Pub Date : 2025-02-20DOI: 10.1016/j.ejmech.2025.117421
Yuexiu Liang , Wenxian Lin , Yuzhen Chen , Weijie Yang , Xiaoyu Zhou , Shishen Ai , Liqin Qiu , Rihui Cao , Junli Wang
A series of novel bivalent quinolines with a spacer of four to six methylene units between the phenoxy group in the position-7 and various substituents in the position-4 of quinoline skeleton, respectively, were synthesized and evaluated as anticancer agents. The data showed that the majority of the compounds had significant antiproliferative activity with IC50 values less than 50 μM against human cancer cell lines. Among them, compound 4b exhibited the strongest antiproliferative activity against HCT116, A549, BGC823, HeLa and MCF-7 cell lines with an IC50 values of 0.26, 2.75, 4.06, 3.71 and 3.08 μM, respectively. Further studies on the anticancer effects in mice of compound 4b showed its capacity to inhibit tumor growth and markedly reduce tumor size of cervical cancer. Moreover investigation on the underlying mechanism of action indicated that compound 4b didn't trigger apoptotic processes in cervical cancer cell lines, but inhibit cervical cancer growth through inducing autophagy via the ATG5/ATG7 pathway.
{"title":"Synthesis and in vitro and in vivo evaluation of novel bivalent quinolines as antitumor agents via targeting autophagy in cervical cancer","authors":"Yuexiu Liang , Wenxian Lin , Yuzhen Chen , Weijie Yang , Xiaoyu Zhou , Shishen Ai , Liqin Qiu , Rihui Cao , Junli Wang","doi":"10.1016/j.ejmech.2025.117421","DOIUrl":"10.1016/j.ejmech.2025.117421","url":null,"abstract":"<div><div>A series of novel bivalent quinolines with a spacer of four to six methylene units between the phenoxy group in the position-7 and various substituents in the position-4 of quinoline skeleton, respectively, were synthesized and evaluated as anticancer agents. The data showed that the majority of the compounds had significant antiproliferative activity with IC<sub>50</sub> values less than 50 μM against human cancer cell lines. Among them, compound <strong>4b</strong> exhibited the strongest antiproliferative activity against HCT116, A549, BGC823, HeLa and MCF-7 cell lines with an IC<sub>50</sub> values of 0.26, 2.75, 4.06, 3.71 and 3.08 μM, respectively. Further studies on the anticancer effects in mice of compound <strong>4b</strong> showed its capacity to inhibit tumor growth and markedly reduce tumor size of cervical cancer. Moreover investigation on the underlying mechanism of action indicated that compound <strong>4b</strong> didn't trigger apoptotic processes in cervical cancer cell lines, but inhibit cervical cancer growth through inducing autophagy <em>via</em> the ATG5/ATG7 pathway.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117421"},"PeriodicalIF":6.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-20DOI: 10.1016/j.ejmech.2025.117428
Zhiyuan Geng , Yingjie Wang , Mingyu Ma, Yan Wei, Wenbin Xie, Jie Cheng, Yutong Chen, Xianhe Fang, Hongbo Wang, Yi Bi
Multidrug Resistance (MDR) is an essential cause of failure of tumor chemotherapy, and P-glycoprotein (P-gp) overexpression is one of the major causes of MDR in tumor cells. Hederagenin (HRG) derivatives showed significant inhibitory effects in P-gp-mediated tumor MDR. Herein, we designed and synthesized 30 HRG derivatives and evaluated these compounds' tumor MDR reversal ability. For the first time, we identified a potential P-gp non-substrate inhibitor of the HRG derivatives 15, which binds to non-substrate active sites in transmembrane structural domains (TMDs) with high binding affinity. Subsequent assays confirmed that 15 exerted significant tumor MDR reversal activity by binding to P-gp and inhibiting P-gp function rather than affecting its expression. It could not be pumped out of the cell by P-gp. In addition, 15 inhibited Rhodamine123 efflux, rendered the KBV cells sensitive to paclitaxel (Ptx), blocked the cells in the G2/M phase, and induced apoptosis. Notably, 15 increased Ptx sensitivity in vivo, significantly inhibited the growth of KBV cell-derived xenograft tumors in nude mice, with a tumor suppression rate as high as 63.71 %.
