Pub Date : 2025-03-10DOI: 10.1016/j.bmcl.2025.130168
Shulei Hu , Qiuyu Zhong , Xiong Xie , Shurui Zhang , Jinlin Wang , Hong Liu , Wenhao Dai
Viral infectious diseases have been seriously affecting human life and health. SARS-CoV-2 was the pathogen that caused Coronavirus Disease 2019 (COVID-19), and the impact of COVID-19 is still existing. Enterovirus 71 (EV71) is the primary pathogen of hand, foot, and mouth disease (HFMD), and no effective direct-acting antiviral drugs targeting EV71 has been approved yet. Innate antiviral strategies play an important role in preventing virus infections depending on the powerful immune regulatory system of body, while viruses have evolved to exploit diverse methods to overcome immune response. Viral proteases, which are known in cleaving viral polyproteins, have also been found to modulate the innate immunity of host cells, thereby promoting viral proliferation. Herein, we reviewed the current development of SARS-CoV-2 3CLpro, PLpro, and EV71 3Cpro and 2Apro, mainly including structure, function, modulation of immune response, and inhibitors of these four proteases, to further deepen the understanding of viral pathogenesis and provide a new perspective for subsequent corresponding drug development.
{"title":"Research progress on critical viral protease inhibitors for coronaviruses and enteroviruses","authors":"Shulei Hu , Qiuyu Zhong , Xiong Xie , Shurui Zhang , Jinlin Wang , Hong Liu , Wenhao Dai","doi":"10.1016/j.bmcl.2025.130168","DOIUrl":"10.1016/j.bmcl.2025.130168","url":null,"abstract":"<div><div>Viral infectious diseases have been seriously affecting human life and health. SARS-CoV-2 was the pathogen that caused Coronavirus Disease 2019 (COVID-19), and the impact of COVID-19 is still existing. Enterovirus 71 (EV71) is the primary pathogen of hand, foot, and mouth disease (HFMD), and no effective direct-acting antiviral drugs targeting EV71 has been approved yet. Innate antiviral strategies play an important role in preventing virus infections depending on the powerful immune regulatory system of body, while viruses have evolved to exploit diverse methods to overcome immune response. Viral proteases, which are known in cleaving viral polyproteins, have also been found to modulate the innate immunity of host cells, thereby promoting viral proliferation. Herein, we reviewed the current development of SARS-CoV-2 3CL<sup>pro</sup>, PL<sup>pro</sup>, and EV71 3C<sup>pro</sup> and 2A<sup>pro</sup>, mainly including structure, function, modulation of immune response, and inhibitors of these four proteases, to further deepen the understanding of viral pathogenesis and provide a new perspective for subsequent corresponding drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130168"},"PeriodicalIF":2.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612729","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 : 2025-03-09DOI: 10.1016/j.bmcl.2025.130159
Wei Liu , Jiayao Du , Zhenzhen Qin , Mei Zhao , Shuaibo Du , Jianwu Xie , Ya Zhang , Mengzhou Wang , Shengzheng Wang
Candida albicans (C. albicans) is the most common cause of invasive Candida infections worldwide. The acquired resistance of C. albicans to fluconazole, a first-line antifungal drug, has been frequently reported, posing significant challenges to treatment. Combination therapy has emerged as an effective strategy to combat drug resistance. In this study, we synthesized a series of sinomenine derivatives and evaluated in vitro synergistic activity against azole-resistant C. albicans. The results demonstrated that compound 3ja exhibited a potent synergistic effect with fluconazole against azole-resistant C. albicans. Mechanism studies revealed that the combination of 3ja and FLC significantly induced reactive oxygen species accumulation, disrupted membrane integrity, altered membrane sterols, and promoted apoptosis in C. albicans.
