Bioorganic & Medicinal Chemistry最新文献_第10页

Synthesis of 6-ethoxyphenyl 4-fluorobenzenesulfonate-tagged thiosemicarbazones as carbonic anhydrase inhibitors: In-vitro and in silico approach 作为碳酸酐酶抑制剂的6-乙氧基苯基4-氟苯磺酸标记的硫代氨基脲的合成：体外和硅法

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-07-09 DOI: 10.1016/j.bmc.2025.118301

Iqra Munir , Hina Aftab , Abdul Asim Farooq , Halil Şenol , Parham Taslimi , Nastaran Sadeghian , Rima D. Alharthy , Asif Rasool , Uzma Ghaffar , Silvia Schenone , Zahid Shafiq

{"title":"Synthesis of 6-ethoxyphenyl 4-fluorobenzenesulfonate-tagged thiosemicarbazones as carbonic anhydrase inhibitors: In-vitro and in silico approach","authors":"Iqra Munir , Hina Aftab , Abdul Asim Farooq , Halil Şenol , Parham Taslimi , Nastaran Sadeghian , Rima D. Alharthy , Asif Rasool , Uzma Ghaffar , Silvia Schenone , Zahid Shafiq","doi":"10.1016/j.bmc.2025.118301","DOIUrl":"10.1016/j.bmc.2025.118301","url":null,"abstract":"<div><div>In this study, a series of 6-ethoxyphenyl-4-fluorobenzenesulphonate-based thiosemicarbazones <strong>(5a–w)</strong> were synthesized <em>via</em> a two-step process and structurally characterized by <sup>1</sup>H NMR and <sup>13</sup>C NMR spectroscopy. Their inhibitory activities against human carbonic anhydrase isoforms I and II (hCA I and hCA II) were evaluated, revealing potent inhibition at low nanomolar concentrations with IC<sub>50</sub> values ranging from 56.36 to 230.17 nM for hCA I and 30.66 to 175.45 nM for hCA II. Compounds <strong>5a, 5</strong><strong>g,</strong> and <strong>5n</strong> exhibited the highest enzyme inhibition, with <strong>5a</strong> identified as the most potent <em>in vitro</em> inhibitor for both isoforms. Molecular docking studies and MM-GBSA binding free energy calculations demonstrated that compound <strong>5n</strong> displayed the strongest binding affinity toward hCA I, stabilized by key interactions including π-π stacking, hydrogen bonds, and coordination to the catalytic zinc ion. Molecular dynamics simulations over 100 ns confirmed the stability and dynamic adaptability of the <strong>5n–hCA I</strong> and <strong>5</strong><strong>g–hCA II</strong> complexes, preserving critical interactions essential for binding. Validation of the docking protocol yielded RMSD values below 2.0 Å, supporting the reliability of the computational approach. Overall, these findings highlight compounds <strong>5n</strong> and <strong>5</strong><strong>g</strong> as promising lead molecules for selective inhibition of hCA I and hCA II, with potential applications in the treatment of carbonic anhydrase-related disorders.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118301"},"PeriodicalIF":3.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of novel thiourea benzenesulfonamides based 1,8-naphthalimide derivatives as carbonic anhydrase IX inhibitors that induce ferroptosis and inhibit triple-negative breast cancer metastasis 发现基于1,8-萘酰亚胺的新型硫脲苯磺酰胺衍生物作为碳酸酐酶IX抑制剂，诱导铁下垂并抑制三阴性乳腺癌转移

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-07-09 DOI: 10.1016/j.bmc.2025.118304

Jiajia Liu , Yanfei Wang , Simin Liang , Zihan Fan , Jiao Ran , Qiaoling Liang , Ye Zhang , Rizhen Huang , Hengshan Wang

