Pub Date : 2025-01-27DOI: 10.1016/j.bmcl.2025.130113
Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar
Vancomycin intermediate-resistant Staphylococcus aureus (VISA) is a pathogen of concern. VraS, a histidine kinase, facilitates the VISA phenotype. Here, we reveal a benzoxazolyl urea (chemical 1) that directly inhibits VraS and enhances vancomycin to below the clinical breakpoint against an archetypal VISA strain, Mu50. 50 μM of 1 enhances vancomycin 16-fold to 0.25 μg/mL. The MIC of oxacillin is enhanced 32-fold to 8 μg/mL, only slightly above its clinical breakpoint. The chemical also showed promising enhancement of oxacillin against several MRSA strains. 1 shows ∼30 % inhibition of ATPase activity in VraS and reduces vra gene auto-upregulation typical upon vancomycin exposure. Therefore, 1 inhibits VraS to block normal vra operon function, leading to potent enhancement of cell wall-directed antibiotics. Interestingly, a molecular modeling approach suggests 1 does not displace ATP from the active site, but acts elsewhere. While VraS inhibitors have previously been reported to function against MRSA, to the best of our knowledge, this is the first direct VraS inhibitor ever reported that shows significant enhancement of vancomycin against VISA.
{"title":"A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus","authors":"Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar","doi":"10.1016/j.bmcl.2025.130113","DOIUrl":"10.1016/j.bmcl.2025.130113","url":null,"abstract":"<div><div>Vancomycin intermediate-resistant <em>Staphylococcus aureus</em> (VISA) is a pathogen of concern. VraS, a histidine kinase, facilitates the VISA phenotype. Here, we reveal a benzoxazolyl urea (chemical <strong><em>1</em></strong>) that directly inhibits VraS and enhances vancomycin to below the clinical breakpoint against an archetypal VISA strain, Mu50. 50 μM of <strong><em>1</em></strong> enhances vancomycin 16-fold to 0.25 μg/mL. The MIC of oxacillin is enhanced 32-fold to 8 μg/mL, only slightly above its clinical breakpoint. The chemical also showed promising enhancement of oxacillin against several MRSA strains. <strong><em>1</em></strong> shows ∼30 % inhibition of ATPase activity in VraS and reduces <em>vra</em> gene auto-upregulation typical upon vancomycin exposure. Therefore, <strong><em>1</em></strong> inhibits VraS to block normal <em>vra</em> operon function, leading to potent enhancement of cell wall-directed antibiotics. Interestingly, a molecular modeling approach suggests <strong><em>1</em></strong> does not displace ATP from the active site, but acts elsewhere. While VraS inhibitors have previously been reported to function against MRSA, to the best of our knowledge, this is the first direct VraS inhibitor ever reported that shows significant enhancement of vancomycin against VISA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130113"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.bmcl.2025.130110
Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan
Nucleoside analogs (NAs), as antiviral drugs, play a significant role in clinical medicine, constituting approximately 50 % of all antiviral therapies in current use. Nucleoside inhibitors function by mimicking the structure of natural nucleosides, integrating themselves into viral genetic material during replication, and subsequently inhibiting the virus’s ability to reproduce. They are used to treat a variety of viral infections, including herpes simplex, hepatitis B, and acquired immunodeficiency syndrome (AIDS). This review offers the development and mechanisms of atypical nucleoside antiviral agents that target novel sites on viral polymerase and other antiviral targets of nucleoside molecules, highlighting their significance in response to emerging viral threats like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
{"title":"Nucleoside antiviral agents with atypical structures and new targets","authors":"Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan","doi":"10.1016/j.bmcl.2025.130110","DOIUrl":"10.1016/j.bmcl.2025.130110","url":null,"abstract":"<div><div>Nucleoside analogs (NAs), as antiviral drugs, play a significant role in clinical medicine, constituting approximately 50 % of all antiviral therapies in current use. Nucleoside inhibitors function by mimicking the structure of natural nucleosides, integrating themselves into viral genetic material during replication, and subsequently inhibiting the virus’s ability to reproduce. They are used to treat a variety of viral infections, including herpes simplex, hepatitis B, and acquired immunodeficiency syndrome (AIDS). This review offers the development and mechanisms of atypical nucleoside antiviral agents that target novel sites on viral polymerase and other antiviral targets of nucleoside molecules, highlighting their significance in response to emerging viral threats like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130110"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.bmcl.2025.130112
Jaquelin Aroujo , Haleigh Parker , Angela Boari , Evan Mason , Mackenzie U. Otakpor , Tania Betancourt , Alexander Kornienko , Maria Letizia Ciavatta , Marianna Carbone , Antonio Evidente , Joseph H. Taube , Daniel Romo
To gain further insights into the importance of the unsaturated 1,4-ketoaldehyde moiety of ophiobolin A (OpA) for the potency and selectivity observed toward cancer stem cells, several derivatives were synthesized through controlled reduction and oxidations of the unsaturated aldehyde and ketone moieties. Structure elucidation of these new OpA derivatives was achieved through detailed NMR studies and comparison to OpA and known isolated congeners possessing variations in these regions. The relative stereochemistry of the newly generated stereocenters was determined by coupling constants in conjunction with conformational analyses (DFT) of the synthetic derivatives. The cytotoxicity of these derivatives was studied against breast cancer and glioblastoma cell lines possessing stem-cell like properties. In addition, the comparative activity toward HMLE and HMLE-TWIST mammary epithelial cells was studied, with the latter cell line representing an epithelial mesenchymal transition positive (EMT+) cell line.