{"title":"Potent synergistic effect of natural product-inspired Sinomenine derivatives with fluconazole against azole-resistant Candida albicans","authors":"Wei Liu , Jiayao Du , Zhenzhen Qin , Mei Zhao , Shuaibo Du , Jianwu Xie , Ya Zhang , Mengzhou Wang , Shengzheng Wang","doi":"10.1016/j.bmcl.2025.130159","DOIUrl":"10.1016/j.bmcl.2025.130159","url":null,"abstract":"<div><div><em>Candida albicans</em> (<em>C. albicans</em>) is the most common cause of invasive <em>Candida</em> infections worldwide. The acquired resistance of <em>C. albicans</em> to fluconazole, a first-line antifungal drug, has been frequently reported, posing significant challenges to treatment. Combination therapy has emerged as an effective strategy to combat drug resistance. In this study, we synthesized a series of sinomenine derivatives and evaluated in vitro synergistic activity against azole-resistant <em>C. albicans</em>. The results demonstrated that compound <strong>3ja</strong> exhibited a potent synergistic effect with fluconazole against azole-resistant <em>C. albicans</em>. Mechanism studies revealed that the combination of <strong>3ja</strong> and FLC significantly induced reactive oxygen species accumulation, disrupted membrane integrity, altered membrane sterols, and promoted apoptosis in <em>C. albicans</em>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130159"},"PeriodicalIF":2.5,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603175","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 : 2025-03-08DOI: 10.1016/j.bmcl.2025.130178
Artem Tsalyy , Michal Kráľ , Róbert Reiberger , Pavel Majer , Jan Konvalinka , Milan Kožíšek , Aleš Machara
The polymerase acidic (PA) subunit of the influenza virus, an endonuclease of the RNA-dependent RNA polymerase, represents a viable target for anti-influenza therapies, as evidenced by the efficacy of the FDA-approved drug Xofluza. A characteristic feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions within the enzyme's catalytic site. Previously, our studies identified luteolin and its C-8-glucoside orientin as potent endonuclease inhibitors. This report details our subsequent investigation into the structural modifications of the phenyl moiety attached to the C-8 position of luteolin. The inhibitory potencies (IC50 values) quantified with AlphaScreen technology indicated that substituting the C-8 glucose moiety of orientin resulted in compounds with comparable inhibitory potency. From a series of eighteen compounds, acid 12 with 3-carboxylphenyl moiety at the C-8 position was the most potent inhibitor with nanomolar potency.
{"title":"Design, synthesis, and activity evaluation of C-8 arylated luteolin derivatives as influenza endonuclease inhibitors","authors":"Artem Tsalyy , Michal Kráľ , Róbert Reiberger , Pavel Majer , Jan Konvalinka , Milan Kožíšek , Aleš Machara","doi":"10.1016/j.bmcl.2025.130178","DOIUrl":"10.1016/j.bmcl.2025.130178","url":null,"abstract":"<div><div>The polymerase acidic (PA) subunit of the influenza virus, an endonuclease of the RNA-dependent RNA polymerase, represents a viable target for anti-influenza therapies, as evidenced by the efficacy of the FDA-approved drug Xofluza. A characteristic feature of endonuclease inhibitors is their ability to chelate Mg<sup>2+</sup> or Mn<sup>2+</sup> ions within the enzyme's catalytic site. Previously, our studies identified luteolin and its C-8-glucoside orientin as potent endonuclease inhibitors. This report details our subsequent investigation into the structural modifications of the phenyl moiety attached to the C-8 position of luteolin. The inhibitory potencies (IC<sub>50</sub> values) quantified with AlphaScreen technology indicated that substituting the C-8 glucose moiety of orientin resulted in compounds with comparable inhibitory potency. From a series of eighteen compounds, acid <strong>12</strong> with 3-carboxylphenyl moiety at the C-8 position was the most potent inhibitor with nanomolar potency.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130178"},"PeriodicalIF":2.5,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595872","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}
In this work, novel 2-substituted-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy) quinoxaline analogues were designed, synthesized, and various analytical techniques, viz., 1H NMR, 13C NMR, and Mass spectrometry, were deployed in the structure confirmation of the final compounds. Synthesized derivatives were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv. Target molecules mainly consist of methyl substituent in the second position of quinoxaline moiety (QM series) or phenyl substituent in the second position (QP series). Among the forty-two compounds synthesized and evaluated for anti-mycobacterial activity, the MIC values ranged between 5.58 μg/mL to >100 μg/mL. Among QM series compounds, QM7, with MIC 5.58 μg /mL, was the most active compound. Among the QP series derivatives, the intermediate QP-Acy with MIC 23.39 μg /mL was the most promising. Most of the analogues tested in the QP series are less potent than the QM series. All the synthesized molecules showed good drug-likeness when evaluated using the SWISS ADME tool. QM7 was evaluated for docking studies using the crystal structure of enoyl-acyl carrier (INH-A) enzyme PDB: 4TZK, and it showed significant docking scores and interactions. MD simulations were carried out to assess the stability of the protein QM7 complex. Single crystals were grown for QM1, QM6, and QPb from these forty-two compounds, and their structures were solved using OLEX. The corresponding CCDC numbers for these compounds are 2,388,310, 2,388,309, and 2,388,291, respectively.