{"title":"Discovery of novel thiourea benzenesulfonamides based 1,8-naphthalimide derivatives as carbonic anhydrase IX inhibitors that induce ferroptosis and inhibit triple-negative breast cancer metastasis","authors":"Jiajia Liu , Yanfei Wang , Simin Liang , Zihan Fan , Jiao Ran , Qiaoling Liang , Ye Zhang , Rizhen Huang , Hengshan Wang","doi":"10.1016/j.bmc.2025.118304","DOIUrl":"10.1016/j.bmc.2025.118304","url":null,"abstract":"<div><div>Carbonic anhydrase IX (CAIX) is an attractive target for therapeutic intervention in many hypoxic tumors. Herein, we described the discovery of novel thiourea benzenesulfonamides based 1,8-naphthalimide derivatives as carbonic anhydrase IX inhibitors that induced ferroptosis and inhibited triple-negative breast cancer metastasis. One of the representative compounds, <strong>11o</strong>, effectively inhibited CA IX enzymatic activity and displayed high selective for CA IX over CA II. Molecular docking study and molecular dynamics simulations were also performed to gain insights into the binding interactions of <strong>11o</strong> in the binding pocket of CAIX and complex stability. Satisfyingly, this compound exhibited superior antitumor activities against MDA-MB-231 cells under hypoxia than normoxic conditions and surpassed reference compound SLC-0111. Mechanism studies revealed that <strong>11o</strong> effectively inhibited topoisomerase I activity, induced cell apoptosis and ferroptosis and suppressed cell migration in MDA-MB-231 cells. Notably, <em>in vivo</em> assays results demonstrated that <strong>11o</strong> exerted efficient antitumor activity and significant anti-metastasis potency in a xenograft model of highly metastatic murine breast cancer 4 T1 cells. These findings suggest that <strong>11o</strong> may serve as a potential candidate for combating triple-negative breast cancer metastasis.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118304"},"PeriodicalIF":3.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis of 2-(3-aminopropyl)benzopyrans as potential antipsychotic agents targeting D2/D3 and 5-HT2A receptors 2-（3-氨基丙基）苯并吡喃作为D2/D3和5-HT2A受体潜在抗精神病药物的合成

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-07-03 DOI: 10.1016/j.bmc.2025.118300

Álvaro Bernabeu-Sanchis , María José Varela , Ainhoa García , Carlos Villarroel-Vicente , Laura Vila , María Isabel Loza , José Brea , Diego Cortes , Nuria Cabedo

{"title":"Synthesis of 2-(3-aminopropyl)benzopyrans as potential antipsychotic agents targeting D2/D3 and 5-HT2A receptors","authors":"Álvaro Bernabeu-Sanchis , María José Varela , Ainhoa García , Carlos Villarroel-Vicente , Laura Vila , María Isabel Loza , José Brea , Diego Cortes , Nuria Cabedo","doi":"10.1016/j.bmc.2025.118300","DOIUrl":"10.1016/j.bmc.2025.118300","url":null,"abstract":"<div><div>The high prevalence and complexity of neurological and psychiatric disorders, such as schizophrenia, makes the development of new, safer and more effective neuroleptic drugs a continuing need. We have synthesized 2-(3-aminopropyl)benzopyrans bearing a chroman-6-ol nucleus, a 3‑carbon atoms side chain, and an ionisable nitrogen into different amine frameworks. The specific affinity of 2-(3-aminopropyl)benzopyrans was determined by competition binding assays of radioligands on membranes from CHO cells stably expressing the cloned human D<sub>2</sub>, D<sub>3</sub> and 5-HT<sub>2A</sub> receptors. Results showed that benzopyrans <strong>9b</strong>, <strong>9e</strong>, <strong>9f</strong> and <strong>11,</strong> all of them with a free phenol group in the chromanol nucleus, displaced the specific radioligand for hD<sub>2</sub> and hD<sub>3</sub> in the submicromolar or low micromolar range. Molecular docking analysis shows that the nitrogen atom of amine substituents plays a key role to bind the orthosteric binding site of both D<sub>2</sub>R and 5-HT<sub>2A</sub>R, as well as the oxygen atom of phenol group for binding to the D<sub>2</sub>R. In addition, functional assays revealed a partial hD<sub>2</sub> agonism and h5-HT<sub>2A</sub> antagonism for <strong>9b</strong>, <strong>9e</strong> and <strong>11</strong> derivatives as new atypical antipsychotic agents, while compound <strong>9f</strong> behaved as a D<sub>2</sub> antagonist like a first-generation neuroleptic.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118300"},"PeriodicalIF":3.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis and biological evaluation of 3-arylisoquinoline derivatives as topoisomerase IIα inhibitors for the therapy of small cell lung cancer 3-芳基异喹啉衍生物拓扑异构酶IIα抑制剂治疗小细胞肺癌的设计、合成及生物学评价

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-07-01 DOI: 10.1016/j.bmc.2025.118299

Xuemei Deng , Xiongqi Yang , Quanwei Yu , Zhenqiang Xia , Yuying Wang , Ridong Huang , Hai Chen , Weimin Li , Yang He

