Pub Date : 2025-10-10DOI: 10.1016/j.bmc.2025.118432
Yutao Zhao , Chuan He
RNA modifications represent an essential regulatory layer of gene expression and have profound implications for cellular homeostasis and human diseases. Advances in high-throughput sequencing technologies have revealed that modifications such as N6-methyladenosine (m6A) and pseudouridine (Ψ) influence cellular processes such as gene transcription, pre-mRNA processing, mRNA stability, and translation. This review begins with a historical overview of the field, highlighting key discoveries and technological advances that gave rise to epitranscriptomics as a discipline. The biological functions of RNA modifications are then examined, with emphasis on their contributions to cancer development. Recent efforts in targeting RNA modification are summarized, including small-molecule inhibitors targeting effector proteins of RNA modification. Several of these inhibitors have demonstrated efficacy in preclinical cancer models, underscoring the therapeutic potential of modulating the epitranscriptome. As research in this area expands, RNA modifications are increasingly recognized as both pivotal drivers of tumorigenesis and promising targets for cancer therapy.
{"title":"RNA modifications in cancer: from biological insights to therapeutic targets","authors":"Yutao Zhao , Chuan He","doi":"10.1016/j.bmc.2025.118432","DOIUrl":"10.1016/j.bmc.2025.118432","url":null,"abstract":"<div><div>RNA modifications represent an essential regulatory layer of gene expression and have profound implications for cellular homeostasis and human diseases. Advances in high-throughput sequencing technologies have revealed that modifications such as <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A) and pseudouridine (Ψ) influence cellular processes such as gene transcription, pre-mRNA processing, mRNA stability, and translation. This review begins with a historical overview of the field, highlighting key discoveries and technological advances that gave rise to epitranscriptomics as a discipline. The biological functions of RNA modifications are then examined, with emphasis on their contributions to cancer development. Recent efforts in targeting RNA modification are summarized, including small-molecule inhibitors targeting effector proteins of RNA modification. Several of these inhibitors have demonstrated efficacy in preclinical cancer models, underscoring the therapeutic potential of modulating the epitranscriptome. As research in this area expands, RNA modifications are increasingly recognized as both pivotal drivers of tumorigenesis and promising targets for cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118432"},"PeriodicalIF":3.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290482","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 : 2025-10-10DOI: 10.1016/j.bmc.2025.118438
Mohamed A. Seleem , Nader S. Abutaleb , Hayam T. Hussein , Ahmed A. Abouelkhair , Kelly Mari Pires de Oliveira , Fabiana Gomes da Silva Dantas , Luana Janaína de Campos , Cameron Drobotka , Fabio Aguiar-Alves , Mohamed N. Seleem , Martin Conda-Sheridan
The increasing emergence of antibiotic resistance highlights the urgent need for the discovery of new antimicrobial agents. Herein, we report the synthesis and antimicrobial evaluation of a series of phenazine sulfonamides (PSAs) based on 9-chloro phenazine carboxylic acid (1a) and saphenic acid (2). Our initial antimicrobial screening identified compounds with promising activity against methicillin-resistant Staphylococcus aureus (MRSA), S. epidermidis, and Neisseria gonorrhoeae. Notably, compound 7i showed activities in the low micromolar range against MRSA and S. epidermidis. In addition, compounds 7k and 7p exhibited antimicrobial effect against N. gonorrhoeae isolates. In subsequent investigations, 7i demonstrated an additive antibacterial effect against S. aureus in combination with linezolid and vancomycin. Compound 7i also improved the antimicrobial efficacy of vancomycin against vancomycin-resistant S. aureus isolates and demonstrated a powerful biofilm formation inhibition against S. aureus JE2 by suppressing key regulatory genes (agrA and saeR) and impairing virulence-associated exoprotein secretion. In addition, 7i possesses a very promising safety profile: no cytotoxicity towards mammalian cells, and lack of hemolytic and mutagenic action. The lead molecules showed promising activity in a simple in vivo model. Altogether, data from this study suggest PSA are a promising scaffold for developing antimicrobial agents.