{"title":"Discovery and biological evaluation of hederagenin derivatives as non-substrate inhibitors of P-glycoprotein-mediated multidrug resistance","authors":"Zhiyuan Geng , Yingjie Wang , Mingyu Ma, Yan Wei, Wenbin Xie, Jie Cheng, Yutong Chen, Xianhe Fang, Hongbo Wang, Yi Bi","doi":"10.1016/j.ejmech.2025.117428","DOIUrl":"10.1016/j.ejmech.2025.117428","url":null,"abstract":"<div><div>Multidrug Resistance (MDR) is an essential cause of failure of tumor chemotherapy, and P-glycoprotein (P-gp) overexpression is one of the major causes of MDR in tumor cells. Hederagenin (<strong>HRG</strong>) derivatives showed significant inhibitory effects in P-gp-mediated tumor MDR. Herein, we designed and synthesized 30 <strong>HRG</strong> derivatives and evaluated these compounds' tumor MDR reversal ability. For the first time, we identified a potential P-gp non-substrate inhibitor of the <strong>HRG</strong> derivatives <strong>15</strong>, which binds to non-substrate active sites in transmembrane structural domains (TMDs) with high binding affinity. Subsequent assays confirmed that <strong>15</strong> exerted significant tumor MDR reversal activity by binding to P-gp and inhibiting P-gp function rather than affecting its expression. It could not be pumped out of the cell by P-gp. In addition, <strong>15</strong> inhibited Rhodamine123 efflux, rendered the KBV cells sensitive to paclitaxel (Ptx), blocked the cells in the G<sub>2</sub>/M phase, and induced apoptosis. Notably, <strong>15</strong> increased Ptx sensitivity <em>in vivo</em>, significantly inhibited the growth of KBV cell-derived xenograft tumors in nude mice, with a tumor suppression rate as high as 63.71 %.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117428"},"PeriodicalIF":6.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-20DOI: 10.1016/j.ejmech.2025.117422
Jianyuan Zhao , Guoning Zhang , YaSheng Li , Ling Ma , Dongrong Yi , Quanjie Li , Yu Shi , Saisai Guo , Tianfu Liu , Yujia Wang , Xiaoyu Li , Yucheng Wang , Wenjie Tan , Jiabin Li , Shan Cen
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen of coronavirus disease (COVID-19) causing a pandemic with growing global transmission. The viral RNA-dependent RNA polymerase (RdRp) is conserved especially for variants of concern (VOCs), making it as an effective antivirals target. Due to the proofreading activity of coronavirus nsp14/nsp10, limited the efficacy of nucleoside analogs in vivo. Herein, we identified that Phenazopyridine hydrochloride (PAP) inhibits SARS-CoV-2 with EC50 of 5.37 μmol/L. Furthermore, PAP can effectively inhibit SARS-CoV-2 RdRp with EC50 value of 7.37 μmol/L, after further optimization, compound PAP-22 exhibits the most potential inhibition, with EC50 of 1.11 μmol/L. PAP and its derivatives can bind directly to SARS-CoV-2 RdRp, fully resistance to the exoribonuclease (ExoN) and exhibit broad spectrum anti-CoV activities. Combined with the current data available on the safe and pharmacokinetics of PAP as an approved drug in clinical use, these results provide a path for the urgently needed antivirals to combat SARS-CoV-2.