{"title":"Exploration of quinoxaline triazoles as antimycobacterial agents: design, synthesis and biological evaluation","authors":"Boddupalli Venkata Siva Kumar , Mahesh Kumar Talamadla , Adinarayana Nandikolla , Yogesh Mahadu Khetmalis , Gauri Shetye , Scott G. Franzblau , Sankaranarayanan Murugesan , Kondapalli Venkata Gowri Chandra Sekhar","doi":"10.1016/j.bmcl.2025.130177","DOIUrl":"10.1016/j.bmcl.2025.130177","url":null,"abstract":"<div><div>In this work, novel 2-substituted-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy) quinoxaline analogues were designed, synthesized, and various analytical techniques, viz., <sup>1</sup>H NMR, <sup>13</sup>C NMR, and Mass spectrometry, were deployed in the structure confirmation of the final compounds. Synthesized derivatives were evaluated for their antimycobacterial activity against <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) H37Rv. Target molecules mainly consist of methyl substituent in the second position of quinoxaline moiety (<strong>QM</strong> series) or phenyl substituent in the second position (<strong>QP</strong> series). Among the forty-two compounds synthesized and evaluated for anti-mycobacterial activity, the MIC values ranged between 5.58 μg/mL to >100 μg/mL. Among <strong>QM</strong> series compounds, <strong>QM7,</strong> with MIC 5.58 μg /mL, was the most active compound. Among the <strong>QP</strong> series derivatives, the intermediate <strong>QP-Acy</strong> with MIC 23.39 μg /mL was the most promising. Most of the analogues tested in the <strong>QP</strong> series are less potent than the <strong>QM</strong> series. All the synthesized molecules showed good drug-likeness when evaluated using the SWISS ADME tool. <strong>QM7</strong> was evaluated for docking studies using the crystal structure of enoyl-acyl carrier (INH-A) enzyme PDB: <span><span>4TZK</span><svg><path></path></svg></span>, and it showed significant docking scores and interactions. MD simulations were carried out to assess the stability of the protein <strong>QM7</strong> complex. Single crystals were grown for <strong>QM1</strong>, <strong>QM6</strong>, and <strong>QPb</strong> from these forty-two compounds, and their structures were solved using OLEX. The corresponding CCDC numbers for these compounds are <strong>2,388,310</strong>, <strong>2,388,309</strong>, and <strong>2,388,291</strong>, respectively.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130177"},"PeriodicalIF":2.5,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584258","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 : 2025-03-07DOI: 10.1016/j.bmcl.2025.130166
Yan Zhang , Xiya Liu , Ziming Li , Xia Wang , Chunlei Tang
Cyclin-dependent kinase 2 (CDK2), a crucial regulator in multiple oncogenic signaling pathways, has emerged as a promising target for the development of innovative anticancer therapies and overcoming resistance to CDK4/6 inhibitors. In this study, three series of compounds were designed and synthesized, using the CDK2 inhibitor fadraciclib (CYC065) as the lead compound, with 9H-purine as the core structure. The design incorporated reported structure-activity relationship data and utilized computer-aided drug design techniques. Compounds in series 1 explored the binding mode between the ATP ribose binding site in CDK2 and C2 substituents, while compounds in series 2 and 3 validated the feasibility of modifying the specific binding region with different substituents and investigated the effects of filling the CDK2 hydrophobic pocket at the N9 position with alkyl substituents. Three compounds, 1f, 2e, and 3a, demonstrated remarkable activity against CDK2-cyclin E2. Notably, 3a exhibited the most potent effect, with a CDK2-cyclin E2 IC50 value of 6.0 ± 0.1 nM, an MV4–11 IC50 value of 489.2 ± 0.2 nM, and excellent selectivity for CDK2. This study evaluated the impact of substitutions at the 2, 6, and 9 positions of the purine ring on the activity of CDK2 small molecule inhibitors. The findings offer a theoretical foundation for future research, broadening the structural diversity and scope of CDK2 inhibitor studies.