{"title":"Synthesis, antimicrobial activity, and preliminary mechanistic studies of phenazine sulfonamides","authors":"Mohamed A. Seleem , Nader S. Abutaleb , Hayam T. Hussein , Ahmed A. Abouelkhair , Kelly Mari Pires de Oliveira , Fabiana Gomes da Silva Dantas , Luana Janaína de Campos , Cameron Drobotka , Fabio Aguiar-Alves , Mohamed N. Seleem , Martin Conda-Sheridan","doi":"10.1016/j.bmc.2025.118438","DOIUrl":"10.1016/j.bmc.2025.118438","url":null,"abstract":"<div><div>The increasing emergence of antibiotic resistance highlights the urgent need for the discovery of new antimicrobial agents. Herein, we report the synthesis and antimicrobial evaluation of a series of phenazine sulfonamides (PSAs) based on 9-chloro phenazine carboxylic acid (<strong>1a</strong>) and saphenic acid (<strong>2</strong>). Our initial antimicrobial screening identified compounds with promising activity against methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), <em>S. epidermidis</em>, and <em>Neisseria gonorrhoeae</em>. Notably, compound <strong>7i</strong> showed activities in the low micromolar range against MRSA and <em>S. epidermidis</em>. In addition, compounds <strong>7k</strong> and <strong>7p</strong> exhibited antimicrobial effect against <em>N. gonorrhoeae</em> isolates. In subsequent investigations, <strong>7i</strong> demonstrated an additive antibacterial effect against <em>S. aureus</em> in combination with linezolid and vancomycin. Compound <strong>7i</strong> also improved the antimicrobial efficacy of vancomycin against vancomycin-resistant <em>S. aureus</em> isolates and demonstrated a powerful biofilm formation inhibition against <em>S. aureus</em> JE2 by suppressing key regulatory genes (<em>agrA</em> and <em>saeR</em>) and impairing virulence-associated exoprotein secretion. In addition, <strong>7i</strong> possesses a very promising safety profile: no cytotoxicity towards mammalian cells, and lack of hemolytic and mutagenic action. The lead molecules showed promising activity in a simple <em>in vivo</em> model. Altogether, data from this study suggest PSA are a promising scaffold for developing antimicrobial agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118438"},"PeriodicalIF":3.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297685","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}
Drug affinity responsive target stability (DARTS) is a powerful label-free technique for detecting target engagement by measuring the increased resistance of a protein to proteolytic degradation upon ligand binding. However, its application to multi-transmembrane channel proteins has been limited due to their intrinsic structural instability and general resistance to protease digestion. To address this challenge, we developed a novel strategy termed Dual-DARTS (D-DARTS), which employs controlled proteolysis in an SDS-containing denaturing buffer to evaluate a target protein's dual stability—namely, resistance to both chemical denaturation and enzymatic degradation. Using this approach, we successfully identified affinity ligands for the NaV1.5 channel, including both inhibitors and agonists. Notably, D-DARTS enabled the discovery of poneratoxin, a peptide derived from bullet ants, as a high-affinity binder to NaV1.5, a finding validated through electrophysiological assays. Preliminary molecular docking analyses suggested that poneratoxin binds to an epitope analogous to that of the alkaloid agonist BTXB. The general utility of the D-DARTS method was further corroborated by its successful application to the mitochondrial membrane protein VDAC1. By enabling target profiling based on binding affinity rather than functional activity, D-DARTS provides a complementary alternative to electrophysiology-based screening for NaV1.5 channel binders, with advantages including operational simplicity, cost-efficiency, and reduced reliance on specialized equipment. This strategy is anticipated to be applicable to target identification and active molecule screening for a wide range of channel proteins and other multi-transmembrane proteins.