{"title":"Derivatization of ophiobolin A and cytotoxicity toward breast and glioblastoma cancer stem cells: Varying the ketone and unsaturated aldehyde moieties","authors":"Jaquelin Aroujo , Haleigh Parker , Angela Boari , Evan Mason , Mackenzie U. Otakpor , Tania Betancourt , Alexander Kornienko , Maria Letizia Ciavatta , Marianna Carbone , Antonio Evidente , Joseph H. Taube , Daniel Romo","doi":"10.1016/j.bmcl.2025.130112","DOIUrl":"10.1016/j.bmcl.2025.130112","url":null,"abstract":"<div><div>To gain further insights into the importance of the unsaturated 1,4-ketoaldehyde moiety of ophiobolin A (OpA) for the potency and selectivity observed toward cancer stem cells, several derivatives were synthesized through controlled reduction and oxidations of the unsaturated aldehyde and ketone moieties. Structure elucidation of these new OpA derivatives was achieved through detailed NMR studies and comparison to OpA and known isolated congeners possessing variations in these regions. The relative stereochemistry of the newly generated stereocenters was determined by coupling constants in conjunction with conformational analyses (DFT) of the synthetic derivatives. The cytotoxicity of these derivatives was studied against breast cancer and glioblastoma cell lines possessing stem-cell like properties. In addition, the comparative activity toward HMLE and HMLE-TWIST mammary epithelial cells was studied, with the latter cell line representing an epithelial mesenchymal transition positive (EMT<sup>+</sup>) cell line.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130112"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1016/j.bmcl.2025.130111
Thomas O. Schrader , Kym I. Lorrain , Matthew R. Nelli , Yu Xue , Yong Chen , Alexander Broadhead , Christopher Baccei , Austin Chen
Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus β-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure–activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound 39, a potent activator of G-protein signaling (GTPγS EC50 = 14 nM, 83 % Emax) that did not elicit a β-arrestin-2 recruitment functional response (Emax < 10 %). Compound 39 demonstrated moderate to high intrinsic clearance in human hepatocytes and low potential for Pgp-mediated efflux when evaluated in the MDR1-MDCK permeability assay. Compound 39 exhibited 60- and 810-fold selectivities versus the related mu (MOR) and delta (DOR) opioid receptors in recombinant radioligand binding (Ki) assays. These findings highlight compound 39 and related structures as potential leads toward safe and tolerable therapeutics that target central nervous system (CNS) disorders for which KOR agonism could provide benefit.