{"title":"Development of 9H-purine scaffold as novel CDK2 inhibitors: Design, synthesis, and biological evaluation","authors":"Yan Zhang , Xiya Liu , Ziming Li , Xia Wang , Chunlei Tang","doi":"10.1016/j.bmcl.2025.130166","DOIUrl":"10.1016/j.bmcl.2025.130166","url":null,"abstract":"<div><div>Cyclin-dependent kinase 2 (CDK2), a crucial regulator in multiple oncogenic signaling pathways, has emerged as a promising target for the development of innovative anticancer therapies and overcoming resistance to CDK4/6 inhibitors. In this study, three series of compounds were designed and synthesized, using the CDK2 inhibitor fadraciclib (CYC065) as the lead compound, with 9<em>H</em>-purine as the core structure. The design incorporated reported structure-activity relationship data and utilized computer-aided drug design techniques. Compounds in series <strong>1</strong> explored the binding mode between the ATP ribose binding site in CDK2 and C2 substituents, while compounds in series <strong>2</strong> and <strong>3</strong> validated the feasibility of modifying the specific binding region with different substituents and investigated the effects of filling the CDK2 hydrophobic pocket at the N9 position with alkyl substituents. Three compounds, <strong>1f</strong>, <strong>2e</strong>, and <strong>3a</strong>, demonstrated remarkable activity against CDK2-cyclin E2. Notably, <strong>3a</strong> exhibited the most potent effect, with a CDK2-cyclin E2 IC<sub>50</sub> value of 6.0 ± 0.1 nM, an MV4–11 IC<sub>50</sub> value of 489.2 ± 0.2 nM, and excellent selectivity for CDK2. This study evaluated the impact of substitutions at the 2, 6, and 9 positions of the purine ring on the activity of CDK2 small molecule inhibitors. The findings offer a theoretical foundation for future research, broadening the structural diversity and scope of CDK2 inhibitor studies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130166"},"PeriodicalIF":2.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584252","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 : 2025-03-07DOI: 10.1016/j.bmcl.2025.130161
Linquan Li , Xi Gu , Jingyi Meng , Yiming Wen , Jing Yi , Fengqian Xu , Li Zhang , Sulin Zhang , Zhili Zuo
The p53 Y220C mutation is frequently observed in human cancers. This mutation renders the p53 Y220C unstable at physiological temperatures, leading to a loss of its normal function and promoting tumor development. In this study, a total of eight compounds were designed and synthesized based on the active compound C8. The protein thermal shift assay revealed that both C8-3b and C8–6 exhibited similar activity of C8, with a ΔTm value of +0.5 °C. Compounds C8-1a, C8-1b, and C8-2b were found to enhance the thermostability of p53 Y220C (ΔTm: + 1.0 °C), the melting temperature exhibits an enhancement of 0.5 °C over the C8, indicating that these compounds possess the ability to stabilize p53 Y220C. The results of the cell viability assay revealed that C8-1b exhibited selective inhibitory effects on the proliferation of tumor cells harboring the p53 Y220C mutation. Furthermore, we utilized molecular docking and two-dimensional interaction analysis to elucidate the binding mode and key interactions of these compounds with p53 Y220C. Our study suggests that these compounds could potentially serve as lead compounds for enhancing the stability of p53 Y220C, thus providing a rational approach for designing small molecule stabilizers against p53 mutations.