{"title":"D-DARTS: an alternative method for NaV1.5 affinity molecules identification based on dual-drug affinity responsive target stability","authors":"Zirui Lü, Xiandong Dai, Huixia Li, Cunlin Wang, Fanhua Meng","doi":"10.1016/j.bmc.2025.118436","DOIUrl":"10.1016/j.bmc.2025.118436","url":null,"abstract":"<div><div>Drug affinity responsive target stability (DARTS) is a powerful label-free technique for detecting target engagement by measuring the increased resistance of a protein to proteolytic degradation upon ligand binding. However, its application to multi-transmembrane channel proteins has been limited due to their intrinsic structural instability and general resistance to protease digestion. To address this challenge, we developed a novel strategy termed Dual-DARTS (D-DARTS), which employs controlled proteolysis in an SDS-containing denaturing buffer to evaluate a target protein's dual stability—namely, resistance to both chemical denaturation and enzymatic degradation. Using this approach, we successfully identified affinity ligands for the NaV1.5 channel, including both inhibitors and agonists. Notably, D-DARTS enabled the discovery of poneratoxin, a peptide derived from bullet ants, as a high-affinity binder to NaV1.5, a finding validated through electrophysiological assays. Preliminary molecular docking analyses suggested that poneratoxin binds to an epitope analogous to that of the alkaloid agonist BTX<img>B. The general utility of the D-DARTS method was further corroborated by its successful application to the mitochondrial membrane protein VDAC1. By enabling target profiling based on binding affinity rather than functional activity, D-DARTS provides a complementary alternative to electrophysiology-based screening for NaV1.5 channel binders, with advantages including operational simplicity, cost-efficiency, and reduced reliance on specialized equipment. This strategy is anticipated to be applicable to target identification and active molecule screening for a wide range of channel proteins and other multi-transmembrane proteins.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118436"},"PeriodicalIF":3.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290492","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 : 2025-10-09DOI: 10.1016/j.bmc.2025.118437
George A. Naclerio , Christopher S. Vennard , Kenneth I. Onyedibe , Dielson da S. Vieira , Nader S. Abutaleb , Marxa L. Figueiredo , Mohamed N. Seleem , Herman O. Sintim
Due to the ever-increasing threat of methicillin-resistant Staphylococcus aureus (MRSA), we have embarked on a campaign to discover novel antibacterial agents which are effective at eradicating both MRSA, as well as acting on pre-formed MRSA biofilms. Using the known scaffold of N-(1,3,4-oxadiazol-2-yl)benzamides, we performed a halogenation study which has led to the identification of HSGN-2241. This novel compound was found to effectively kill many multi-drug resistant Gram-positive clinical isolates in a bactericidal manner. The growth inhibition mechanism of HSGN-2241 was found to be via potassium ion release and subsequent depolarization of the cell membrane. As an initial safety test, HSGN-2241 was found to not lyse human red blood cells, so it is a promising lead compound for the treatment of bacterial infections caused by Staphylococcus aureus.
{"title":"Halogenated N-(1,3,4-oxadiazol-2-yl) benzamides are effective eradicators of methicillin-resistant Staphylococcus aureus biofilms","authors":"George A. Naclerio , Christopher S. Vennard , Kenneth I. Onyedibe , Dielson da S. Vieira , Nader S. Abutaleb , Marxa L. Figueiredo , Mohamed N. Seleem , Herman O. Sintim","doi":"10.1016/j.bmc.2025.118437","DOIUrl":"10.1016/j.bmc.2025.118437","url":null,"abstract":"<div><div>Due to the ever-increasing threat of methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), we have embarked on a campaign to discover novel antibacterial agents which are effective at eradicating both MRSA, as well as acting on pre-formed MRSA biofilms. Using the known scaffold of <em>N</em>-(1,3,4-oxadiazol-2-yl)benzamides, we performed a halogenation study which has led to the identification of <strong>HSGN-2241</strong>. This novel compound was found to effectively kill many multi-drug resistant Gram-positive clinical isolates in a bactericidal manner. The growth inhibition mechanism of <strong>HSGN-2241</strong> was found to be via potassium ion release and subsequent depolarization of the cell membrane. As an initial safety test, <strong>HSGN-2241</strong> was found to not lyse human red blood cells, so it is a promising lead compound for the treatment of bacterial infections caused by <em>Staphylococcus aureus.</em></div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118437"},"PeriodicalIF":3.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353157","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 : 2025-10-09DOI: 10.1016/j.bmc.2025.118434
Eman A. El-Khouly , Eman M. Ahmed , Madiha K. El-Sobky , Shaymaa G. Ibrahim , Khaled M. Gouda , Ahmed A.M. Ibraheem
