Pub Date : 2025-02-19DOI: 10.1016/j.bmcl.2025.130152
Anisa Ulhusna , Asako Murata , Kazuhiko Nakatani
Base Excision Repair (BER) pathway is correlated with nucleotide repeat instability. In this report, we investigated the modulatory effects of a DNA-binding small molecule, naphthyridine azaquinolone (NA), towards BER in an in vitro system. Thermal melting analyses demonstrated binding of NA to deaminated 5’-CAG-3′/5’-CAG-3′ triads in DNA. Furthermore, binding of NA to the deaminated CAG repeat hairpin was found to partially inhibit UNG2- and APE1-catalyzed reaction, suggesting a potential mechanism for NA-induced CAG repeat contraction via BER pathway.
{"title":"Studies on in vitro modulatory effects to base excision repair enzymes induced by small molecule binding to Deaminated CAG repeat hairpin","authors":"Anisa Ulhusna , Asako Murata , Kazuhiko Nakatani","doi":"10.1016/j.bmcl.2025.130152","DOIUrl":"10.1016/j.bmcl.2025.130152","url":null,"abstract":"<div><div>Base Excision Repair (BER) pathway is correlated with nucleotide repeat instability. In this report, we investigated the modulatory effects of a DNA-binding small molecule, naphthyridine azaquinolone (NA), towards BER in an in vitro system. Thermal melting analyses demonstrated binding of NA to deaminated 5’-CAG-3′/5’-CAG-3′ triads in DNA. Furthermore, binding of NA to the deaminated CAG repeat hairpin was found to partially inhibit UNG2- and APE1-catalyzed reaction, suggesting a potential mechanism for NA-induced CAG repeat contraction via BER pathway.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130152"},"PeriodicalIF":2.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472007","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}
The Plasmodium falciparum parasite, which is responsible for malaria, has developed resistance to several first-line antimalarial drugs. To address this issue, researchers have been developing novel hybrid molecules that can inhibit parasite growth. In this study, a total of 38 chalcone oxime ethers, consisting of four different types, were evaluated for in vitro blood-stage antiplasmodial activity against P. falciparum (3D7) using SYBR green I assay. The four classes of oxime ethers showed promising to moderate antiplasmodial activity. At least one molecule from each class was potent, with the IC50 values of less than 5 μg/mL. Among the four classes, chalcone-chalconeoxime ethers (CCOE) were the most effective, with the IC50 values of 1.55 μg/mL and 1.4 μg/mL for CCOE-2 and CCOE-5, respectively. The most potent molecules, CKOE-13, COAE-2, CCOE-2, and CCOE-5, were tested against the chloroquine-resistant strain P. falciparum (INDO) exhibited IC50 values of less than 5 μg/mL. Notably, the most potent molecules did not induce hemolysis at concentrations up to 50 μg/mL. These findings highlight a new class of chalconeoxime ethers as potent antiplasmodial agents, warranting further exploration of their biological activities.