{"title":"Discovery and optimization of phenazopyridine hydrochloride as novel SARS-CoV-2 RdRp inhibitors","authors":"Jianyuan Zhao , Guoning Zhang , YaSheng Li , Ling Ma , Dongrong Yi , Quanjie Li , Yu Shi , Saisai Guo , Tianfu Liu , Yujia Wang , Xiaoyu Li , Yucheng Wang , Wenjie Tan , Jiabin Li , Shan Cen","doi":"10.1016/j.ejmech.2025.117422","DOIUrl":"10.1016/j.ejmech.2025.117422","url":null,"abstract":"<div><div>The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen of coronavirus disease (COVID-19) causing a pandemic with growing global transmission. The viral RNA-dependent RNA polymerase (RdRp) is conserved especially for variants of concern (VOCs), making it as an effective antivirals target. Due to the proofreading activity of coronavirus nsp14/nsp10, limited the efficacy of nucleoside analogs in vivo. Herein, we identified that Phenazopyridine hydrochloride (PAP) inhibits SARS-CoV-2 with EC<sub>50</sub> of 5.37 μmol/L. Furthermore, PAP can effectively inhibit SARS-CoV-2 RdRp with EC<sub>50</sub> value of 7.37 μmol/L, after further optimization, compound PAP-22 exhibits the most potential inhibition, with EC<sub>50</sub> of 1.11 μmol/L. PAP and its derivatives can bind directly to SARS-CoV-2 RdRp, fully resistance to the exoribonuclease (ExoN) and exhibit broad spectrum anti-CoV activities. Combined with the current data available on the safe and pharmacokinetics of PAP as an approved drug in clinical use, these results provide a path for the urgently needed antivirals to combat SARS-CoV-2.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117422"},"PeriodicalIF":6.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 10.1016/j.ejmech.2025.117410
Danni Rao , Yiting Wang , Xiaolong Yang , Zhiwen Chen , Feifei Wu , Ran Ren , Yaoliang Sun , Yuanhui Lai , Lijie Peng , Lei Yu , Zhang Zhang , Shilin Xu
Targeting histone lysine demethylase 4 (KDM4) has emerged as a promising approach for cancer therapy. Despite significant progress in developing KDM4 inhibitors, many of these compounds demonstrate poor selectivity or limited cellular efficacy, and none have received approval for marketing. In this study, we designed and synthesized a series of novel KDM4-targeted proteolysis targeting chimeras (PROTAC) degraders, as exemplified by compound 11 (RDN8011). RDN8011 effectively degrades KDM4A-C while sparing KDM4D, and displays potent antiproliferative activity in esophageal cancer cells. Furthermore, this compound inhibits histone H3 lysine demethylation and induces cell cycle arrest and apoptosis. Collectively, this study provides a valuable chemical tool for exploring the functions of KDM4, and presents a novel effective strategy for targeting KDM4 in cancer treatment.
{"title":"Discovery of a first-in-class PROTAC degrader of histone lysine demethylase KDM4","authors":"Danni Rao , Yiting Wang , Xiaolong Yang , Zhiwen Chen , Feifei Wu , Ran Ren , Yaoliang Sun , Yuanhui Lai , Lijie Peng , Lei Yu , Zhang Zhang , Shilin Xu","doi":"10.1016/j.ejmech.2025.117410","DOIUrl":"10.1016/j.ejmech.2025.117410","url":null,"abstract":"<div><div>Targeting histone lysine demethylase 4 (KDM4) has emerged as a promising approach for cancer therapy. Despite significant progress in developing KDM4 inhibitors, many of these compounds demonstrate poor selectivity or limited cellular efficacy, and none have received approval for marketing. In this study, we designed and synthesized a series of novel KDM4-targeted proteolysis targeting chimeras (PROTAC) degraders, as exemplified by compound <strong>11</strong> (RDN8011). RDN8011 effectively degrades KDM4A-C while sparing KDM4D, and displays potent antiproliferative activity in esophageal cancer cells. Furthermore, this compound inhibits histone H3 lysine demethylation and induces cell cycle arrest and apoptosis. Collectively, this study provides a valuable chemical tool for exploring the functions of KDM4, and presents a novel effective strategy for targeting KDM4 in cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117410"},"PeriodicalIF":6.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143444341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 10.1016/j.ejmech.2025.117423
Azzurra Stefanucci , Federica Santoro , Sara D'Ingiullo , Lorenza Marinaccio , Eleonora Procino , Soraya Learte-Aymamí , Jessica Rodriguez , José Luis Mascareñas , Jussara Amato , Valentina Arciuolo , Antonio Randazzo , Martina De Rosa , Diego Brancaccio , Adriano Mollica , Alfonso Carotenuto