A new series of triazolopyridazine-based derivatives were designed and synthesized. Biological targets were predicted for compounds IIIa-k, IVa-c, V, and VI using Swiss Target Prediction combined with pharmacological network analysis. Functional annotation and enrichment analysis of the common targets was performed using ShinyGO 0.80. Based on KEGG pathway analysis and identified genes in each pathway, the HepG2 liver carcinoma cell line was selected as the most suitable model for experimental validation, given its relevance to key target genes including CDK2, CDK4, ATM, and MAPK10. The synthesized compounds were evaluated for cytotoxic efficacy against the HepG2 human liver carcinoma cell line. Eight compounds (IIIa, b, c, d, f, g, h, and k) demonstrated superior antiproliferative activity compared to cisplatin, with potency ranging from 1.03- to 3.35-fold higher against the HepG2 cell line. Compounds IIId and IIIk exhibited the most promising cytotoxicity with selectivity indices of 7.42 and 7.80, respectively, toward HepG2 cancer cells. Further investigation of compounds IIId and IIIk included in vitro CDK4 inhibition assays, which revealed IC₅₀ values of 0.685 and 0.347 μM, respectively. Molecular docking simulations explained their significant CDK4 inhibition by demonstrating favorable binding interactions within the CDK4 active site. Finally, compounds IIId and IIIk induced cell cycle arrest in the G₀-G₁ phase in HepG2 cancer cells and promoted apoptosis and necrosis at levels 7.18- and 5.36-fold higher than control, respectively.
{"title":"Design, synthesis, and biological evaluation of new triazolopyridazine-based derivatives as cyclin dependent kinase-4 inhibitors with apoptosis-inducing and tumor-suppressive effects","authors":"Eman A. El-Khouly , Eman M. Ahmed , Madiha K. El-Sobky , Shaymaa G. Ibrahim , Khaled M. Gouda , Ahmed A.M. Ibraheem","doi":"10.1016/j.bmc.2025.118434","DOIUrl":"10.1016/j.bmc.2025.118434","url":null,"abstract":"<div><div>A new series of triazolopyridazine-based derivatives were designed and synthesized. Biological targets were predicted for compounds <strong>IIIa-k, IVa-c, V</strong>, and <strong>VI</strong> using Swiss Target Prediction combined with pharmacological network analysis. Functional annotation and enrichment analysis of the common targets was performed using ShinyGO 0.80. Based on KEGG pathway analysis and identified genes in each pathway, the HepG2 liver carcinoma cell line was selected as the most suitable model for experimental validation, given its relevance to key target genes including CDK2, CDK4, ATM, and MAPK10. The synthesized compounds were evaluated for cytotoxic efficacy against the HepG2 human liver carcinoma cell line. Eight compounds (<strong>IIIa, b, c, d, f, g, h,</strong> and <strong>k</strong>) demonstrated superior antiproliferative activity compared to cisplatin, with potency ranging from 1.03- to 3.35-fold higher against the HepG2 cell line. Compounds <strong>IIId</strong> and <strong>IIIk</strong> exhibited the most promising cytotoxicity with selectivity indices of 7.42 and 7.80, respectively, toward HepG2 cancer cells. Further investigation of compounds <strong>IIId</strong> and <strong>IIIk</strong> included in vitro CDK4 inhibition assays, which revealed IC₅₀ values of 0.685 and 0.347 μM, respectively. Molecular docking simulations explained their significant CDK4 inhibition by demonstrating favorable binding interactions within the CDK4 active site. Finally, compounds <strong>IIId</strong> and <strong>IIIk</strong> induced cell cycle arrest in the G₀-G₁ phase in HepG2 cancer cells and promoted apoptosis and necrosis at levels 7.18- and 5.36-fold higher than control, respectively.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118434"},"PeriodicalIF":3.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297758","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}
Drug resistance caused by epidermal growth factor receptor (EGFR) mutation has significantly limited the clinical efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we selected fourth-generation EGFR-TKIs (compounds A, B, and C) and EGFR-TKI D as ligands for EGFR, along with VHL-L1 and VHL-L2 as ligands for the E3 ligase, using acyl linkers to design novel PROTACs targeting EGFR triple mutants. We synthesized and evaluated compounds EP1–EP12. Among them, EP7, EP8, EP9, EP11 and EP12 exhibited potent antiproliferative activities against cells expressing EGFR mutants. Notably, EP9 and EP12 effectively induced the degradation of EGFR triple mutants (EGFRDel19/T790M/C797S and EGFRL858R/T790M/C797S) and significantly suppressed EGFR pathway signal transduction. Mechanism studies revealed that the degradation process requires the formation of ternary complexes and the ubiquitination of the EGFR protein, with the degradation being associated with lysosomal activity. In conclusion, compounds EP9 and EP12 were identified as potent degraders of EGFR triple mutants, offering new insights into the development of PROTACs for targeting these mutations.