{"title":"Novel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor","authors":"Thomas O. Schrader , Kym I. Lorrain , Matthew R. Nelli , Yu Xue , Yong Chen , Alexander Broadhead , Christopher Baccei , Austin Chen","doi":"10.1016/j.bmcl.2025.130111","DOIUrl":"10.1016/j.bmcl.2025.130111","url":null,"abstract":"<div><div>Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus <em>β</em>-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure–activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound <strong>39</strong>, a potent activator of G-protein signaling (GTPγS EC<sub>50</sub> = 14 nM, 83 % <em>E</em><sub>max</sub>) that did not elicit a <em>β</em>-arrestin-2 recruitment functional response (<em>E</em><sub>max</sub> < 10 %). Compound <strong>39</strong> demonstrated moderate to high intrinsic clearance in human hepatocytes and low potential for Pgp-mediated efflux when evaluated in the MDR1-MDCK permeability assay. Compound <strong>39</strong> exhibited 60- and 810-fold selectivities versus the related mu (MOR) and delta (DOR) opioid receptors in recombinant radioligand binding (<em>K</em><sub>i</sub>) assays. These findings highlight compound <strong>39</strong> and related structures as potential leads toward safe and tolerable therapeutics that target central nervous system (CNS) disorders for which KOR agonism could provide benefit.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130111"},"PeriodicalIF":2.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.bmcl.2025.130108
Gabrielle Martinez, Kirsten Tolentino, Paridhi Sukheja, Jasmine Webb, Case W. McNamara, Arnab K. Chatterjee, Baiyuan Yang
Screening of the ChemDiv molecular library in cholesterol media against Mycobacterium tuberculosis (Mtb) H37Rv strain identified a novel isoxazole thiophene hit as a putative Rv1625c/Cya activator with a promising in vitro activity and good pharmacokinetic properties. Twenty-nine analogs were synthesized to assess the structure–activity relationships (SAR) to further improve potency. The most notable analog was P15, which showed an intramacrophage EC50 = 1.96 µM and exhibited 58.0 % oral bioavailability when it was dosed orally at 20 mg/kg in a mouse pharmacokinetic (PK) study. The overall medicinal chemistry campaign revealed limited SAR that did not support further investigation into this series.
{"title":"Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis","authors":"Gabrielle Martinez, Kirsten Tolentino, Paridhi Sukheja, Jasmine Webb, Case W. McNamara, Arnab K. Chatterjee, Baiyuan Yang","doi":"10.1016/j.bmcl.2025.130108","DOIUrl":"10.1016/j.bmcl.2025.130108","url":null,"abstract":"<div><div>Screening of the ChemDiv molecular library in cholesterol media against <em>Mycobacterium tuberculosis</em> (Mtb) H37Rv strain identified a novel isoxazole thiophene hit as a putative Rv1625c/Cya activator with a promising <em>in vitro</em> activity and good pharmacokinetic properties. Twenty-nine analogs were synthesized to assess the structure–activity relationships (SAR) to further improve potency. The most notable analog was P15, which showed an intramacrophage EC<sub>50</sub> = 1.96 µM and exhibited 58.0 % oral bioavailability when it was dosed orally at 20 mg/kg in a mouse pharmacokinetic (PK) study. The overall medicinal chemistry campaign revealed limited SAR that did not support further investigation into this series.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130108"},"PeriodicalIF":2.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We describe here the design, synthesis, and X-ray structural studies of a new class of HIV-1 protease inhibitors containing 8-oxabicyclo[3.2.1]octanol-derived P2 ligands. We investigated the functional effect of these stereochemically defined fused-poly cyclic ligands on enzyme inhibition and antiviral activity in MT-2 cells. The tricyclic core of 8-oxabicyclo[3.2.1]octan-6-ol is designed to interact with the residues in the S2 subsite of HIV-1 protease. The syntheses of the ligands were carried out using the [5+2]-cycloaddition as the key step. Several inhibitors exhibited potent enzyme inhibitory activity. High resolution room-temperature X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important molecular insights for further design and optimization of inhibitor potency.