{"title":"Oxime functionalized Chalcones: Unveiling a new class of Chalcones with potent Antiplasmodial activity against blood-stages of Plasmodium falciparum in culture","authors":"Reeta Chaudhary , Ayushee , Vinoth Rajendran , T.M. Rangarajan","doi":"10.1016/j.bmcl.2025.130143","DOIUrl":"10.1016/j.bmcl.2025.130143","url":null,"abstract":"<div><div>The <em>Plasmodium falciparum</em> parasite, which is responsible for malaria, has developed resistance to several first-line antimalarial drugs. To address this issue, researchers have been developing novel hybrid molecules that can inhibit parasite growth. In this study, a total of 38 chalcone oxime ethers, consisting of four different types, were evaluated for <em>in vitro</em> blood-stage antiplasmodial activity against <em>P. falciparum</em> (3D7) using SYBR green I assay. The four classes of oxime ethers showed promising to moderate antiplasmodial activity. At least one molecule from each class was potent, with the IC<sub>50</sub> values of less than 5 μg/mL. Among the four classes, chalcone-chalconeoxime ethers (CCOE) were the most effective, with the IC<sub>50</sub> values of 1.55 μg/mL and 1.4 μg/mL for <strong>CCOE-2</strong> and <strong>CCOE-5</strong>, respectively. The most potent molecules, <strong>CKOE-13</strong>, <strong>COAE-2</strong>, <strong>CCOE-2</strong>, and <strong>CCOE-5</strong>, were tested against the chloroquine-resistant strain <em>P. falciparum</em> (INDO) exhibited IC<sub>50</sub> values of less than 5 μg/mL. Notably, the most potent molecules did not induce hemolysis at concentrations up to 50 μg/mL. These findings highlight a new class of chalconeoxime ethers as potent antiplasmodial agents, warranting further exploration of their biological activities.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130143"},"PeriodicalIF":2.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466586","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 : 2025-02-17DOI: 10.1016/j.bmcl.2025.130140
M.S. Ajay Krishna , K.T. Ashitha , Meghashyama Prabhakara Bhat , Muthuraj Rudrappa , K.S. Sandhya , N.C. Lima , D. Basavaraja , Sunil Varughese , Sreenivasa Nayaka , Sasidhar B. Somappa
The quest for novel antimicrobials is critical due to emerging resistance by new microorganism strains. In these circumstances, we designed and synthesized a series of β-aminothiochromones by employing an aziridines ring-opening strategy to discover antimicrobial agents that are effective against multidrug-resistant (MDR) bacteria. Structures of the compounds [3(a-m) and 3a(a-o)] were well characterized and confirmed by the spectroscopic, analytical and single crystal X-ray analysis. Further, we conducted the in vitro antimicrobial assessment studies against selected Gram-positive, and Gram-negative bacterial strains and two fungal strains. In preliminary screening, all synthesized compounds exhibited moderate activity compared to tested standard drugs Ampicillin, Ciprofloxacin and Fluconazole wherein, 3m and 3ae displayed higher anti-microbial activities. In addition, these analogues exhibited anti-angiogenic properties on HepG2 cells. The in-silico studies on promising hits, 3m and 3ae on proteins DNA gyrase and Topoisomerase IV indicate that these hybrids possess better binding energy in comparison with standard drugs. Thus, based on in vitro and silico studies, the newly synthesized compounds appear to be potential scaffolds for antimicrobial and anti-angiogenic drug discovery initiatives.
{"title":"Dual-acting β-Aminothiochromones: Design, synthesis, and evaluation as antimicrobial and anti-angiogenic agents","authors":"M.S. Ajay Krishna , K.T. Ashitha , Meghashyama Prabhakara Bhat , Muthuraj Rudrappa , K.S. Sandhya , N.C. Lima , D. Basavaraja , Sunil Varughese , Sreenivasa Nayaka , Sasidhar B. Somappa","doi":"10.1016/j.bmcl.2025.130140","DOIUrl":"10.1016/j.bmcl.2025.130140","url":null,"abstract":"<div><div>The quest for novel antimicrobials is critical due to emerging resistance by new microorganism strains. In these circumstances, we designed and synthesized a series of β-aminothiochromones by employing an aziridines ring-opening strategy to discover antimicrobial agents that are effective against multidrug-resistant (MDR) bacteria. Structures of the compounds [<strong>3(a-m)</strong> and <strong>3a(a-o)</strong>] were well characterized and confirmed by the spectroscopic, analytical and single crystal X-ray