{"title":"Synthesis and degradation effect of PROTACs targeting EGFR triple mutants","authors":"Xiao-Xiao Xi, Hong-Yi Zhao, Minhang Xin, Shuai Mao, San-Qi Zhang","doi":"10.1016/j.bmc.2025.118427","DOIUrl":"10.1016/j.bmc.2025.118427","url":null,"abstract":"<div><div>Drug resistance caused by epidermal growth factor receptor (EGFR) mutation has significantly limited the clinical efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we selected fourth-generation EGFR-TKIs (compounds <strong>A</strong>, <strong>B</strong>, and <strong>C</strong>) and EGFR-TKI <strong>D</strong> as ligands for EGFR, along with VHL-L1 and VHL-L2 as ligands for the E3 ligase, using acyl linkers to design novel PROTACs targeting EGFR triple mutants. We synthesized and evaluated compounds EP1–EP12. Among them, <strong>EP7</strong>, <strong>EP8</strong>, <strong>EP9</strong>, <strong>EP11</strong> and <strong>EP12</strong> exhibited potent antiproliferative activities against cells expressing EGFR mutants. Notably, <strong>EP9</strong> and <strong>EP12</strong> effectively induced the degradation of EGFR triple mutants (EGFR<sup>Del19/T790M/C797S</sup> and EGFR<sup>L858R/T790M/C797S</sup>) and significantly suppressed EGFR pathway signal transduction. Mechanism studies revealed that the degradation process requires the formation of ternary complexes and the ubiquitination of the EGFR protein, with the degradation being associated with lysosomal activity. In conclusion, compounds EP9 and EP12 were identified as potent degraders of EGFR triple mutants, offering new insights into the development of PROTACs for targeting these mutations.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118427"},"PeriodicalIF":3.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145264923","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 : 2025-10-06DOI: 10.1016/j.bmc.2025.118433
Shu-Mei Pan , Wen-Cai Liu , Chun-Yu Xing , Xin-Yue Pu , Qian-Qian Wang , Xuan Zhao , Qi-Chen Zhang , Dan-Dan Wang , Ya-di Zhu
Uridine-5′-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) is a key enzyme in the regulation of bilirubin metabolism and detoxification of a variety of internal and external substances, and its insufficient function can lead to hyperbilirubinemia and affect the metabolic clearance of drugs, food additives, and environmental toxicants. However, there is a lack of safe and effective UGT1A1 inducers in the clinic. This study presents Corylin, an efficient UGT1A1 inducer identified from a series of natural flavonoids and isoflavonoids. Notably, Corylin demonstrated potent induction of intracellular UGT1A1. Furthermore, nuclear receptor reporter gene assays revealed that Corylin dose-dependently activated PPARs and AhR nuclear receptors, with the most robust activation observed in the PPARβ/δ subtype. Animal experiments indicated that Corylin exhibited favorable safety profiles and significant hepatoprotective effects in mice with APAP-induced liver injury, accompanied by marked UGT1A1 expression. Collectively, this study suggests that Corylin is a potential UGT1A1 inducer and a promising candidate for the intervention of liver-related disorders.
