces the 20-carbon isoprenoid species used in protein geranylgeranylation reactions. Inhibition of GGDPS has emerged as a novel means of disrupting the activity of geranylgeranylated proteins in cancers such as myeloma and osteosarcoma. We have focused on developing a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, demonstrating a complex structure–activity relationship (SAR), not only at the enzymatic level, but also at the cellular and whole organism levels. To further investigate this SAR, we have prepared a family of novel derivatives that have a fixed phosphorus position by virtue of vinyl, epoxy or cyclopropyl groups that incorporate the α-carbon position. Additional modifications include compounds with homocitronellyl chains instead of homogeranyl or homoneryl chains. All new compounds were evaluated in GGDPS enzyme assays and in cellular assays involving a panel of human myeloma and osteosarcoma cell lines. The homocitronellyl derivatives displayed markedly reduced activity in both enzymatic and cellular assays. While all of the homogeranyl/homoneryl vinyl/epoxy/cyclopropyl compounds had relatively similar activity in the enzyme assay (IC<sub>50</sub>’s 0.37–2.87 μM), the cellular potencies varied more dramatically (ranging from 10 nM to no activity at 100 μM), depending on the olefin stereochemistry, the specific α-carbon modification and the tumor cell type. These findings, coupled with POM-prodrug and membrane permeability studies, support the hypothesis that there are specific membrane transporters mediating cellular uptake of these GGDPS inhibitors. Future studies focused on the identification of the membrane transporters responsible for the cellular uptake will enable further understanding of this complex SAR.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118140"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551749","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 : 2025-02-26DOI: 10.1016/j.bmc.2025.118138
Xuan Li , Linqian Mu , Jiaying Liu , Kaidi Pengyang, Siqi Qin, Mingxing Zhou, Xiaoqian Chen, Yuyang Guo, Rui Wang
In this review, we examine and expound upon the most recent and groundbreaking advancements in the sequencing of tRNA modifications, focusing specifically on the innovative chemical treatment approaches that have revolutionized this field. By delving into the intricate details of these cutting-edge methodologies, we aim to provide an overview of the current state of the art in tRNA modification sequencing, highlighting their unique strengths, limitations, and potential applications.
{"title":"Advancements in chemically inducible modified tRNA sequencing techniques: Elucidating novel insights into tRNA epitranscriptomics","authors":"Xuan Li , Linqian Mu , Jiaying Liu , Kaidi Pengyang, Siqi Qin, Mingxing Zhou, Xiaoqian Chen, Yuyang Guo, Rui Wang","doi":"10.1016/j.bmc.2025.118138","DOIUrl":"10.1016/j.bmc.2025.118138","url":null,"abstract":"<div><div>In this review, we examine and expound upon the most recent and groundbreaking advancements in the sequencing of tRNA modifications, focusing specifically on the innovative chemical treatment approaches that have revolutionized this field. By delving into the intricate details of these cutting-edge methodologies, we aim to provide an overview of the current state of the art in tRNA modification sequencing, highlighting their unique strengths, limitations, and potential applications.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118138"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529479","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 : 2025-02-26DOI: 10.1016/j.bmc.2025.118139
Cecilie Elisabeth Olsen , Signe Simonsen , Srinivas Reddy Merugu , Vaclav Eigner , Finn L. Aachmann , Birthe B. Kragelund , Eirik Sundby , Bård Helge Hoff
Bacterial β sliding clamp (β-clamp) is an emerging drug target currently lacking small-molecule inhibitors with good in vivo activity. Thus, there is a need for fast and simple screening methods for identifying inhibitor candidates. Here we demonstrate the use of nuclear magnetic resonance spectroscopy (NMR) for evaluating compound binding to the E. coli β-clamp. To identify suitable molecular probes, a series of tetrahydrocarbazoles were synthesized, some of which contain fluorine. Key challenges in the synthesis were formation of regioisomers during the Fischer indole reaction and reducing racemization at the stereogenic center. The tetrahydrocarbazoles were assayed against the E. coli β-clamp by saturation-transfer difference (STD) NMR, waterLOGSY and T1ρ. Analysis by isothermal titration calorimetry gave KD-values of 1.7–14 μM for three fluorinated probe candidates, and NMR chemical shift perturbation experiments confirmed these molecules to directly interact with the β-clamp binding pocket. Binding of the fluorinated molecules to β-clamp was easily observed with 19F-observed T2-based binding experiments, and proof of concept for a fluorine-based binding assay for E. coli β-clamp binders is provided.
