Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Design, synthesis and biological evaluation of Streptazolin analogs as anti-inflammatory agents","authors":"Shan Lu ,&nbsp;Zhuang Li ,&nbsp;Peng Jiang ,&nbsp;Bo Jiang ,&nbsp;Shanqin Huang ,&nbsp;Xinhang Su ,&nbsp;Ke Ma ,&nbsp;Ying Xu ,&nbsp;Lingling Ding ,&nbsp;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}

{"title":"Radiosynthesis and in vivo evaluation of [18F]BEAN as a potential mitochondria-based PET biomarker for metabolic disorders","authors":"Charalambos Kaittanis ,&nbsp;Hyunjung Kim ,&nbsp;Tyler Teceno ,&nbsp;Yoann Petibon ,&nbsp;Ashley Knight ,&nbsp;Matthew Crouthamel ,&nbsp;Anthony P. Belanger ,&nbsp;Zhaoming Xiong ,&nbsp;Wanida Ruangsiriluk ,&nbsp;Meera Modi ,&nbsp;Rizwana Islam ,&nbsp;Madhu Natarajan ,&nbsp;Nikolaos Papaioannou ,&nbsp;Christopher T. Winkelmann ,&nbsp;Johannes Tauscher ,&nbsp;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 [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.</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}

{"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 ,&nbsp;Jaimin D. Bhatt ,&nbsp;Bharat C. Dixit ,&nbsp;Shazia Anjum ,&nbsp;Anju Singh ,&nbsp;Tohasib Yusub Chaudhari ,&nbsp;Fatima Heyat ,&nbsp;Hari Madhav ,&nbsp;Mahim Sattar ,&nbsp;Tarosh S. Patel ,&nbsp;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>IC₅₀ 3.18</strong> and <strong>3.98 µM</strong> respectively, and <strong>QS13</strong> with <strong>IC₅₀ 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>IC₅₀ 3.9</strong> and <strong>4.9 µM</strong>) and <strong><em>Pf</em>FP-3</strong> (<strong>IC₅₀ 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}

{"title":"Design, synthesis, and biological evaluation of 5ʹ-deoxy (N)-methanocarbanucleoside derivatives as A3 adenosine receptor ligands","authors":"Minjae Kim ,&nbsp;Siddhi D. Naik ,&nbsp;Seung Woo Kim ,&nbsp;Misuk Joung ,&nbsp;Yun A. Yum ,&nbsp;Vikas R. Aswar ,&nbsp;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>⁶ 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 A₃AR 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}

{"title":"Synthesis and evaluation of a novel bifunctional ligand 3o-C-NETA for Yttrium-90 and Lutetium-177","authors":"Hua Xu,&nbsp;Pengfei Dong,&nbsp;Haixing Wang,&nbsp;Inseok Sin,&nbsp;Chi Soo Kang,&nbsp;Siyuan Ren,&nbsp;Xiang Sun,&nbsp;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 ⁹⁰Y and ¹⁷⁷Lu. 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 ⁹⁰Y and ¹⁷⁷Lu. The new bifunctional ligand (3o-<em>C</em>-NETA) rapidly bound to ⁹⁰Y or ¹⁷⁷Lu, and the corresponding ⁹⁰Y- or ¹⁷⁷Lu-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}

{"title":"Isolation, synthesis and structure–activity relationships of gallotannin derivatives as cathepsin C inhibitor","authors":"Hung-Chen Liao ,&nbsp;Liang-Mou Kuo ,&nbsp;Wei-Ting Chen ,&nbsp;Yu-Ling Huang ,&nbsp;Bidyadhar Sethy ,&nbsp;Ganesh Kumar Dhandabani ,&nbsp;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 IC₅₀ 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}

{"title":"ZLDI-8 facilitates pexophagy by ROS-mediated activation of TFEB and ATM in HeLa cells","authors":"Yong Hwan Kim ,&nbsp;Joon Bum Kim ,&nbsp;Ji-Eun Bae ,&nbsp;Na Yeon Park ,&nbsp;Seong Hyun Kim ,&nbsp;Daeun Park ,&nbsp;Jun Hee So ,&nbsp;Jae Man Lee ,&nbsp;Kwiwan Jeong ,&nbsp;Dong Kyu Choi ,&nbsp;Doo Sin Jo ,&nbsp;Dong-Hyung Cho","doi":"10.1016/j.bmcl.2025.130130","DOIUrl":"10.1016/j.bmcl.2025.130130","url":null,"abstract":"<div><div>Autophagy-mediated organelle quality control is vital for cellular homeostasis. However, the mechanisms underlying selective autophagy of peroxisomes, known as pexophagy, are less well understood than those of other organelles, such as mitochondria. In this study, we screened a phosphatase inhibitor library using a cell-based system and identified several potent pexophagy inducers, including ZLDI-8, a known inhibitor of lymphoid-specific tyrosine phosphatase. Notably, treatment with ZLDI-8 selectively induces the loss of peroxisomes without affecting other organelles, such as mitochondria, the endoplasmic reticulum, or the Golgi apparatus. The peroxisome loss induced by ZLDI-8 was significantly blocked in <em>ATG5</em>-knockout HeLa cells, confirming its dependence on autophagy. We further found that ZLDI-8 treatment increases both cellular and peroxisomal reactive oxygen species (ROS), which were effectively scavenged by <em>N</em>-acetylcysteine (NAC). The increase in peroxisomal ROS leads to the activation of ATM kinase and the dephosphorylation of TFEB. Moreover, ROS scavenging prevents all of these processes. Taken together, these findings demonstrate that ZLDI-8 induces pexophagy through a mechanism involving peroxisomal ROS-mediated activation of TFEB and ATM. This study provides valuable insights into the molecular mechanisms regulating selective peroxisome degradation and potential therapeutic strategies for targeting pexophagy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130130"},"PeriodicalIF":2.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381182","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}