{"title":"Corylin induces UGT1A1 via PPARs/AhR and exerts hepatoprotection in mice","authors":"Shu-Mei Pan , Wen-Cai Liu , Chun-Yu Xing , Xin-Yue Pu , Qian-Qian Wang , Xuan Zhao , Qi-Chen Zhang , Dan-Dan Wang , Ya-di Zhu","doi":"10.1016/j.bmc.2025.118433","DOIUrl":"10.1016/j.bmc.2025.118433","url":null,"abstract":"<div><div>Uridine-5′-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) is a key enzyme in the regulation of bilirubin metabolism and detoxification of a variety of internal and external substances, and its insufficient function can lead to hyperbilirubinemia and affect the metabolic clearance of drugs, food additives, and environmental toxicants. However, there is a lack of safe and effective UGT1A1 inducers in the clinic. This study presents Corylin, an efficient UGT1A1 inducer identified from a series of natural flavonoids and isoflavonoids. Notably, Corylin demonstrated potent induction of intracellular UGT1A1. Furthermore, nuclear receptor reporter gene assays revealed that Corylin dose-dependently activated PPARs and AhR nuclear receptors, with the most robust activation observed in the PPARβ/δ subtype. Animal experiments indicated that Corylin exhibited favorable safety profiles and significant hepatoprotective effects in mice with APAP-induced liver injury, accompanied by marked UGT1A1 expression. Collectively, this study suggests that Corylin is a potential UGT1A1 inducer and a promising candidate for the intervention of liver-related disorders.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118433"},"PeriodicalIF":3.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145256933","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 : 2025-10-05DOI: 10.1016/j.bmc.2025.118430
Zhiying Liu , Le Zhou , Shuangshuang Ma , Yaping Guo , Zhendan He , Jinhui Wang , Shuyun Wang , Dahong Yao , Yan Wu
Tenuistones A–H (1–8), eight undescribed flavonoid derivatives were isolated from the twigs and leaves of Miliusa tenuistipitata. Compound 1 is a flavonol-naphthoquinone hybrid contained a unique 2-isopentenyl-2-methoxyacetyl-6-methyl-1,4-naphthoquinone unit with new carbon skeleton. Compound 2 represent the first example of flavonol-homogentisic acid-monoterpene hybrid. Compounds 3–8 are six novel flavonol-sesquiterpene hybrids. Seven pairs of enantiomers [(+)/(−)-1–4, (+)/(−)-6–8] were further resolved by chiral HPLC resolution. Their structures were established by a combination analysis of the NMR and MS data, along with chemical calculations. A plausible biogenetic pathway of compound 1 was proposed. Enantiomer (−)-3 displays profound anti-proliferative and anti-migration activities against triple-negative breast cancer cells.