{"title":"Potent HIV‑1 protease inhibitors containing oxabicyclo octanol-derived P2-ligands: Design, synthesis, and X‑ray structural studies of inhibitor-HIV-1 protease complexes","authors":"Arun K. Ghosh , Monika Yadav , Ashish Sharma , Megan Johnson , Ajay K. Ghosh , Rangu Prasad , Masayuki Amano , Oksana Gerlits , Andrey Kovalevsky , Hiroaki Mitsuya","doi":"10.1016/j.bmcl.2025.130109","DOIUrl":"10.1016/j.bmcl.2025.130109","url":null,"abstract":"<div><div>We describe here the design, synthesis, and X-ray structural studies of a new class of HIV-1 protease inhibitors containing 8-oxabicyclo[3.2.1]octanol-derived P2 ligands. We investigated the functional effect of these stereochemically defined fused-poly cyclic ligands on enzyme inhibition and antiviral activity in MT-2 cells. The tricyclic core of 8-oxabicyclo[3.2.1]octan-6-ol is designed to interact with the residues in the S2 subsite of HIV-1 protease. The syntheses of the ligands were carried out using the [5+2]-cycloaddition as the key step. Several inhibitors exhibited potent enzyme inhibitory activity. High resolution room-temperature X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important molecular insights for further design and optimization of inhibitor potency.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130109"},"PeriodicalIF":2.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cyclic diguanosine monophosphate (c-di-GMP) is the key second messenger regulating bacterial biofilm formation related genes. Several c-di-GMP analogues have demonstrated biofilm inhibition activity. In this study, ribose-phosphate macrocyclic skeleton containing 1′-azido groups was constructed, and CDN analogues were prepared via click chemistry. The biofilm formation inhibition activity of the analogues was evaluated, and compound 17 illustrated better activity than c-di-GMP. This high-throughput strategy could be extended to synthesize cyclic analogues for biological research and immunotherapeutic development.
{"title":"Synthesis and biofilm inhibitory activity of cyclic dinucleotide analogues prepared with macrocyclic ribose-phosphate skeleton","authors":"Di Xie, Lingyun Xu, Shuwei Yuan, Jiayin Yan, Peng Zhou, Wenpei Dong, Jinliang Ma, Changpo Chen","doi":"10.1016/j.bmcl.2025.130107","DOIUrl":"10.1016/j.bmcl.2025.130107","url":null,"abstract":"<div><div>Cyclic diguanosine monophosphate (c-di-GMP) is the key second messenger regulating bacterial biofilm formation related genes. Several c-di-GMP analogues have demonstrated biofilm inhibition activity. In this study, ribose-phosphate macrocyclic skeleton containing 1′-azido groups was constructed, and CDN analogues were prepared via click chemistry. The biofilm formation inhibition activity of the analogues was evaluated, and compound <strong>17</strong> illustrated better activity than c-di-GMP. This high-throughput strategy could be extended to synthesize cyclic analogues for biological research and immunotherapeutic development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130107"},"PeriodicalIF":2.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.bmcl.2025.130106
Yongjian Liu , Hao Liu , Shuqi Li , Shaojun Yu , Heng Chen , Jinling Ge , Yonggang Liu
Harmaline as a natural compound possessed a wide range of pharmacological activities. In this study, 22 novel harmaline-based derivatives were synthesized and screened for in vitro anti-proliferation activity against three cancer cell lines, HCT116, MCF7, and MGC803. The modification site was at the position N-9 of harmaline. The 24-hour IC50 of compound HL22 against HCT116, MGC803, and MCF7 was 3.84 ± 0.11 μM, 5.26 ± 0.46 μM, and 8.67 ± 0.13 μM, respectively. Compound HL22 significantly reduced the migratory ability of MGC803 cells. The monoclonal formation of MGC803 cells was also inhibited by HL22. The 1H NMR metabolomics analysis suggested that the antiproliferative mechanism could be associated for the metabolism of glycine, serine and threonine, the metabolism of taurine and hypotaurine, glutathione metabolism, and the metabolism of nicotinic acid and nicotinamide. The significance of this study is that the anti-cancer activity of the modified N-9 derivatives of harmaline has been explored for the first time.
{"title":"Synthesis of harmaline N-9 derivatives and investigation of in vitro anticancer activity","authors":"Yongjian Liu , Hao Liu , Shuqi Li , Shaojun Yu , Heng Chen , Jinling Ge , Yonggang Liu","doi":"10.1016/j.bmcl.2025.130106","DOIUrl":"10.1016/j.bmcl.2025.130106","url":null,"abstract":"<div><div>Harmaline as a natural compound possessed a wide range of pharmacological activities. In this study, 22 novel harmaline-based derivatives were synthesized and screened for <em>in vitro</em> anti-proliferation activity against three cancer cell lines, HCT116, MCF7, and MGC803. The modification site was at the position N-9 of harmaline. The 24-hour IC<sub>50</sub> of compound <strong>HL22</strong> against HCT116, MGC803, and MCF7 was 3.84 ± 0.11 μM, 5.26 ± 0.46 μM, and 8.67 ± 0.13 μM, respectively. Compound <strong>HL22</strong> significantly reduced the migratory ability of MGC803 cells. The monoclonal formation of MGC803 cells was also inhibited by <strong>HL22</strong>. The <sup>1</sup>H NMR metabolomics analysis suggested that the antiproliferative mechanism could be associated for the metabolism of glycine, serine and threonine, the metabolism of taurine and hypotaurine, glutathione metabolism, and the metabolism of nicotinic acid and nicotinamide. The significance of this study is that the anti-cancer activity of the modified N-9 derivatives of harmaline has been explored for the first time.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130106"},"PeriodicalIF":2.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Current CML treatments often suffer from undesired side effects. Herein we report the computation-assisted optimization of Bcr-Abl/C-Src dual kinase inhibitor. We surmised the improved toxicity profile was achieved via disrupted ligand-target binding. The development of compound 21b highlighted our strategy with ∼1000-fold weaker Bcr-Abl/C-Src inhibition but same level of antiproliferation compared to that of bosutinib. We demonstrated that the introduction of acryloyl group could serves as a potential strategy to maintain antitumor activity.