{"title":"Design, synthesis, and activity evaluation of indole derivatives as potential stabilizers for p53 Y220C","authors":"Linquan Li , Xi Gu , Jingyi Meng , Yiming Wen , Jing Yi , Fengqian Xu , Li Zhang , Sulin Zhang , Zhili Zuo","doi":"10.1016/j.bmcl.2025.130161","DOIUrl":"10.1016/j.bmcl.2025.130161","url":null,"abstract":"<div><div>The p53 Y220C mutation is frequently observed in human cancers. This mutation renders the p53 Y220C unstable at physiological temperatures, leading to a loss of its normal function and promoting tumor development. In this study, a total of eight compounds were designed and synthesized based on the active compound <strong>C8</strong>. The protein thermal shift assay revealed that both <strong>C8-3b</strong> and <strong>C8–6</strong> exhibited similar activity of <strong>C8</strong>, with a ΔT<sub>m</sub> value of +0.5 °C. Compounds <strong>C8-1a</strong>, <strong>C8-1b</strong>, and <strong>C8-2b</strong> were found to enhance the thermostability of p53 Y220C (ΔT<sub>m</sub>: + 1.0 °C), the melting temperature exhibits an enhancement of 0.5 °C over the <strong>C8</strong>, indicating that these compounds possess the ability to stabilize p53 Y220C. The results of the cell viability assay revealed that <strong>C8-1b</strong> exhibited selective inhibitory effects on the proliferation of tumor cells harboring the p53 Y220C mutation. Furthermore, we utilized molecular docking and two-dimensional interaction analysis to elucidate the binding mode and key interactions of these compounds with p53 Y220C. Our study suggests that these compounds could potentially serve as lead compounds for enhancing the stability of p53 Y220C, thus providing a rational approach for designing small molecule stabilizers against p53 mutations.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130161"},"PeriodicalIF":2.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584250","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 : 2025-03-06DOI: 10.1016/j.bmcl.2025.130162
Zhi-Zheng Wang , Chen-Xu Xiao , Wen-Li Huang , Yang Hu , Hui-Ting Zhang , Zhang Liu , Sheng-Hao Peng , Zigong Wei
Porcine reproductive and respiratory syndrome virus (PRRSV) causes serious threat to the global pig industry, and there was still no efficient treatment for porcine reproductive and respiratory syndrome (PRRS). Flavonol compounds were reported to show antiviral activity against a series of different virus. In this study, we designed a series of flavonol derivatives as promising lead structure for PRRSV inhibitors. A flavonol derivative database with diverse structures was first generated, and their anti-PRRSV activity were test. Among these compounds, compound 4s showed promising anti-PRRSV activity with EC50 values of 0.45 μM. In addition, it exhibited low cytotoxicity with CC50 higher than 100 μM. We also found that compound 4s inhibited PRRSV might be by repressing the activity of nsp4 protease. Molecular modeling study revealed that compound 4s binding to nsp4 mainly relies on a salt bridge and hydrophobic interaction. Our results might provide a new way for the development of PRRSV inhibitors.
{"title":"Discovery of Flavonol derivatives as porcine reproductive and respiratory syndrome virus inhibitors","authors":"Zhi-Zheng Wang , Chen-Xu Xiao , Wen-Li Huang , Yang Hu , Hui-Ting Zhang , Zhang Liu , Sheng-Hao Peng , Zigong Wei","doi":"10.1016/j.bmcl.2025.130162","DOIUrl":"10.1016/j.bmcl.2025.130162","url":null,"abstract":"<div><div>Porcine reproductive and respiratory syndrome virus (PRRSV) causes serious threat to the global pig industry, and there was still no efficient treatment for porcine reproductive and respiratory syndrome (PRRS). Flavonol compounds were reported to show antiviral activity against a series of different virus. In this study, we designed a series of flavonol derivatives as promising lead structure for PRRSV inhibitors. A flavonol derivative database with diverse structures was first generated, and their anti-PRRSV activity were test. Among these compounds, compound <strong>4s</strong> showed promising anti-PRRSV activity with EC<sub>50</sub> values of 0.45 μM. In addition, it exhibited low cytotoxicity with CC<sub>50</sub> higher than 100 μM. We also found that compound <strong>4s</strong> inhibited PRRSV might be by repressing the activity of nsp4 protease. Molecular modeling study revealed that compound <strong>4s</strong> binding to nsp4 mainly relies on a salt bridge and hydrophobic interaction. Our results might provide a new way for the development of PRRSV inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130162"},"PeriodicalIF":2.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584255","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 : 2025-03-04DOI: 10.1016/j.bmcl.2025.130158
Taofeng Lin , Zhongqi Li , Juanchan Yuan , Tinfeng Ren , Wan Pang , Songhui Xu
Kaiso, a potential target for the treatment of lung cancer. Our research focuses on Kaiso inhibitros. Through virtual screening and molecular dynamic simulations, we discovered a promising Kaiso inhibitor called compound 5 (ZINC20577650). By modifying the structure of compound 5, a series of novel Kaiso inhibitors that contain a diphenyl ether ring were synthesized. Among them, compound 20 exhibited the strongest inhibitory activity against A549 cells (IC50 = 0.34 μM). Notably, its inhibitory activity surpassed that of the positive control MIRA-1 (IC50 = 654.065 μM). Molecular docking and dynamic studies revealed that the binding of the compound's amino and ester moieties to the active site of kaiso protein, as well as the extension of the benzene ring towards the Asn561 position in the cavity, contributed significantly to its potency. These findings provide valuable insights for the development of new Kaiso inhibitors.