{"title":"Synthesis and evaluation of fluorinated tetrahydrocarbazoles as probes in NMR based binding assay of the E. coli β sliding clamp","authors":"Cecilie Elisabeth Olsen , Signe Simonsen , Srinivas Reddy Merugu , Vaclav Eigner , Finn L. Aachmann , Birthe B. Kragelund , Eirik Sundby , Bård Helge Hoff","doi":"10.1016/j.bmc.2025.118139","DOIUrl":"10.1016/j.bmc.2025.118139","url":null,"abstract":"<div><div>Bacterial β sliding clamp (β-clamp) is an emerging drug target currently lacking small-molecule inhibitors with good <em>in vivo</em> activity. Thus, there is a need for fast and simple screening methods for identifying inhibitor candidates. Here we demonstrate the use of nuclear magnetic resonance spectroscopy (NMR) for evaluating compound binding to the <em>E. coli</em> β-clamp. To identify suitable molecular probes, a series of tetrahydrocarbazoles were synthesized, some of which contain fluorine. Key challenges in the synthesis were formation of regioisomers during the Fischer indole reaction and reducing racemization at the stereogenic center. The tetrahydrocarbazoles were assayed against the <em>E. coli</em> β-clamp by saturation-transfer difference (STD) NMR, waterLOGSY and <em>T</em><sub>1ρ</sub>. Analysis by isothermal titration calorimetry gave <em>K</em><sub>D</sub>-values of 1.7–14 μM for three fluorinated probe candidates, and NMR chemical shift perturbation experiments confirmed these molecules to directly interact with the β-clamp binding pocket. Binding of the fluorinated molecules to β-clamp was easily observed with <sup>19</sup>F-observed <em>T</em><sub>2</sub>-based binding experiments, and proof of concept for a fluorine-based binding assay for <em>E. coli</em> β-clamp binders is provided.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118139"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535165","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 : 2025-02-25DOI: 10.1016/j.bmc.2025.118134
Edward A. FitzGerald , Moira M. Rachman , Daniela Cederfelt , Nadine E.M. Myers , Daria Kovryzchenko , He Zhang , Xavier Barril , Konrad Koehler , U. Helena Danielson
SMYD3 (SET- and MYND-domain containing protein 3) is an epigenetic enzyme with lysine methyl transferase activity and multiple protein binding partners. It is implicated in cancer development and active site inhibitors with antitumor activity have been developed. We have previously discovered that diperodon is an allosteric SMYD3 ligand and are interested in developing ligands that can interfere with non-catalytic functions of SMYD3, while avoiding conceivable draw-backs of targeting a conserved site in an enzyme with several close family members. Herein, the features of the diperodon site were explored via computational modelling and served as a basis for identifying analogues in commercial compound space, thus avoiding the need for in-house compound synthesis. Time-resolved grating coupled interferometry (GCI) biosensor analysis confirmed that two out of 21 acquired analogues interacted with SMYD3, with similar affinities as diperodon (KD ∼ 180 and 210 vs. ∼200 µM). As a second approach, fragmentation of diperodon followed by growing of fragments identified an additional 11 compounds in commercial compound space. GCI analysis confirmed that N-phenylformamide and three compounds evolved from this fragment interacted with SMYD3. These four ligands varied structurally from diperodon and had higher affinities (KD = 0.4–130 µM) and superior ligand efficiencies. However, all ligands interacted with rapid kinetics and weak affinities, indicating that the site had poor ligandability, possibly a result of its extremely flexible structure. Difficulties in protein production and the overall flexible structure of SMYD3, prevented NMR experiments and X-ray crystallography. Nevertheless, the combination of computational ligand design supported by biosensor-based analyses resulted in new allosteric ligands with minimal resources in a short time.