{"title":"Disrupted target binding with acryloyl group as potential Bcr-Abl/C-Src dual kinase inhibitor optimization strategies with maintained antitumor activity","authors":"Ching Lin , Hsin-Yi Chiang , Grace Shiahuy Chen , Ji-Wang Chern , Chao-Wu Yu","doi":"10.1016/j.bmcl.2025.130105","DOIUrl":"10.1016/j.bmcl.2025.130105","url":null,"abstract":"<div><div>Current CML treatments often suffer from undesired side effects. Herein we report the computation-assisted optimization of Bcr-Abl/C-Src dual kinase inhibitor. We surmised the improved toxicity profile was achieved via disrupted ligand-target binding. The development of compound <strong>21b</strong> highlighted our strategy with ∼1000-fold weaker Bcr-Abl/C-Src inhibition but same level of antiproliferation compared to that of bosutinib. We demonstrated that the introduction of acryloyl group could serves as a potential strategy to maintain antitumor activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130105"},"PeriodicalIF":2.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.bmcl.2025.130096
Han Wang , Xiaolong Ma , Longkang Sun , Tongyu Bi , Weibo Yang
The discovery of novel anticancer agents remains a critical goal in medicinal chemistry, with innovative synthetic methodologies playing a pivotal role in advancing this field. Recent breakthroughs in CH activation reactions, cyclization reactions, multicomponent reactions, cross-coupling reactions, and photo- and electro-catalytic reactions have enabled the efficient synthesis of new molecular scaffolds exhibiting potent biological activities, including anticancer properties. These methodologies have facilitated the functionalization of natural products, the modification of bioactive molecules, and the generation of entirely new compounds, many of which demonstrate strong antitumor activity. This review summarizes the latest synthetic strategies employed over the past five years for discovering anticancer agents, focusing on their influence on drug design. Additionally, the role of new chemical reactions in expanding chemical space and overcoming challenges, such as drug resistance and selectivity, is highlighted, further emphasizing the importance of discovering novel reactions as a key trend in future drug development.
{"title":"Applications of innovative synthetic strategies in anticancer drug discovery: The driving force of new chemical reactions","authors":"Han Wang , Xiaolong Ma , Longkang Sun , Tongyu Bi , Weibo Yang","doi":"10.1016/j.bmcl.2025.130096","DOIUrl":"10.1016/j.bmcl.2025.130096","url":null,"abstract":"<div><div>The discovery of novel anticancer agents remains a critical goal in medicinal chemistry, with innovative synthetic methodologies playing a pivotal role in advancing this field. Recent breakthroughs in C<img>H activation reactions, cyclization reactions, multicomponent reactions, cross-coupling reactions, and photo- and electro-catalytic reactions have enabled the efficient synthesis of new molecular scaffolds exhibiting potent biological activities, including anticancer properties. These methodologies have facilitated the functionalization of natural products, the modification of bioactive molecules, and the generation of entirely new compounds, many of which demonstrate strong antitumor activity. This review summarizes the latest synthetic strategies employed over the past five years for discovering anticancer agents, focusing on their influence on drug design. Additionally, the role of new chemical reactions in expanding chemical space and overcoming challenges, such as drug resistance and selectivity, is highlighted, further emphasizing the importance of discovering novel reactions as a key trend in future drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130096"},"PeriodicalIF":2.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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