{"title":"Design, synthesis and evaluation of diphenyl ether-based kaiso inhibitors with enhanced potency","authors":"Taofeng Lin , Zhongqi Li , Juanchan Yuan , Tinfeng Ren , Wan Pang , Songhui Xu","doi":"10.1016/j.bmcl.2025.130158","DOIUrl":"10.1016/j.bmcl.2025.130158","url":null,"abstract":"<div><div>Kaiso, a potential target for the treatment of lung cancer. Our research focuses on Kaiso inhibitros. Through virtual screening and molecular dynamic simulations, we discovered a promising Kaiso inhibitor called compound <strong>5</strong> (ZINC20577650). By modifying the structure of compound <strong>5</strong>, a series of novel Kaiso inhibitors that contain a diphenyl ether ring were synthesized. Among them, compound <strong>20</strong> exhibited the strongest inhibitory activity against A549 cells (IC<sub>50</sub> = 0.34 μM). Notably, its inhibitory activity surpassed that of the positive control <strong>MIRA-1</strong> (IC<sub>50</sub> = 654.065 μM). Molecular docking and dynamic studies revealed that the binding of the compound's amino and ester moieties to the active site of kaiso protein, as well as the extension of the benzene ring towards the Asn561 position in the cavity, contributed significantly to its potency. These findings provide valuable insights for the development of new Kaiso inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130158"},"PeriodicalIF":2.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571741","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 : 2025-03-03DOI: 10.1016/j.bmcl.2025.130163
Tiffany Gu , Rushika Raval , Zachary Bashkin , Carina Zhou , Sanghyuk Ko , Natalie Kong , Seoyeon Hong , Aditya Bhaskara , Samarth Shah , Aditi Joshi , Samahith Thellakal , Kaitlyn Rim , Anushree Marimuthu , Srishti Venkatesan , Emma Wang , Sophia Li , Aditi Jayabalan , Alice Tao , Yilin Fang , Lorelei Xia , Edward Njoo
Andrographolide, a labdane diterpenoid isolated from Andrographis paniculata, putatively functions through covalent inhibition of NF-κB, a transcription factor that modulates tumor survival and metastasis. Previous studies have found that functionalization of the C-19 hydroxyl alters the primary mode of action from inhibition of NF-κB to the modulation of the Wnt1/β-catenin signaling pathway. Here, we synthesized a series of twelve C-19 trityl and silyl ether analogs, including three novel substituted trityl analogs and four novel substituted silyl analogs of andrographolide. MTT assays revealed cell line selectivity between colorectal and breast cancer cells, which is consistent with known mechanisms of β-catenin-driven cell proliferation in colorectal cancer cell lines. Most compounds exhibited cell line specific antiproliferative activity in HCT-116 and HT-29 colorectal cancer cell lines. Specifically, within 24 h, C-19 analogs of andrographolide exhibit far more limited antiproliferative activity in MCF-7 breast cancer cells compared to HCT-116, HT-29, and MDA-MB-231 cells. Through in vitro TNF-α-dependent NF-κB reporter and Wnt1-dependent luciferase reporter assays, we observed that several analogs generally exhibit greater inhibitory activity compared to andrographolide. Fluorescence imaging demonstrated that cells treated with andrographolide and its C-19 analogs retained similar distributions of active β-catenin, but notable differences in antiproliferative potency upon co-delivery with GSK-3β inhibitor CHIR99021 indicate that several lead compounds exhibit attenuated biological activity selectively in HT-29 cells. Collectively, this work indicates that modest structural modifications at C-19 of andrographolide can have profound implications for its biological activity in mechanisms connected to its anticancer activity.