analysis. Further, we conducted the in vitro antimicrobial assessment studies against selected Gram-positive, and Gram-negative bacterial strains and two fungal strains. In preliminary screening, all synthesized compounds exhibited moderate activity compared to tested standard drugs Ampicillin, Ciprofloxacin and Fluconazole wherein, <strong>3</strong> <strong>m</strong> and <strong>3ae</strong> displayed higher anti-microbial activities. In addition, these analogues exhibited anti-angiogenic properties on HepG2 cells. The in-silico studies on promising hits, <strong>3</strong> <strong>m</strong> and <strong>3ae</strong> on proteins DNA gyrase and Topoisomerase IV indicate that these hybrids possess better binding energy in comparison with standard drugs. Thus, based on in vitro and silico studies, the newly synthesized compounds appear to be potential scaffolds for antimicrobial and anti-angiogenic drug discovery initiatives.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130140"},"PeriodicalIF":2.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456544","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 : 2025-02-15DOI: 10.1016/j.bmcl.2025.130141
Byul Moon , Ahra Go , Seulki Park , Hyun Jin Kim , Dongju An , Jaehoon Kim , Joo-Youn Lee , Jeong-Hoon Kim , Jong Yeon Hwang , Jung-Ae Kim
The Werner protein, WRN, is a member of the RecQ helicase family implicated in genome maintenance. Several large-scale functional genomics screens have identified WRN as a synthetic lethal target in cancer cell lines with microsatellite instability-high (MSI-H). Accordingly, WRN is considered a potential therapeutic target in MSI-H cancers. HRO761, a non-covalent WRN inhibitor developed by Novartis, entered clinical trial for patients with MSI-H colorectal cancer (CRC). In this study, we investigated bioisosteric replacement of the hydroxyl pyrimidine residue of HRO761 with several bicyclic structures to obtain a novel chemical entity. In vitro ATPase and cell proliferation assays revealed two candidate chemicals that showed similar or better effects than HRO761. Additionally, an in vivo study demonstrated that KWR095, a newly synthesized WRN inhibitor, has significant anti-proliferative effects compared with vehicle.
{"title":"Discovery of novel WRN inhibitors for treating MSI-H colorectal cancers","authors":"Byul Moon , Ahra Go , Seulki Park , Hyun Jin Kim , Dongju An , Jaehoon Kim , Joo-Youn Lee , Jeong-Hoon Kim , Jong Yeon Hwang , Jung-Ae Kim","doi":"10.1016/j.bmcl.2025.130141","DOIUrl":"10.1016/j.bmcl.2025.130141","url":null,"abstract":"<div><div>The Werner protein, WRN, is a member of the RecQ helicase family implicated in genome maintenance. Several large-scale functional genomics screens have identified WRN as a synthetic lethal target in cancer cell lines with microsatellite instability-high (MSI-H). Accordingly, WRN is considered a potential therapeutic target in MSI-H cancers. HRO761, a non-covalent WRN inhibitor developed by Novartis, entered clinical trial for patients with MSI-H colorectal cancer (CRC). In this study, we investigated bioisosteric replacement of the hydroxyl pyrimidine residue of HRO761 with several bicyclic structures to obtain a novel chemical entity. <em>In vitro</em> ATPase and cell proliferation assays revealed two candidate chemicals that showed similar or better effects than HRO761. Additionally, an <em>in vivo</em> study demonstrated that KWR095, a newly synthesized WRN inhibitor, has significant anti-proliferative effects compared with vehicle.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130141"},"PeriodicalIF":2.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432076","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}
Pub Date : 2025-02-14DOI: 10.1016/j.bmcl.2025.130139
Shan Lu , Zhuang Li , Peng Jiang , Bo Jiang , Shanqin Huang , Xinhang Su , Ke Ma , Ying Xu , Lingling Ding , Di Mao
A plant endophytic actinomycete Streptomyces sp. JS39–4 was isolated from the root of water spinach (Ipomoea aquatica Forsk.). Its main secondary metabolite streptazolin (1) was purified in a high yield under the optimized cultural condition. Sixteen analogs of streptazolin with modification at C-5 were synthesized. Among them, compound 2e exhibits the most potent anti-inflammatory activity in LPS-induced RAW 264.7 mouse macrophages. The current research provides the first report on the anti-inflammatory activity of streptazolin analogs.