{"title":"Integrated computational and biosensor-based strategies for the discovery of allosteric SMYD3 ligands using diperodon as a starting point","authors":"Edward A. FitzGerald , Moira M. Rachman , Daniela Cederfelt , Nadine E.M. Myers , Daria Kovryzchenko , He Zhang , Xavier Barril , Konrad Koehler , U. Helena Danielson","doi":"10.1016/j.bmc.2025.118134","DOIUrl":"10.1016/j.bmc.2025.118134","url":null,"abstract":"<div><div>SMYD3 (SET- and MYND-domain containing protein 3) is an epigenetic enzyme with lysine methyl transferase activity and multiple protein binding partners. It is implicated in cancer development and active site inhibitors with antitumor activity have been developed. We have previously discovered that diperodon is an allosteric SMYD3 ligand and are interested in developing ligands that can interfere with non-catalytic functions of SMYD3, while avoiding conceivable draw-backs of targeting a conserved site in an enzyme with several close family members. Herein, the features of the diperodon site were explored via computational modelling and served as a basis for identifying analogues in commercial compound space, thus avoiding the need for in-house compound synthesis. Time-resolved grating coupled interferometry (GCI) biosensor analysis confirmed that two out of 21 acquired analogues interacted with SMYD3, with similar affinities as diperodon (<em>K</em><sub>D</sub> ∼ 180 and 210 <em>vs.</em> ∼200 µM). As a second approach, fragmentation of diperodon followed by growing of fragments identified an additional 11 compounds in commercial compound space. GCI analysis confirmed that <em>N</em>-phenylformamide and three compounds evolved from this fragment interacted with SMYD3. These four ligands varied structurally from diperodon and had higher affinities (<em>K</em><sub>D</sub> = 0.4–130 µM) and superior ligand efficiencies. However, all ligands interacted with rapid kinetics and weak affinities, indicating that the site had poor ligandability, possibly a result of its extremely flexible structure. Difficulties in protein production and the overall flexible structure of SMYD3, prevented NMR experiments and X-ray crystallography. Nevertheless, the combination of computational ligand design supported by biosensor-based analyses resulted in new allosteric ligands with minimal resources in a short time.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118134"},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526675","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 : 2025-02-25DOI: 10.1016/j.bmc.2025.118133
Shuting Yao , Chao Fang , Binjie Xu , Yue Hu , Zhou Chen , Xiaoyan Xue , Jiping Liu , Mingkai Li , Pengyu Li
Due to the prolonged misuse of antimicrobial agents and the development of various resistance mechanisms, Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a leading threat to the public health. The production of a penicillin binding protein 2a (PBP2a) plays a crucial role in cell wall synthesis of MRSA, and conformational alterations in PBP2a impede the effective binding of β-lactam antibiotics, the most effective class of antibiotic, to the active site. The PBP2a allosteric site located 60 Å from the active site, and binding of allosteric site significantly influences the conformational dynamics of the active site. Based on the effect of nucleoside which re-sensitizes MRSA to β-lactam antibiotics, we conducted extensive virtual screening to design and synthesize a series of novel nucleoside inhibitors targeting the allosteric site of MRSA PBP2a. These inhibitors exhibit a distinct chemical structure compared to existing clinical antibiotics. Notably, compound 13e demonstrated a minimum inhibitory concentration (MIC) of 16 µg/mL against MRSA strain, showcasing superior antibacterial activity relative to the reference antibiotic. Time-kill curve indicated that compound 13e effectively inhibit bacterial growth. Interestingly, a synergistic effect was observed at low concentrations of compound 13e in combination treatment with Oxacillin, whereas antagonism occurred at higher concentrations of compound 13e. The morphological observation showed the integrity of the bacterial cell wall was disrupted after compound 13e treatment, and it exhibited a lower propensity for developing resistance compared to cephalosporin. Additionally, this compound did not affect the viability of normal human intestinal epithelial cells (HIEC) and brain microvascular endothelial cells at concentration much higher than MIC. Over all, this unique antibacterial mechanism underscores the optimization potential of these nucleoside compounds, providing new perspectives and methodologies for the development of novel antimicrobial agents.