{"title":"Tenuistones A–H, novel flavonoid derivatives from Miliusa tenuistipitata with anti-proliferative and anti-migration activities against triple-negative breast cancer cells","authors":"Zhiying Liu , Le Zhou , Shuangshuang Ma , Yaping Guo , Zhendan He , Jinhui Wang , Shuyun Wang , Dahong Yao , Yan Wu","doi":"10.1016/j.bmc.2025.118430","DOIUrl":"10.1016/j.bmc.2025.118430","url":null,"abstract":"<div><div>Tenuistones A–H (<strong>1</strong>–<strong>8</strong>), eight undescribed flavonoid derivatives were isolated from the twigs and leaves of <em>Miliusa tenuistipitata</em>. Compound <strong>1</strong> is a flavonol-naphthoquinone hybrid contained a unique 2-isopentenyl-2-methoxyacetyl-6-methyl-1,4-naphthoquinone unit with new carbon skeleton. Compound <strong>2</strong> represent the first example of flavonol-homogentisic acid-monoterpene hybrid. Compounds <strong>3</strong>–<strong>8</strong> are six novel flavonol-sesquiterpene hybrids. Seven pairs of enantiomers [(+)/(−)-<strong>1</strong>–<strong>4</strong>, (+)/(−)-<strong>6</strong>–<strong>8</strong>] were further resolved by chiral HPLC resolution. Their structures were established by a combination analysis of the NMR and MS data, along with chemical calculations. A plausible biogenetic pathway of compound <strong>1</strong> was proposed. Enantiomer (−)-<strong>3</strong> displays profound anti-proliferative and anti-migration activities against triple-negative breast cancer cells.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118430"},"PeriodicalIF":3.0,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145248986","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}
Encephalomyocarditis virus (EMCV) is an important pathogen; however, current prevention and treatment methods and drugs are limited. 18β-Glycyrrhetinic acid (GA) is widely used in traditional Chinese medicine as a key active ingredient in Glycyrrhiza glabra and has anti-inflammatory, antiviral, antioxidant, and hepatoprotective pharmacological effects. However, the bioavailability of GA is significantly reduced by its low water solubility and high toxicity. Amantadine (AM) is a versatile antiviral drug. We reduced the toxicity and increased the bioavailability of GA by introducing AM into the GA backbone, and further explored its antiviral mechanism. The chemical structures of the new 18β-glycyrrhetinic acid derivative grafted with amantadine (GA-AM) were confirmed by IR, 1HNMR and ESI-MS. The cytotoxicity of GA-AM in BHK-21 and HEK-293 cells was determined using the CCK-8 assay. The antiviral effect and mechanism of action of the EMCV virus of GA-AM were detected in vitro and in vivo using TCID50, RT-qPCR, Western blotting, IFA, and ELISA. Compared to GA, GA-AM exhibited lower cytotoxicity in BHK-21 and HEK-293T cells and demonstrated more significant antiviral effects against EMCV. GA-AM can also protect EMCV-infected cells and reduce the amount of the VP1 capsid protein in cells. Mechanistic investigations revealed that GA-AM might exert antiviral effects by regulating the NF-κB signaling pathway and modulating downstream cytokines, including TNF-α and IL-6. Furthermore, GA-AM alleviated these signs in EMCV-infected mice. The novel drug GA-AM has lower cytotoxicity and more significant antiviral effects. It may therefore serve as a new, low-toxicity antiviral agent.
{"title":"18β-glycyrrhetinic acid-amantadine hybrid: Synthesis and anti-EMCV activity via NF-κB modulation","authors":"Weijiao Xue , Tengyu Zhang , Yanqiao Wen , Yan Zhang , Jixia Hou , Jieying Zhao , Ruofei Feng , Chunxia Tan","doi":"10.1016/j.bmc.2025.118431","DOIUrl":"10.1016/j.bmc.2025.118431","url":null,"abstract":"<div><div>Encephalomyocarditis virus (EMCV) is an important pathogen; however, current prevention and treatment methods and drugs are limited. 18β-Glycyrrhetinic acid (GA) is widely used in traditional Chinese medicine as a key active ingredient in <em>Glycyrrhiza glabra</em> and has anti-inflammatory, antiviral, antioxidant, and hepatoprotective pharmacological effects. However, the bioavailability of GA is significantly reduced by its low water solubility and high toxicity. Amantadine (AM) is a versatile antiviral drug. We reduced the toxicity and increased the bioavailability of GA by introducing AM into the GA backbone, and further explored its antiviral mechanism. The chemical structures of the new 18β-glycyrrhetinic acid derivative grafted with amantadine (GA-AM) were confirmed by IR, <sup>1</sup>HNMR and ESI-MS. The cytotoxicity of GA-AM in BHK-21 and HEK-293 cells was determined using the CCK-8 assay. The antiviral effect and mechanism of action of the EMCV virus of GA-AM were detected in vitro and in vivo using TCID<sub>50</sub>, RT-qPCR, Western blotting, IFA, and ELISA. Compared to GA, GA-AM exhibited lower cytotoxicity in BHK-21 and HEK-293T cells and demonstrated more significant antiviral effects against EMCV. GA-AM can also protect EMCV-infected cells and reduce the amount of the VP1 capsid protein in cells. Mechanistic investigations revealed that GA-AM might exert antiviral effects by regulating the NF-κB signaling pathway and modulating downstream cytokines, including TNF-α and IL-6. Furthermore, GA-AM alleviated these signs in EMCV-infected mice. The novel drug GA-AM has lower cytotoxicity and more significant antiviral effects. It may therefore serve as a new, low-toxicity antiviral agent.