{"title":"Design, synthesis and biological evaluation of Streptazolin analogs as anti-inflammatory agents","authors":"Shan Lu , Zhuang Li , Peng Jiang , Bo Jiang , Shanqin Huang , Xinhang Su , Ke Ma , Ying Xu , Lingling Ding , Di Mao","doi":"10.1016/j.bmcl.2025.130139","DOIUrl":"10.1016/j.bmcl.2025.130139","url":null,"abstract":"<div><div>A plant endophytic actinomycete <em>Streptomyces</em> sp. JS39–4 was isolated from the root of water spinach (<em>Ipomoea aquatica</em> Forsk.). Its main secondary metabolite streptazolin (<strong>1</strong>) was purified in a high yield under the optimized cultural condition. Sixteen analogs of streptazolin with modification at C-5 were synthesized. Among them, compound <strong>2e</strong> exhibits the most potent anti-inflammatory activity in LPS-induced RAW 264.7 mouse macrophages. The current research provides the first report on the anti-inflammatory activity of streptazolin analogs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130139"},"PeriodicalIF":2.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429879","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 : 2025-02-14DOI: 10.1016/j.bmcl.2025.130142
Charalambos Kaittanis , Hyunjung Kim , Tyler Teceno , Yoann Petibon , Ashley Knight , Matthew Crouthamel , Anthony P. Belanger , Zhaoming Xiong , Wanida Ruangsiriluk , Meera Modi , Rizwana Islam , Madhu Natarajan , Nikolaos Papaioannou , Christopher T. Winkelmann , Johannes Tauscher , Paul McQuade
Changes in metabolism are associated with several prevalent and rare diseases, like Hunter syndrome (MPS II). These alterations result in changes in mitochondrial function, therefore having non-invasive imaging biomarkers to detect this pathophysiological hallmark is a key objective of translational medicine. Here we report the synthesis and in vivo evaluation of the [18F]berberine analogue ([18F]BEAN), in both wildtype animals and a mouse model of Hunter's disease. PET/CT imaging revealed that [18F]BEAN could detect mitochondrial dysfunction in the heart, liver, and brain of Hunter's disease (Ids KO) mice. These data suggest that [18F]BEAN may be a viable translational PET biomarker for the imaging of diverse pathologies that have impaired mitochondrial function.
{"title":"Radiosynthesis and in vivo evaluation of [18F]BEAN as a potential mitochondria-based PET biomarker for metabolic disorders","authors":"Charalambos Kaittanis , Hyunjung Kim , Tyler Teceno , Yoann Petibon , Ashley Knight , Matthew Crouthamel , Anthony P. Belanger , Zhaoming Xiong , Wanida Ruangsiriluk , Meera Modi , Rizwana Islam , Madhu Natarajan , Nikolaos Papaioannou , Christopher T. Winkelmann , Johannes Tauscher , Paul McQuade","doi":"10.1016/j.bmcl.2025.130142","DOIUrl":"10.1016/j.bmcl.2025.130142","url":null,"abstract":"<div><div>Changes in metabolism are associated with several prevalent and rare diseases, like Hunter syndrome (MPS II). These alterations result in changes in mitochondrial function, therefore having non-invasive imaging biomarkers to detect this pathophysiological hallmark is a key objective of translational medicine. Here we report the synthesis and <em>in vivo</em> evaluation of the [<sup>18</sup>F]berberine analogue ([<sup>18</sup>F]BEAN), in both wildtype animals and a mouse model of Hunter's disease. PET/CT imaging revealed that [<sup>18</sup>F]BEAN could detect mitochondrial dysfunction in the heart, liver, and brain of Hunter's disease (Ids KO) mice. These data suggest that [<sup>18</sup>F]BEAN may be a viable translational PET biomarker for the imaging of diverse pathologies that have impaired mitochondrial function.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130142"},"PeriodicalIF":2.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432078","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}
Pub Date : 2025-02-13DOI: 10.1016/j.bmcl.2025.130135
Abdur Rahman , Jaimin D. Bhatt , Bharat C. Dixit , Shazia Anjum , Anju Singh , Tohasib Yusub Chaudhari , Fatima Heyat , Hari Madhav , Mahim Sattar , Tarosh S. Patel , Nasimul Hoda
Malaria, an infectious disease, impacts approximately half of the global population. To tackle the growing problem of drug resistance to treatments such as artemisinin-based combination therapies (ACT), we synthesized thiourea-based compounds (QS1-QS16) by blending quinazoline and oxospirochromane. These compounds underwent testing to assess their in-vitro efficacy against both drug-sensitive and drug-resistant strains of the Plasmodium parasite. Among all the synthesized compounds, QS5 showed good inhibitory efficacy against Pf3D7 and PfW2 with IC50 3.18 and 3.98 µM respectively, and QS13 with IC50 3.56 and 4.43 µM respectively. The promising compounds were screened against the Plasmodium parasite’s falcipain-2 and falcipain-3 enzymes. The ligands QS5 and QS13 displayed inhibition against PfFP-2 (IC50 3.9 and 4.9 µM) and PfFP-3 (IC50 4.6 and 5.9 µM) respectively. Furthermore, the selected molecules showed no significant cytotoxicity in non-cancerous Vero cell lines, and hemolysis assays on healthy RBCs confirmed the molecules’ specific antiplasmodial activity. Docking investigations explored ligand interaction with PfFP2 and PfFP3 binding sites. We investigated thiourea-based compounds, notably QS5 and QS13, as potential solutions to combat drug-resistant malaria strains. Our findings suggest that these compounds exhibit promising activity against the parasite at its early stages, offering hope for developing new antimalarial therapies.