{"title":"Designing novel nucleoside inhibitors targeting the allosteric site of PBP2a: A strategic approach to overcome resistance in MRSA","authors":"Shuting Yao , Chao Fang , Binjie Xu , Yue Hu , Zhou Chen , Xiaoyan Xue , Jiping Liu , Mingkai Li , Pengyu Li","doi":"10.1016/j.bmc.2025.118133","DOIUrl":"10.1016/j.bmc.2025.118133","url":null,"abstract":"<div><div>Due to the prolonged misuse of antimicrobial agents and the development of various resistance mechanisms, Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) has emerged as a leading threat to the public health. The production of a penicillin binding protein 2a (PBP2a) plays a crucial role in cell wall synthesis of MRSA, and conformational alterations in PBP2a impede the effective binding of β-lactam antibiotics, the most effective class of antibiotic, to the active site. The PBP2a allosteric site located 60 Å from the active site, and binding of allosteric site significantly influences the conformational dynamics of the active site. Based on the effect of nucleoside which re-sensitizes MRSA to β-lactam antibiotics, we conducted extensive virtual screening to design and synthesize a series of novel nucleoside inhibitors targeting the allosteric site of MRSA PBP2a. These inhibitors exhibit a distinct chemical structure compared to existing clinical antibiotics. Notably, compound <strong>13e</strong> demonstrated a minimum inhibitory concentration (MIC) of 16 µg/mL against MRSA strain, showcasing superior antibacterial activity relative to the reference antibiotic. Time-kill curve indicated that compound <strong>13e</strong> effectively inhibit bacterial growth. Interestingly, a synergistic effect was observed at low concentrations of compound <strong>13e</strong> in combination treatment with Oxacillin, whereas antagonism occurred at higher concentrations of compound <strong>13e</strong>. The morphological observation showed the integrity of the bacterial cell wall was disrupted after compound <strong>13e</strong> treatment, and it exhibited a lower propensity for developing resistance compared to cephalosporin. Additionally, this compound did not affect the viability of normal human intestinal epithelial cells (HIEC) and brain microvascular endothelial cells at concentration much higher than MIC. Over all, this unique antibacterial mechanism underscores the optimization potential of these nucleoside compounds, providing new perspectives and methodologies for the development of novel antimicrobial agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118133"},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535166","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 : 2025-02-24DOI: 10.1016/j.bmc.2025.118128
Yidan Sun , Shuhan Tang , Yaqi Xu , Hao Li , Pengyu Li , Masao Hattori , Hailong Zhang , Xianna Li , Zhigang Wang
Swertiamarin, a predominant component in many traditional Chinese swertia herbs, shows significant anti-HBV activity clinically. (R)-gentiandiol and (S)-gentiandiol are the metabolites of swertiamarin in vivo. In this study, HBsAg, HBeAg and HBV-DNA were determined in liver tissue of HBV-transgenic C57BL/6NCrl mice to analyze anti-HBV activities of swertiamarin, (R)-gentiandiol and (S)-gentiandiol. It was found that HBsAg, HBeAg and HBV-DNA levels were significantly reduced in a dose-dependent manner when (R)-gentiandiol was administered at 1.5, 3 and 6 mg/kg. However, (S)-gentiandiol showed no anti-HBV activity at all. In addition, we also performed untargeted metabolomics to discover biomarkers and metabolic pathways of swertiamarin and (R)-gentiandiol in HBV-transgenic C57BL/6NCrl mice. A total of 15 candidate biomarkers were obtained. Meanwhile, the metabolic disorders including 8 metabolic pathways, such as taurine and hypotaurine metabolism were explored. Taurine and hypotaurine metabolism was the primary pathway for (R)-gentiandiol to regulate HBV-transgenic C57BL/6NCrl mice. It is the first time to clarify real active anti-HBV metabolites of swertiamarin, which can offer more insights into anti-HBV activities of swertia herbs, and bring novel ideas for new drug development in anti-HBV herbs.