In general, biological macromolecules such as proteins interact with the major groove of the ds-DNA via hydrogen bonds formation, thus blocking the site access of TFs to specific DNA sequences. Considering that the primary sequence of arc repressor responsible for DNA binding is well-characterized as well as the 3D-conformational requisites for its optimal interactions with the specific DNA base-pairs, a series of well-tailored arc analogues could be designed using computational molecular tools and available structural data. These novel molecular entities have been synthesized following ultrasound assisted-solid phase peptide synthesis (US-SPPS), characterized by NMR experiments and screened for TAGA box selectivity on DNA oligomers using a battery of DNA displacement assays. Data obtained show a clear tendency of peptide ACAS_4 to assume a 3-D β-sheet like structure responsible of the interaction with DNA major groove and to bind selectively to the consensus sequence of DNA. For the best of our knowledge this is the first report on a β-sheet arc mimetic endowed with topological and sequence selectivity for the TAGA box of DNA.
{"title":"Development of linear β-turn inducers containing peptides as arc mimetics with DNA topological and sequence selectivity","authors":"Azzurra Stefanucci , Federica Santoro , Sara D'Ingiullo , Lorenza Marinaccio , Eleonora Procino , Soraya Learte-Aymamí , Jessica Rodriguez , José Luis Mascareñas , Jussara Amato , Valentina Arciuolo , Antonio Randazzo , Martina De Rosa , Diego Brancaccio , Adriano Mollica , Alfonso Carotenuto","doi":"10.1016/j.ejmech.2025.117423","DOIUrl":"10.1016/j.ejmech.2025.117423","url":null,"abstract":"<div><div>In general, biological macromolecules such as proteins interact with the major groove of the ds-DNA via hydrogen bonds formation, thus blocking the site access of TFs to specific DNA sequences. Considering that the primary sequence of arc repressor responsible for DNA binding is well-characterized as well as the 3D-conformational requisites for its optimal interactions with the specific DNA base-pairs, a series of well-tailored arc analogues could be designed using computational molecular tools and available structural data. These novel molecular entities have been synthesized following ultrasound assisted-solid phase peptide synthesis (US-SPPS), characterized by NMR experiments and screened for TAGA box selectivity on DNA oligomers using a battery of DNA displacement assays. Data obtained show a clear tendency of peptide <strong>ACAS_4</strong> to assume a 3-D β-sheet like structure responsible of the interaction with DNA major groove and to bind selectively to the consensus sequence of DNA. For the best of our knowledge this is the first report on a β-sheet arc mimetic endowed with topological and sequence selectivity for the TAGA box of DNA.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117423"},"PeriodicalIF":6.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18DOI: 10.1016/j.ejmech.2025.117399
Luca Pozzetti, Maja M. Pinhammer, Christopher R.M. Asquith
The Dimroth Rearrangement (DR) is an isomerization process involving the translocation of exo- and endocyclic nitrogen atoms in heterocyclic systems via a ring opening, rotation, and ring closure mechanism. Originally discovered over 120 years ago, the mechanistic occurrence of the DR on multiple heterocycles has been widely studied, and its application to the synthesis of biologically active compounds is well documented, albeit on some occasions not directly referenced. A surprisingly high number of drug discovery programs take advantage of the DR for the synthesis of heterocycle-containing compounds, including 4-aminopyrimidines and 4-anilinoquinazolines. Evidence of the flexibility and valuable potential of the DR can be found in the use of this reaction in the manufacture processes of several active pharmaceutical ingredients (APIs) on a commercial scale, allowing a reduction in the manufacturing costs and the environmental burden of the synthetic routes. The aim of this review is to outline the generality and broad applicability of the DR to the synthesis of biologically active compounds and highlight the opportunities to utilize this tool more widely within the medicinal chemistry toolbox.