{"title":"Identifying thiourea-based hybrids of quinazoline and oxospirochromane as inhibitors of Plasmodium cysteine proteases arresting the parasitic growth at the early trophozoite stage","authors":"Abdur Rahman , Jaimin D. Bhatt , Bharat C. Dixit , Shazia Anjum , Anju Singh , Tohasib Yusub Chaudhari , Fatima Heyat , Hari Madhav , Mahim Sattar , Tarosh S. Patel , Nasimul Hoda","doi":"10.1016/j.bmcl.2025.130135","DOIUrl":"10.1016/j.bmcl.2025.130135","url":null,"abstract":"<div><div>Malaria, an infectious disease, impacts approximately half of the global population. To tackle the growing problem of drug resistance to treatments such as artemisinin-based combination therapies (ACT), we synthesized thiourea-based compounds (QS1-QS16) by blending quinazoline and oxospirochromane. These compounds underwent testing to assess their in-vitro efficacy against both drug-sensitive and drug-resistant strains of the <em>Plasmodium</em> parasite. Among all the synthesized compounds, <strong>QS5</strong> showed good inhibitory efficacy against <em>Pf</em>3D7 and <em>Pf</em>W2 with <strong>IC<sub>50</sub> 3.18</strong> and <strong>3.98 µM</strong> respectively, and <strong>QS13</strong> with <strong>IC<sub>50</sub> 3.56</strong> and <strong>4.43 µM</strong> respectively. The promising compounds were screened against the <em>Plasmodium</em> parasite’s falcipain-2 and falcipain-3 enzymes. The ligands <strong>QS5</strong> and <strong>QS13</strong> displayed inhibition against <strong><em>Pf</em>FP-2</strong> (<strong>IC<sub>50</sub> 3.9</strong> and <strong>4.9 µM</strong>) and <strong><em>Pf</em>FP-3</strong> (<strong>IC<sub>50</sub> 4.6</strong> and <strong>5.9 µM</strong>) respectively. Furthermore, the selected molecules showed no significant cytotoxicity in non-cancerous Vero cell lines, and hemolysis assays on healthy RBCs confirmed the molecules’ specific antiplasmodial activity. Docking investigations explored ligand interaction with <em>Pf</em>FP2 and <em>Pf</em>FP3 binding sites. We investigated thiourea-based compounds, notably <strong>QS5</strong> and <strong>QS13</strong>, as potential solutions to combat drug-resistant malaria strains. Our findings suggest that these compounds exhibit promising activity against the parasite at its early stages, offering hope for developing new antimalarial therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130135"},"PeriodicalIF":2.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424734","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 : 2025-02-11DOI: 10.1016/j.bmcl.2025.130136
Hua Xu, Pengfei Dong, Haixing Wang, Inseok Sin, Chi Soo Kang, Siyuan Ren, Xiang Sun, Hyun-Soon Chong
A bifunctional ligand is an essential component for targeted cancer therapy using cytotoxic radionuclides. We report the synthesis and evaluation of a novel bifunctional ligand, 3o-C-NETA, designed for labeling a bioactive small molecule or an antibody with β-particle emitting radionuclides 90Y and 177Lu. 3o-C-NETA is an octadentate chelating agent and contains both a macrocyclic backbone (1,4,7-triazacyclononane, TACN) and pendant donor groups. 3o-C-NETA was efficiently synthesized via the regiospecific ring opening of a functionalized aziridinium ion with tert-Butyl protected NODA (1,4,7-triazacyclononane-1,4-diacetic acid) and evaluated for radiolabeling kinetics and in vitro complex stability with 90Y and 177Lu. The new bifunctional ligand (3o-C-NETA) rapidly bound to 90Y or 177Lu, and the corresponding 90Y- or 177Lu-labeled 3o-C-NETA remained stable in human serum for two weeks.