{"title":"Anti-HBV activity of (R)-gentiandiol, a metabolite of Swertiamarin, in transgenic mice: Insights from non-targeted serum metabolomics","authors":"Yidan Sun , Shuhan Tang , Yaqi Xu , Hao Li , Pengyu Li , Masao Hattori , Hailong Zhang , Xianna Li , Zhigang Wang","doi":"10.1016/j.bmc.2025.118128","DOIUrl":"10.1016/j.bmc.2025.118128","url":null,"abstract":"<div><div>Swertiamarin, a predominant component in many traditional Chinese swertia herbs, shows significant anti-HBV activity clinically. (<em>R</em>)-gentiandiol and (<em>S</em>)-gentiandiol are the metabolites of swertiamarin <em>in vivo</em>. In this study, HBsAg, HBeAg and HBV-DNA were determined in liver tissue of HBV-transgenic C57BL/6NCrl mice to analyze anti-HBV activities of swertiamarin, (<em>R</em>)-gentiandiol and (<em>S</em>)-gentiandiol. It was found that HBsAg, HBeAg and HBV-DNA levels were significantly reduced in a dose-dependent manner when (<em>R</em>)-gentiandiol was administered at 1.5, 3 and 6 mg/kg. However, (<em>S</em>)-gentiandiol showed no anti-HBV activity at all. In addition, we also performed untargeted metabolomics to discover biomarkers and metabolic pathways of swertiamarin and (<em>R</em>)-gentiandiol in HBV-transgenic C57BL/6NCrl mice. A total of 15 candidate biomarkers were obtained. Meanwhile, the metabolic disorders including 8 metabolic pathways, such as taurine and hypotaurine metabolism were explored. Taurine and hypotaurine metabolism was the primary pathway for (<em>R</em>)-gentiandiol to regulate HBV-transgenic C57BL/6NCrl mice. It is the first time to clarify real active anti-HBV metabolites of swertiamarin, which can offer more insights into anti-HBV activities of swertia herbs, and bring novel ideas for new drug development in anti-HBV herbs.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118128"},"PeriodicalIF":3.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520520","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 : 2025-02-23DOI: 10.1016/j.bmc.2025.118130
Fengbin Song , Jie Chen , Shannon Dallas , Wing Lam , Heng-Keang Lim , Ronghui Zhou , Tetsuo Kokubun , Richard Phipps , Jonathan Steele , Rhys Salter
JNJ-61393215, a deuterated compound, is a selective OX1R antagonist. In both preclinical and clinical studies, a hydroxylated metabolite designated M54 was observed to be the most abundant metabolite in plasma. Screening of Hypha PolyCYPs®+ kit revealed PolyCYP 152 was the most proficient at producing M54 from JNJ-61393215 and subsequent scale up with PolyCYP 152 provided small but sufficient quantities of M54 for initial structure elucidation by NMR analyses. A microbial biosynthesis, using a Streptomyces strain from which PolyCYP 152 was genetically derived, provided gram quantities of M54. It allowed chemical epimerization of the chiral hydroxylated carbon of M54 and unequivocally established the metabolite’s absolute stereo-configuration. The biotransformation provided remarkably efficient methodologies for quick synthesis of the metabolite M54 with stereoselective hydroxylation on the deuterated unique 2-aza-[2.2.1]-bicycle core structure, for which structure assignment via classical synthesis of speculative structures would be challenging and resource-intensive. Moreover, the microbial biosynthesis provided M54 with high purity for ongoing preclinical studies.
{"title":"Biosynthesis and structure assignment of a hydroxylated metabolite of the orexin-1 receptor antagonist JNJ-61393215","authors":"Fengbin Song , Jie Chen , Shannon Dallas , Wing Lam , Heng-Keang Lim , Ronghui Zhou , Tetsuo Kokubun , Richard Phipps , Jonathan Steele , Rhys Salter","doi":"10.1016/j.bmc.2025.118130","DOIUrl":"10.1016/j.bmc.2025.118130","url":null,"abstract":"<div><div>JNJ-61393215, a deuterated compound, is a selective OX1R antagonist. In both preclinical and clinical studies, a hydroxylated metabolite designated M54 was observed to be the most abundant metabolite in plasma. Screening of Hypha PolyCYPs®<sup>+</sup> kit revealed PolyCYP 152 was the most proficient at producing M54 from JNJ-61393215 and subsequent scale up with PolyCYP 152 provided small but sufficient quantities of M54 for initial structure elucidation by NMR analyses. A microbial biosynthesis, using a Streptomyces strain from which PolyCYP 152 was genetically derived, provided gram quantities of M54. It allowed chemical epimerization of the chiral hydroxylated carbon of M54 and unequivocally established the metabolite’s absolute stereo-configuration. The biotransformation provided remarkably efficient methodologies for quick synthesis of the metabolite M54 with stereoselective hydroxylation on the deuterated unique 2-aza-[2.2.1]-bicycle core structure, for which structure assignment via classical synthesis of speculative structures would be challenging and resource-intensive. Moreover, the microbial biosynthesis provided M54 with high purity for ongoing preclinical studies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118130"},"PeriodicalIF":3.3,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520616","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}
l-Cysteine (Cys) is a tumor-related biomarker. The photo- and Cys-activatable theranostic agent 4 was designed and synthesized based on 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (3). Compound 4 exhibited negligible fluorescence and photosensitizing activity in the absence of Cys. However, when activated by Cys, 3 was released, resulting in fluorescence and photosensitization. Moreover, upon irradiation with 660 nm light, 4 displayed selective and effective fluorescence and photo-cytotoxicity exclusively against cancer cells, such as HeLa and A549 cells, which express high levels of Cys. This wavelength of light falls within the phototherapeutic window.