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118431"},"PeriodicalIF":3.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145256937","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 : 2025-10-01DOI: 10.1016/j.bmc.2025.118428
Wenjun Li , Junlong Chen , Yunyan Liu , Qizhi Chen , Yanjin Li , Fangzhou Linli , Sisi Feng , Xianggui Chen
The overuse of antibiotics has highlighted the antimicrobial peptides (AMPs) as critical agents against pathogenic bacteria. However, natural AMPs like anoplin face significant limitations, including instability and suboptimal antimicrobial efficacy. Although previous studies have demonstrated the crucial role of stable secondary structures in enhancing antimicrobial activity, concerns have arisen regarding the increased hemolytic toxicity associated with hydrophobic side chains introduced by the RCM stapling strategy. To address this challenge, we propose a sulfonium-stabilized cyclization strategy that stabilizes peptide conformation through covalent cyclization and enhances cationic charge density via sulfur-based positive charges. Notably, the improved cationic charge could help to increase the peptide's antimicrobial activity while avoiding the enhancement of hemolytic toxicity. Experimental validation revealed that sulfonium-stabilized anoplin cyclic peptides (AP[5,9]-Ph) exhibited potent antibacterial activity, extended proteolytic stability, and preserved biocompatibility. Murine wound infection models demonstrated accelerated healing rates and reduced bacterial loads in treated groups. These findings suggest that sulfonium-stabilized anoplin cyclic peptides are promising candidates for novel antimicrobial agents. Moreover, the sulfonium-stabilized stapling strategy holds potential as a powerful approach for optimizing the bioactivity of natural antimicrobial peptides like anoplin, advancing the development of new antimicrobial agents.
{"title":"Sulfonium-stabilized anoplin cyclic peptides with enhanced electro-positivity for effective antimicrobial activity, stability, and biocompatibility","authors":"Wenjun Li , Junlong Chen , Yunyan Liu , Qizhi Chen , Yanjin Li , Fangzhou Linli , Sisi Feng , Xianggui Chen","doi":"10.1016/j.bmc.2025.118428","DOIUrl":"10.1016/j.bmc.2025.118428","url":null,"abstract":"<div><div>The overuse of antibiotics has highlighted the antimicrobial peptides (AMPs) as critical agents against pathogenic bacteria. However, natural AMPs like anoplin face significant limitations, including instability and suboptimal antimicrobial efficacy. Although previous studies have demonstrated the crucial role of stable secondary structures in enhancing antimicrobial activity, concerns have arisen regarding the increased hemolytic toxicity associated with hydrophobic side chains introduced by the RCM stapling strategy. To address this challenge, we propose a sulfonium-stabilized cyclization strategy that stabilizes peptide conformation through covalent cyclization and enhances cationic charge density via sulfur-based positive charges. Notably, the improved cationic charge could help to increase the peptide's antimicrobial activity while avoiding the enhancement of hemolytic toxicity. Experimental validation revealed that sulfonium-stabilized anoplin cyclic peptides (AP[5,9]-Ph) exhibited potent antibacterial activity, extended proteolytic stability, and preserved biocompatibility. Murine wound infection models demonstrated accelerated healing rates and reduced bacterial loads in treated groups. These findings suggest that sulfonium-stabilized anoplin cyclic peptides are promising candidates for novel antimicrobial agents. Moreover, the sulfonium-stabilized stapling strategy holds potential as a powerful approach for optimizing the bioactivity of natural antimicrobial peptides like anoplin, advancing the development of new antimicrobial agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118428"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360024","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号