{"title":"Synthesis and evaluation of a novel bifunctional ligand 3o-C-NETA for Yttrium-90 and Lutetium-177","authors":"Hua Xu, Pengfei Dong, Haixing Wang, Inseok Sin, Chi Soo Kang, Siyuan Ren, Xiang Sun, Hyun-Soon Chong","doi":"10.1016/j.bmcl.2025.130136","DOIUrl":"10.1016/j.bmcl.2025.130136","url":null,"abstract":"<div><div>A bifunctional ligand is an essential component for targeted cancer therapy using cytotoxic radionuclides. We report the synthesis and evaluation of a novel bifunctional ligand, 3o-<em>C</em>-NETA, designed for labeling a bioactive small molecule or an antibody with β-particle emitting radionuclides <sup>90</sup>Y and <sup>177</sup>Lu. 3o-<em>C</em>-NETA is an octadentate chelating agent and contains both a macrocyclic backbone (1,4,7-triazacyclononane, TACN) and pendant donor groups. 3o-<em>C</em>-NETA was efficiently synthesized via the regiospecific ring opening of a functionalized aziridinium ion with <em>tert</em>-Butyl protected NODA (1,4,7-triazacyclononane-1,4-diacetic acid) and evaluated for radiolabeling kinetics and <em>in vitro</em> complex stability with <sup>90</sup>Y and <sup>177</sup>Lu. The new bifunctional ligand (3o-<em>C</em>-NETA) rapidly bound to <sup>90</sup>Y or <sup>177</sup>Lu, and the corresponding <sup>90</sup>Y- or <sup>177</sup>Lu-labeled 3o-<em>C</em>-NETA remained stable in human serum for two weeks.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130136"},"PeriodicalIF":2.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412641","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 : 2025-02-11DOI: 10.1016/j.bmcl.2025.130134
Minjae Kim , Siddhi D. Naik , Seung Woo Kim , Misuk Joung , Yun A. Yum , Vikas R. Aswar , Lak Shin Jeong
Based on the potent and selective antagonism exhibited by truncated North (N)-methanocarba adenosine analogs, we synthesized a series of 5ʹ-deoxy (N)-methanocarba nucleosides to explore their structure–activity relationships (SAR). The stereoselective synthesis of the North cyclopropyl-fused alcohol was achieved from d-ribose using ring-closing metathesis, oxidative rearrangement, and cyclopropanation as key steps. Mitsunobu reactions were employed to condense nucleobases with glycosyl donors, followed by N6 functionalization with various amines. Despite their innovative design, all synthesized analogs exhibited lower binding affinity compared to the 4ʹ-thio series and fully truncated (N)-methanocarba adenosine. Docking studies revealed that the 4ʹ-methyl group of the rigid North conformational sugar introduces steric clashes, which likely contribute to the reduced affinity. These findings underscore the critical role of sugar conformation and steric effects in receptor interactions, providing valuable insights for the development of potent and selective A3AR ligands.