{"title":"Zirconium oxide nano-catalyzed bis(indolyl)methanes: A sustainable route to anticancer therapies","authors":"Komal Rathi ,&nbsp;Suryakant Kumar ,&nbsp;Bidya Bhushan ,&nbsp;Varun Rawat ,&nbsp;Ashwani Kumar ,&nbsp;Aman Bhardwaj ,&nbsp;Anand Prakash ,&nbsp;Ved Prakash Verma","doi":"10.1016/j.bmcl.2025.130132","DOIUrl":"10.1016/j.bmcl.2025.130132","url":null,"abstract":"<div><div>Bis(indolyl)methanes (BIMs) are a class of compounds known for their diverse biological activities, including potential anticancer properties. Modern synthetic chemistry techniques are examined in this work to develop and manufacture novel anticancer medications with increased effectiveness and fewer side effects. The cytotoxic efficacy of a moderate and very effective method for creating pharmacologically active BIMs <strong>3a–j</strong> using ZrO2 nanoparticles as a catalyst was assessed against the MCF-7 breast cancer cell line. Remarkably, compounds <strong>3a</strong> and <strong>3b</strong> exhibited exceptional potency, with IC₅₀ values of 0.17 and 0.13 μM, respectively, surpassing the activity of standard anticancer agents sorafenib (IC₅₀: 1.23 μM). Another compound <strong>3j</strong> demonstrated moderate inhibition effect with an IC₅₀ value of 8.6 μM. These results highlight the potential of BIMs as promising anticancer agents and warrant further investigation into their mechanism of action and therapeutic applications.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130132"},"PeriodicalIF":2.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143376779","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}

{"title":"Cytosine mimic azophenoxazine tCOAzo quenches FAM fluorescence and provides concentration-dependent Raman quenching upon molecular beacon hybridization","authors":"Dmitriy Y. Ryazantsev ,&nbsp;Nadezda F. Meshcheryakova ,&nbsp;Vera A. Alferova ,&nbsp;Polina N. Kamzeeva ,&nbsp;Ekaterina V. Ryabukhina ,&nbsp;Timofei S. Zatsepin ,&nbsp;Elena G. Zavyalova ,&nbsp;Andrey V. Aralov","doi":"10.1016/j.bmcl.2025.130131","DOIUrl":"10.1016/j.bmcl.2025.130131","url":null,"abstract":"<div><div>The molecular beacon (MB) strategy finds diverse applications in bioimaging, biosensing and disorders diagnostics. Classic MBs are stem-loop oligonucleotides modified with a reporter and a quencher at the 5′- and 3′- ends. Hybridization with a specific target leads to spatial separation of the quencher and the reporter with subsequent changes in spectral signal, for example, an increase in reporter fluorescence emission. However, hydrophobic interactions between a conventional bulky quencher and the reporter might influence hybridization properties and limit stem length in MB design. In this work, we studied the synthetic nucleobase analog <strong>tC^o_Azo</strong> mimicking cytosine, capable of quenching reporter (FAM) fluorescence in folded MBs while minimally affecting their tharmal stability compared to MBs with classic FAM/BHQ1 labels. In addition, we conducted a preliminary assessment of the applicability of FAM/<strong>tC^o_Azo</strong>-modified MBs for SERS-based techniques using short single-stranded and long double-stranded DNA fragments from <em>Fusarium avenaceum</em> elongation factor 1a DNA as matrices. SERS intensity was decreased in the presence of matrix DNA compared to the scrambled sequence; and the MB modified with three <strong>tC^o_Azo</strong> residues provided a concentration-dependent signal. The results indicate that <strong>tC^o_Azo</strong> is a promising tool for fine tuning MB properties for fluorescent- and SERS-based diagnostic applications.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130131"},"PeriodicalIF":2.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381175","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}

{"title":"Corrigendum to “Synthesis and biological evaluations of new nitric oxide-anti-inflammatory drug hybrids” [Bioorg. Med. Chem. Lett. 27(18) (2017) 4358–4369]","authors":"Eman K.A. Abdelall ,&nbsp;Abdou O. Abdelhamid ,&nbsp;Amany A. Azouz","doi":"10.1016/j.bmcl.2025.130119","DOIUrl":"10.1016/j.bmcl.2025.130119","url":null,"abstract":"","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130119"},"PeriodicalIF":2.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187704","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}