{"title":"Design, synthesis and biological evaluation of 3-arylisoquinoline derivatives as topoisomerase IIα inhibitors for the therapy of small cell lung cancer","authors":"Xuemei Deng , Xiongqi Yang , Quanwei Yu , Zhenqiang Xia , Yuying Wang , Ridong Huang , Hai Chen , Weimin Li , Yang He","doi":"10.1016/j.bmc.2025.118299","DOIUrl":"10.1016/j.bmc.2025.118299","url":null,"abstract":"<div><div>There is a pressing need to search for efficient therapeutic molecular candidates for the treatment of small cell lung cancer (SCLC). Here, we designed a series of 3-arylisoquinoline derivatives by introducing either flexible tertiary amino groups or rigid imidazole rings, aiming to enhance anti-SCCL efficay. Among them, compound <strong>52</strong> with a symmetrical dibutylamine side chain demonstrated a remarkable inhibitory potency on Topoismerase II (Topo II). In vitro studies revealed that <strong>52</strong> exhibited superior inhibitory activity to etoposide against SCLC cells (IC50 = 0.6 μM in NCI-H446 cells and 0.1 μM in NCI-H1048 cells). Molecular docking studies indicated that <strong>52</strong> could intercalate into DNA strands. Comet assays accordingly confirmed it induced DNA damage, which subsequently triggered intrinsic mitochondrial apoptosis. Moreover, <strong>52</strong> effectively attenuated the phosphorylation of the PI3K/Akt/mTOR signaling pathway, which in turn effectively suppressed proliferation, invasion, and migration of SCLC cells. In the NCI-H446 cell-derived xenograft (CDX) model, <strong>52</strong> demonstrated a significant tumor inhibition effect. At a low dose of 2.5 mg/kg, the tumor inhibition rate was 71.58 %, and at a high dose of 5 mg/kg, it reached 88.16 %. In contrast, the positive control etoposide, at a dose of 5 mg/kg, only showed a tumor inhibition rate of 41.77 %, highlighting the superiority of <strong>52</strong>. In addition, <strong>52</strong> exhibited a better safety profile in the tested mice. Overall, this study lays a solid foundation for the development of 3-arylisoquinoline compounds as potential anti-SCLC agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118299"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and biological evaluation of Sulforaphane derivatives with dual functions: Ischemia-reperfusion injury protection and antitumor effects 具有缺血再灌注损伤保护和抗肿瘤双重功能的萝卜硫素衍生物的合成及生物学评价

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-06-29 DOI: 10.1016/j.bmc.2025.118298

Yi Peng , Xingyu Shi , Qiong Wang , Ying Pan , Xinghao Wang , Kang Yan , Zikai Feng , Jinhong Zheng , Jinzhi Wang

{"title":"Synthesis and biological evaluation of Sulforaphane derivatives with dual functions: Ischemia-reperfusion injury protection and antitumor effects","authors":"Yi Peng , Xingyu Shi , Qiong Wang , Ying Pan , Xinghao Wang , Kang Yan , Zikai Feng , Jinhong Zheng , Jinzhi Wang","doi":"10.1016/j.bmc.2025.118298","DOIUrl":"10.1016/j.bmc.2025.118298","url":null,"abstract":"<div><div>Reperfusion therapy for the treatment of acute myocardial infarction (AMI) often leads to ischemia-reperfusion (I/R) injuries, characterized by excessive ROS. Sulforaphane (SFN) homologous, known for their anti-inflammatory and antioxidant properties, activate the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway and reduce mitochondrial ROS but are limited by poor stability and short half-life. SFN derivatives were synthesized through structural modifications of the dithiocarbamate and thiourea moieties at the isothiocyanate group, aiming to enhance stability and maintain therapeutic efficacy. Compound <strong>3</strong><strong>g</strong> emerged as a promising candidate, demonstrating superior protection against hypoxia-reoxygenation (H/R) injury in cardiac microvascular endothelial cells (CMECs) and exhibiting good antitumor activity. Specifically, <strong>3</strong><strong>g</strong> reduced ROS levels by 24.5 % (compared to nifedipine at 17.8 %), increased NO production to 48.0 μM (vs. 44.0 μM), lowered TNF-α secretion to 22.6 pg/mL (vs. 23.9 pg/mL). Concurrently, <strong>3</strong><strong>g</strong> showed potent antiproliferative activity (IC<sub>50</sub> = 7.5 μM), with 3.8-fold greater potency than 5-fluorouracil (IC<sub>50</sub> = 28.2 μM). Stability studies showed enhanced resistance in both protic and aprotic solvents. Density functional theory (DFT) was applied to characterize the molecular properties of the optimal compounds. Molecular docking and ADMET analysis revealed that aromatic substitution and sulfur oxidation significantly improved Nrf2/Keap1 pathway targeting, highlighting the derivative's potential for stability and therapeutic efficacy. These findings suggest that <strong>3</strong><strong>g</strong> is a promising candidate for treating I/R-induced injury and oxidative stress-related cardiovascular conditions.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118298"},"PeriodicalIF":3.3,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring novel green synthetic pathways and recent advances in pyrrole and its derivatives 探索新的绿色合成途径和吡咯及其衍生物的最新进展

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-06-28 DOI: 10.1016/j.bmc.2025.118295