{"title":"Design, synthesis, and biological evaluation of 5ʹ-deoxy (N)-methanocarbanucleoside derivatives as A3 adenosine receptor ligands","authors":"Minjae Kim , Siddhi D. Naik , Seung Woo Kim , Misuk Joung , Yun A. Yum , Vikas R. Aswar , Lak Shin Jeong","doi":"10.1016/j.bmcl.2025.130134","DOIUrl":"10.1016/j.bmcl.2025.130134","url":null,"abstract":"<div><div>Based on the potent and selective antagonism exhibited by truncated North (<em>N</em>)-methanocarba adenosine analogs, we synthesized a series of 5ʹ-deoxy (<em>N</em>)-methanocarba nucleosides to explore their structure–activity relationships (SAR). The stereoselective synthesis of the North cyclopropyl-fused alcohol was achieved from <strong><span>d</span></strong>-ribose using ring-closing metathesis, oxidative rearrangement, and cyclopropanation as key steps. Mitsunobu reactions were employed to condense nucleobases with glycosyl donors, followed by <em>N</em><sup>6</sup> functionalization with various amines. Despite their innovative design, all synthesized analogs exhibited lower binding affinity compared to the 4ʹ-thio series and fully truncated (<em>N</em>)-methanocarba adenosine. Docking studies revealed that the 4ʹ-methyl group of the rigid North conformational sugar introduces steric clashes, which likely contribute to the reduced affinity. These findings underscore the critical role of sugar conformation and steric effects in receptor interactions, providing valuable insights for the development of potent and selective A<sub>3</sub>AR ligands.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130134"},"PeriodicalIF":2.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412640","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}
Cathepsin C (CatC), a key enzyme in neutrophil serine protease activation, is a promising target for treating neutrophilic inflammatory diseases like acute lung injury, ARDS, and COVID-19. Despite its therapeutic potential, no CatC inhibitors are currently available. In this study, a series of gallotannin derivatives were isolated from the traditional Chinese medicine Rhois Galla. Among these, 1,2,3,6-tetra-O-galloyl-β-d-glucose (1) inhibited CatC with an IC50 of 32.69 ± 2.95 nM. Subsequently, fifteen derivatives of 1 were synthesized and evaluated, revealing key structure–activity relationships. Compound 1 emerged as a potent and selective CatC inhibitor, while a novel synthetic derivative, 15, demonstrated dual inhibitory effects on CatC and cathepsin L. Structural features, including O-galloyl groups at positions 1, 2, and 6 of β-glucose and a hydrogen donor at position 4, were identified as favorable for CatC inhibition. These findings provide valuable insights for developing novel CatC inhibitors.
{"title":"Isolation, synthesis and structure–activity relationships of gallotannin derivatives as cathepsin C inhibitor","authors":"Hung-Chen Liao , Liang-Mou Kuo , Wei-Ting Chen , Yu-Ling Huang , Bidyadhar Sethy , Ganesh Kumar Dhandabani , Pei-Wen Hsieh","doi":"10.1016/j.bmcl.2025.130133","DOIUrl":"10.1016/j.bmcl.2025.130133","url":null,"abstract":"<div><div>Cathepsin C (CatC), a key enzyme in neutrophil serine protease activation, is a promising target for treating neutrophilic inflammatory diseases like acute lung injury, ARDS, and COVID-19. Despite its therapeutic potential, no CatC inhibitors are currently available. In this study, a series of gallotannin derivatives were isolated from the traditional Chinese medicine Rhois Galla. Among these, 1,2,3,6-tetra-<em>O</em>-galloyl-β-<span>d</span>-glucose (<strong>1</strong>) inhibited CatC with an IC<sub>50</sub> of 32.69 ± 2.95 nM. Subsequently, fifteen derivatives of <strong>1</strong> were synthesized and evaluated, revealing key structure–activity relationships. Compound <strong>1</strong> emerged as a potent and selective CatC inhibitor, while a novel synthetic derivative, <strong>15</strong>, demonstrated dual inhibitory effects on CatC and cathepsin L. Structural features, including <em>O</em>-galloyl groups at positions 1, 2, and 6 of β-glucose and a hydrogen donor at position 4, were identified as favorable for CatC inhibition. These findings provide valuable insights for developing novel CatC inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130133"},"PeriodicalIF":2.5,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397684","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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