{"title":"Medicinal chemistry applications of the Dimroth Rearrangement to the synthesis of biologically active compounds","authors":"Luca Pozzetti, Maja M. Pinhammer, Christopher R.M. Asquith","doi":"10.1016/j.ejmech.2025.117399","DOIUrl":"10.1016/j.ejmech.2025.117399","url":null,"abstract":"<div><div>The Dimroth Rearrangement (DR) is an isomerization process involving the translocation of exo- and endocyclic nitrogen atoms in heterocyclic systems <em>via</em> a ring opening, rotation, and ring closure mechanism. Originally discovered over 120 years ago, the mechanistic occurrence of the DR on multiple heterocycles has been widely studied, and its application to the synthesis of biologically active compounds is well documented, albeit on some occasions not directly referenced. A surprisingly high number of drug discovery programs take advantage of the DR for the synthesis of heterocycle-containing compounds, including 4-aminopyrimidines and 4-anilinoquinazolines. Evidence of the flexibility and valuable potential of the DR can be found in the use of this reaction in the manufacture processes of several active pharmaceutical ingredients (APIs) on a commercial scale, allowing a reduction in the manufacturing costs and the environmental burden of the synthetic routes. The aim of this review is to outline the generality and broad applicability of the DR to the synthesis of biologically active compounds and highlight the opportunities to utilize this tool more widely within the medicinal chemistry toolbox.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117399"},"PeriodicalIF":6.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18DOI: 10.1016/j.ejmech.2025.117387
Qionglu Duan , Min Yuan , Xican Ma , Yifan Zheng , Runze Meng , Wenjing Shi , Yanan Ni , Chen Zhao , Yonghua Liu , Zhihui Yu , Jingyang Zhu , Yulong Shi , Xi Zhu , Li Li , Shuyi Si , Yan Li , Yinghong Li , Danqing Song
The prevalence of MDR Gram-negative bacteria has posed a great impetus for the discovery of new therapeutic approaches. Here, we synthesized a series of pyrylium derivatives as antibiotic adjuvants based on IMB-0042, and evaluated their activities against Acinetobacter baumannii (A. baumannii) and Escherichia coli (E. coli). Compound 4a significantly synergized polymyxin B in combating A. baumannii and E. coli both in vitro and on the infected Galleria mellonella models. Furthermore, we identified 4a to be an effective perturbant of the Gram-negative outer membrane (OM) through the blockage on LptA/LptC interaction via targeting Met47 in LptA. And cationic pyrylium reduced the OM densification by electrostatic interaction with anion-rich lipopolysaccharide (LPS). Thus, pyrylium derivatives constitute a new class of multi-target OM permeabilizers, which can significantly potentiate antibiotics against MDR Gram-negative bacteria.