{"title":"Synthesis, antiproliferative activity, and biological profiling of C-19 trityl and silyl ether andrographolide analogs in colon cancer and breast cancer cells","authors":"Tiffany Gu , Rushika Raval , Zachary Bashkin , Carina Zhou , Sanghyuk Ko , Natalie Kong , Seoyeon Hong , Aditya Bhaskara , Samarth Shah , Aditi Joshi , Samahith Thellakal , Kaitlyn Rim , Anushree Marimuthu , Srishti Venkatesan , Emma Wang , Sophia Li , Aditi Jayabalan , Alice Tao , Yilin Fang , Lorelei Xia , Edward Njoo","doi":"10.1016/j.bmcl.2025.130163","DOIUrl":"10.1016/j.bmcl.2025.130163","url":null,"abstract":"<div><div>Andrographolide, a labdane diterpenoid isolated from <em>Andrographis paniculata</em>, putatively functions through covalent inhibition of NF-κB, a transcription factor that modulates tumor survival and metastasis. Previous studies have found that functionalization of the C-19 hydroxyl alters the primary mode of action from inhibition of NF-κB to the modulation of the Wnt1/β-catenin signaling pathway. Here, we synthesized a series of twelve C-19 trityl and silyl ether analogs, including three novel substituted trityl analogs and four novel substituted silyl analogs of andrographolide. MTT assays revealed cell line selectivity between colorectal and breast cancer cells, which is consistent with known mechanisms of β-catenin-driven cell proliferation in colorectal cancer cell lines. Most compounds exhibited cell line specific antiproliferative activity in HCT-116 and HT-29 colorectal cancer cell lines. Specifically, within 24 h, C-19 analogs of andrographolide exhibit far more limited antiproliferative activity in MCF-7 breast cancer cells compared to HCT-116, HT-29, and MDA-MB-231 cells. Through <em>in vitro</em> TNF-α-dependent NF-κB reporter and Wnt1-dependent luciferase reporter assays, we observed that several analogs generally exhibit greater inhibitory activity compared to andrographolide. Fluorescence imaging demonstrated that cells treated with andrographolide and its C-19 analogs retained similar distributions of active β-catenin, but notable differences in antiproliferative potency upon co-delivery with GSK-3β inhibitor CHIR99021 indicate that several lead compounds exhibit attenuated biological activity selectively in HT-29 cells. Collectively, this work indicates that modest structural modifications at C-19 of andrographolide can have profound implications for its biological activity in mechanisms connected to its anticancer activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130163"},"PeriodicalIF":2.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562694","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 : 2025-03-03DOI: 10.1016/j.bmcl.2025.130165
Melanie A. Franklin , Mariam N. Salib , Juliette Gafni , Isaac N. Pessah , Tadeusz F. Molinski
The RYR1 Ca2+ channel mediates essential steps of excitation-contraction in skeletal muscle. Bastadins-5 and -6, highly brominated macrodilactams assembled from tyrosine and tyramine by the marine sponge Ianthella basta, were identified as potent sensitizers of RYR1 channel activation. Here, we present a structure-activity relationships study of a wide panel of bastadins, and related analogs, and define the minimum requirements for stabilizing the RYR1 complex open or closed conformations.
{"title":"Structure-activity of Bastadins from the marine sponge Ianthella basta. Modulators of the RYR1 Ca2+ channel","authors":"Melanie A. Franklin , Mariam N. Salib , Juliette Gafni , Isaac N. Pessah , Tadeusz F. Molinski","doi":"10.1016/j.bmcl.2025.130165","DOIUrl":"10.1016/j.bmcl.2025.130165","url":null,"abstract":"<div><div>The RYR1 Ca<sup>2+</sup> channel mediates essential steps of excitation-contraction in skeletal muscle. Bastadins-5 and -6, highly brominated macrodilactams assembled from tyrosine and tyramine by the marine sponge <em>Ianthella basta</em>, were identified as potent sensitizers of RYR1 channel activation. Here, we present a structure-activity relationships study of a wide panel of bastadins, and related analogs, and define the minimum requirements for stabilizing the RYR1 complex open or closed conformations.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130165"},"PeriodicalIF":2.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562693","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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