{"title":"A novel porphyrin-based theranostic agent activated by cysteine over-expressed in cancer cells shows promise for tumour-targeted monitoring and phototherapy","authors":"Fumihisa Ishida, Satoe Moriya, Daisuke Takahashi, Kazunobu Toshima","doi":"10.1016/j.bmc.2025.118131","DOIUrl":"10.1016/j.bmc.2025.118131","url":null,"abstract":"<div><div><span>l</span>-Cysteine (Cys) is a tumor-related biomarker. The photo- and Cys-activatable theranostic agent <strong>4</strong> was designed and synthesized based on 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (<strong>3</strong>). Compound <strong>4</strong> exhibited negligible fluorescence and photosensitizing activity in the absence of Cys. However, when activated by Cys, <strong>3</strong> was released, resulting in fluorescence and photosensitization. Moreover, upon irradiation with 660 nm light, <strong>4</strong> displayed selective and effective fluorescence and photo-cytotoxicity exclusively against cancer cells, such as HeLa and A549 cells, which express high levels of Cys. This wavelength of light falls within the phototherapeutic window.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118131"},"PeriodicalIF":3.3,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520615","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}
Natural products play a key role in drug discovery and development. The natural sesquiterpene, β-elemene, has been approved as an antitumor drug in China. Despite showing few side effects, the moderate antitumor potency of β-elemene hampers its wide application in clinic. A second round of design and synthesis of β-elemene derivatives was carried out based on our previous prodrug-like ester derivatives. The resulting twenty-nine compounds (except 10c) exhibited enhanced antitumor activity compared with β-elemene and its ester derivative 3. The optimal compound 10a possessed low micromolar antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and U87), more potent than positive control cisplatin. The mechanism studies indicate that compound 10a caused arrest of the cell cycle along with inhibition of microtubules, induced apoptosis via a ROS-involved mitochondrial apoptotic pathway, and dampened cell migration and invasion with changes of related protein (MMP-9 and p-FAKY397) expressions. Collectively, the promising antitumor efficacy of compound 10a would make it a potential lead compound in anticancer drug development.
{"title":"Novel agents derived from natural product β-elemene: A second round of design and synthesis to enhance antitumor properties","authors":"Zhouyan Liu , Tong Li , Chenglei Gu , Cheng Chen , Ziwei Tang , Yanyan Feng , Chen Zhou , Jinyi Xu , Jichao Chen","doi":"10.1016/j.bmc.2025.118129","DOIUrl":"10.1016/j.bmc.2025.118129","url":null,"abstract":"<div><div>Natural products play a key role in drug discovery and development. The natural sesquiterpene, <em>β</em>-elemene, has been approved as an antitumor drug in China. Despite showing few side effects, the moderate antitumor potency of <em>β</em>-elemene hampers its wide application in clinic. A second round of design and synthesis of <em>β</em>-elemene derivatives was carried out based on our previous prodrug-like ester derivatives. The resulting twenty-nine compounds (except <strong>10c</strong>) exhibited enhanced antitumor activity compared with <em>β</em>-elemene and its ester derivative <strong>3</strong>. The optimal compound <strong>10a</strong> possessed low micromolar antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and U87), more potent than positive control cisplatin. The mechanism studies indicate that compound <strong>10a</strong> caused arrest of the cell cycle along with inhibition of microtubules, induced apoptosis via a ROS-involved mitochondrial apoptotic pathway, and dampened cell migration and invasion with changes of related protein (MMP-9 and <em>p</em>-FAK<sup>Y397</sup>) expressions. Collectively, the promising antitumor efficacy of compound <strong>10a</strong> would make it a potential lead compound in anticancer drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118129"},"PeriodicalIF":3.3,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510686","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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