{"title":"Pyrylium derivatives as outer membrane permeabilizers against MDR gram-negative bacteria via multi-target mode of action","authors":"Qionglu Duan , Min Yuan , Xican Ma , Yifan Zheng , Runze Meng , Wenjing Shi , Yanan Ni , Chen Zhao , Yonghua Liu , Zhihui Yu , Jingyang Zhu , Yulong Shi , Xi Zhu , Li Li , Shuyi Si , Yan Li , Yinghong Li , Danqing Song","doi":"10.1016/j.ejmech.2025.117387","DOIUrl":"10.1016/j.ejmech.2025.117387","url":null,"abstract":"<div><div>The prevalence of MDR Gram-negative bacteria has posed a great impetus for the discovery of new therapeutic approaches. Here, we synthesized a series of pyrylium derivatives as antibiotic adjuvants based on IMB-0042, and evaluated their activities against <em>Acinetobacter baumannii</em> (<em>A</em>. <em>baumannii</em>) and <em>Escherichia coli</em> (<em>E. coli</em>). Compound <strong>4a</strong> significantly synergized polymyxin B in combating <em>A. baumannii</em> and <em>E</em>. <em>coli</em> both <em>in vitro</em> and on the infected <em>Galleria mellonella</em> models. Furthermore, we identified <strong>4a</strong> to be an effective perturbant of the Gram-negative outer membrane (OM) through the blockage on LptA/LptC interaction via targeting Met47 in LptA. And cationic pyrylium reduced the OM densification by electrostatic interaction with anion-rich lipopolysaccharide (LPS). Thus, pyrylium derivatives constitute a new class of multi-target OM permeabilizers, which can significantly potentiate antibiotics against MDR Gram-negative bacteria.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117387"},"PeriodicalIF":6.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18DOI: 10.1016/j.ejmech.2025.117402
Gianluigi Lauro , Michela Aliberti , Mauro De Nisco , Silvana Pedatella , Giacomo Pepe , Manuela Giovanna Basilicata , Maria Giovanna Chini , Katrin Fischer , Robert K. Hofstetter , Oliver Werz , Maria Grazia Ferraro , Marialuisa Piccolo , Carlo Irace , Anella Saviano , Pietro Campiglia , Alessia Bertamino , Carmine Ostacolo , Tania Ciaglia , Michele Manfra , Giuseppe Bifulco
We report the identification of a new set of compounds based on the furazanopyrazine core interfering with eicosanoid biosynthesis and acting as potentially effective anti-inflammatory and anticancer agents. Based on our previous promising results on a set of furazanopyrazine-based compounds against the microsomal prostaglandin E2 synthase-1 (mPGES-1) enzyme, we here identified derivatives with improved pharmacokinetic properties by replacing the ester moiety with a more stable ether group.
A focused virtual library of 1 × 104 molecules was built and screened against mPGES-1 through molecular docking experiments, leading to the selection of 10 candidates for synthesis and biological evaluation. Several molecules were found to inhibit mPGES-1 and, among them, two items featured IC50 values in the low micromolar range. Additional computational studies on the collection of synthesized compounds demonstrated that compound 3b, previously emerged as an mPGES-1 inhibitor, interfered with soluble epoxide hydrolase (sEH) activity, thus emerging as a valuable dual mPGES-1/sEH inhibitor. The pharmacokinetic features of the most potent compounds were accurately estimated. Unfortunately, poor outcomes were obtained for 3b; on the other hand, compound 7e exhibited promising mPGES-1 inhibition and excellent pharmacokinetic profile, demonstrating that the novel furazanopyrazine-based items with ether moiety possess improved pharmacokinetic properties compared to the ester-based compounds reported in our previous study. Additionally, the anticancer properties of 7e and 7d, the latter emerged as the most active mPGES-1 inhibitor, were evaluated and both compounds showed promising activities against HCT-116 human colorectal cancer (CRC) cells.
These findings highlight the furazanopyrazine core as a promising scaffold for disclosing new anti-inflammatory drugs with the ability to inhibit targets belonging to arachidonic acid cascade.
{"title":"Furazanopyrazine-based novel promising anticancer agents interfering with the eicosanoid biosynthesis pathways by dual mPGES-1 and sEH inhibition","authors":"Gianluigi Lauro , Michela Aliberti , Mauro De Nisco , Silvana Pedatella , Giacomo Pepe , Manuela Giovanna Basilicata , Maria Giovanna Chini , Katrin Fischer , Robert K. Hofstetter , Oliver Werz , Maria Grazia Ferraro , Marialuisa Piccolo , Carlo Irace , Anella Saviano , Pietro Campiglia , Alessia Bertamino , Carmine Ostacolo , Tania Ciaglia , Michele Manfra , Giuseppe Bifulco","doi":"10.1016/j.ejmech.2025.117402","DOIUrl":"10.1016/j.ejmech.2025.117402","url":null,"abstract":"<div><div>We report the identification of a new set of compounds based on the furazanopyrazine core interfering with eicosanoid biosynthesis and acting as potentially effective anti-inflammatory and anticancer agents. Based on our previous promising results on a set of furazanopyrazine-based compounds against the microsomal prostaglandin E<sub>2</sub> synthase-1 (mPGES-1) enzyme, we here identified derivatives with improved pharmacokinetic properties by replacing the ester moiety with a more stable ether group.</div><div>A focused virtual library of 1 × 10<sup>4</sup> molecules was built and screened against mPGES-1 through molecular docking experiments, leading to the selection of 10 candidates for synthesis and biological evaluation. Several molecules were found to inhibit mPGES-1 and, among them, two items featured IC<sub>50</sub> values in the low micromolar range. Additional computational studies on the collection of synthesized compounds demonstrated that compound <strong>3b</strong>, previously emerged as an mPGES-1 inhibitor, interfered with soluble epoxide hydrolase (sEH) activity, thus emerging as a valuable dual mPGES-1/sEH inhibitor. The pharmacokinetic features of the most potent compounds were accurately estimated. Unfortunately, poor outcomes were obtained for <strong>3b</strong>; on the other hand, compound <strong>7e</strong> exhibited promising mPGES-1 inhibition and excellent pharmacokinetic profile, demonstrating that the novel furazanopyrazine-based items with ether moiety possess improved pharmacokinetic properties compared to the ester-based compounds reported in our previous study. Additionally, the anticancer properties of <strong>7e</strong> and <strong>7d</strong>, the latter emerged as the most active mPGES-1 inhibitor, were evaluated and both compounds showed promising activities against HCT-116 human colorectal cancer (CRC) cells.</div><div>These findings highlight the furazanopyrazine core as a promising scaffold for disclosing new anti-inflammatory drugs with the ability to inhibit targets belonging to arachidonic acid cascade.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117402"},"PeriodicalIF":6.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18DOI: 10.1016/j.ejmech.2025.117414
Qi Zhang, Wenbing Dai, Da-Le Guo, Hao Chen, Xilei Wang, Ruiran Xu, Juan Liu, Mei-Mei Li, Yun Deng
Isoquinolone represents a significant and promising molecular scaffold for drug development. As green chemistry advances, light-mediated C(sp3)-H bond oxidation has emerged as a pivotal tool for medicinal chemists in constructing isoquinolone framework and enabling late-stage functionalization. However, existing methods often rely on metal catalysts, hazardous peroxides, dye sensitizers, or high-temperature atmosphere, which pose environmental concerns. Inspired by “GreenMedChem”, we initially developed a light-air mediated C(sp3)-H bond oxidation strategy for isoquinolone framework constructing, which offers the benefits of straightforward operation, mild reaction conditions, atomic economy, and broad substrate scope. A total of 54 isoquinolones were obtained, achieving a yield of up to 97 % under ambient conditions, using air as the sole oxygen source, and the 2H NMR analysis further verified that water was the only byproduct. Subsequently, three pharmacological agents were prepared via the late-stage C–H bond oxidation strategy.
{"title":"GreenMedChem-inspired light-air mediated C(sp3)-H bond oxidation: A new tool for isoquinolone synthesis","authors":"Qi Zhang, Wenbing Dai, Da-Le Guo, Hao Chen, Xilei Wang, Ruiran Xu, Juan Liu, Mei-Mei Li, Yun Deng","doi":"10.1016/j.ejmech.2025.117414","DOIUrl":"10.1016/j.ejmech.2025.117414","url":null,"abstract":"<div><div>Isoquinolone represents a significant and promising molecular scaffold for drug development. As green chemistry advances, light-mediated C(<em>sp</em><sup>3</sup>)-H bond oxidation has emerged as a pivotal tool for medicinal chemists in constructing isoquinolone framework and enabling late-stage functionalization. However, existing methods often rely on metal catalysts, hazardous peroxides, dye sensitizers, or high-temperature atmosphere, which pose environmental concerns. Inspired by “GreenMedChem”, we initially developed a light-air mediated C(<em>sp</em><sup>3</sup>)-H bond oxidation strategy for isoquinolone framework constructing, which offers the benefits of straightforward operation, mild reaction conditions, atomic economy, and broad substrate scope. A total of 54 isoquinolones were obtained, achieving a yield of up to 97 % under ambient conditions, using air as the sole oxygen source, and the <sup>2</sup>H NMR analysis further verified that water was the only byproduct. Subsequently, three pharmacological agents were prepared via the late-stage C–H bond oxidation strategy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117414"},"PeriodicalIF":6.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18DOI: 10.1016/j.ejmech.2025.117416
Jing Liang , Yang Liu , Qing Guan , Yan Li , Meng-Zhu Zheng , Xiao-Lian Zhang , Li-Xia Chen , Hua Li
Tuberculosis (TB) is one of the ten major factors threatening human life and health. At present, many factors limit the application of existing anti-tuberculosis drugs, such as a small range of available drug options, poor treatment compliance, and severe toxic and side effects. It is extremely urgent to develop novel anti-tuberculosis drugs. DprE1 is a potential anti-mycobacterial cell wall target, and some DprE1 inhibitors have entered the clinical research stage. Our research group found DprE1 inhibitor G50 with similar activity as isoniazid through virtual screening in the early stage. To obtain better DprE1 inhibitors, 45 new compounds were designed and synthesized based on the structure of G50. Among them, 12 selected DprE1 enzyme inhibitors could significantly inhibit the growth of Mycobacterium tuberculosis (M.tb) H37Ra and H37Rv growth in vitro. The MIC50 value of compound 42 against M.tb H37Ra is 1.071 ± 0.041 μM, with the selective index (SI) value of 186.74 (the SI value of linezolid is 119.9). Compared to G50, compound 42 exhibits a 5-fold increase in DprE1 enzyme inhibitory activity. In addition, the binding affinity of compound 42 is equivalent to that of G50. This study further enriches the examples of developing DprE1 inhibitors based on the backbone of pyrimidinetrione and also provides potential anti-tuberculosis lead compounds.
{"title":"Discovery of novel pyrimidinetrione derivatives as DprE1 inhibitors with potent antimycobacterial activities","authors":"Jing Liang , Yang Liu , Qing Guan , Yan Li , Meng-Zhu Zheng , Xiao-Lian Zhang , Li-Xia Chen , Hua Li","doi":"10.1016/j.ejmech.2025.117416","DOIUrl":"10.1016/j.ejmech.2025.117416","url":null,"abstract":"<div><div>Tuberculosis (TB) is one of the ten major factors threatening human life and health. At present, many factors limit the application of existing anti-tuberculosis drugs, such as a small range of available drug options, poor treatment compliance, and severe toxic and side effects. It is extremely urgent to develop novel anti-tuberculosis drugs. DprE1 is a potential anti-mycobacterial cell wall target, and some DprE1 inhibitors have entered the clinical research stage. Our research group found DprE1 inhibitor <strong>G50</strong> with similar activity as isoniazid through virtual screening in the early stage. To obtain better DprE1 inhibitors, 45 new compounds were designed and synthesized based on the structure of <strong>G50</strong>. Among them, 12 selected DprE1 enzyme inhibitors could significantly inhibit the growth of <em>Mycobacterium tuberculosis</em> (<em>M.tb</em>) H37Ra and H37Rv growth <em>in vitro</em>. The MIC<sub>50</sub> value of compound <strong>42</strong> against <em>M.tb</em> H37Ra is 1.071 ± 0.041 μM, with the selective index (SI) value of 186.74 (the SI value of linezolid is 119.9). Compared to <strong>G50</strong>, compound <strong>42</strong> exhibits a 5-fold increase in DprE1 enzyme inhibitory activity. In addition, the binding affinity of compound <strong>42</strong> is equivalent to that of <strong>G50</strong>. This study further enriches the examples of developing DprE1 inhibitors based on the backbone of pyrimidinetrione and also provides potential anti-tuberculosis lead compounds.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117416"},"PeriodicalIF":6.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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