Rajveer Kaur , Poonam Sharma , Suman Lata , Ankita Bharwal , Vikrant Abbot

{"title":"Exploring novel green synthetic pathways and recent advances in pyrrole and its derivatives","authors":"Rajveer Kaur , Poonam Sharma , Suman Lata , Ankita Bharwal , Vikrant Abbot","doi":"10.1016/j.bmc.2025.118295","DOIUrl":"10.1016/j.bmc.2025.118295","url":null,"abstract":"<div><div>Pyrrole has fascinated scientists since its first isolation in the 19th century, particularly due to its importance in natural compounds such as heme and chlorophyll. Its unique aromatic structure and diverse reactivity have established it as a key building block in both organic and medicinal chemistry. Over the years, the interest in pyrrole derivatives has grown, especially as researchers seek greener and more sustainable synthesis methods. This review examines the evolution of pyrrole chemistry, from traditional approaches to more modern, environmentally friendly techniques, including solvent-free reactions, microwave-assisted processes, and the utilization of renewable feedstocks. It explores the diverse range of biological activities exhibited by pyrrole-based molecules, including antimicrobial, anticancer, and neuroprotective effects. Additionally, the potential applications of pyrrole compounds extend beyond pharmaceuticals, reaching into materials science and electronics. The article concludes by identifying current research gaps and suggesting future directions that could advance pyrrole chemistry in alignment with green and sustainable development goals.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118295"},"PeriodicalIF":3.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144536026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis and evaluation of vanillin derivatives as dual-target inhibitors for the treatment of Alzheimer's disease 香兰素衍生物作为治疗阿尔茨海默病双靶点抑制剂的设计、合成和评价

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-06-28 DOI: 10.1016/j.bmc.2025.118296

Zong Huan Li, Hai Ming Liu, Zeng Yi Fan, Wan Pang, Li Ping Cheng

{"title":"Design, synthesis and evaluation of vanillin derivatives as dual-target inhibitors for the treatment of Alzheimer's disease","authors":"Zong Huan Li, Hai Ming Liu, Zeng Yi Fan, Wan Pang, Li Ping Cheng","doi":"10.1016/j.bmc.2025.118296","DOIUrl":"10.1016/j.bmc.2025.118296","url":null,"abstract":"<div><div>The purpose of this study is to develop more effective therapeutic agents to slow or prevent Alzheimer's progression. A lead compound <strong>ZINC4372573</strong> was identified by using molecular docking and molecular dynamics simulation techniques. A series of novel vanillin derivatives were designed and synthesized as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The in vitro assay results show that compound <strong>4c</strong> exhibits the most potent inhibitory activity against both AChE and BuChE, with IC<sub>50</sub> values of 0.18 μM and 7.61 μM, respectively. This performance is superior to the positive control drug <strong>galantamine</strong> (AChE IC<sub>50</sub> = 3.65 μM; BuChE IC<sub>50</sub> = 15.29 μM). Molecular docking study reveals that the good activity of <strong>4c</strong> may be attributed to the preferable docking mode, robust intermolecular interactions (including π-π stacking and hydrogen bonding), and the superior binding properties of the indole ring. Cytotoxicity test for compound <strong>4c</strong> was further performed by CCK-8 method, with results indicating a favorable safety profile. In addition, antioxidant test for <strong>4c</strong> reveals its notable antioxidant activity. These findings suggest that <strong>4c</strong> holds potential as a promising dual AChE/BuChE inhibitor for the development of novel therapeutic agents targeting Alzheimer's disease. Subsequent investigations will prioritize comprehensive evaluation of in vivo therapeutic efficacy and pharmacokinetic characterization, thereby facilitating translational development toward clinical applications.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118296"},"PeriodicalIF":3.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advances in DNA-based proteolysis-targeting chimeras technology: Novel strategies for targeting previously undruggable proteins in cancer therapy 基于dna的蛋白水解靶向嵌合体技术的进展：靶向癌症治疗中先前不可药物蛋白的新策略

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-06-28 DOI: 10.1016/j.bmc.2025.118297

Min Hou , Mingda Li , Yulin Li , Xiaobo Wu , Die Long , Di Sun , Jincheng Zeng

{"title":"Advances in DNA-based proteolysis-targeting chimeras technology: Novel strategies for targeting previously undruggable proteins in cancer therapy","authors":"Min Hou , Mingda Li , Yulin Li , Xiaobo Wu , Die Long , Di Sun , Jincheng Zeng","doi":"10.1016/j.bmc.2025.118297","DOIUrl":"10.1016/j.bmc.2025.118297","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) technology has emerged as a transformative therapeutic strategy for selectively eliminating aberrant proteins across diverse pathological conditions. This comprehensive review systematically examines recent advances in DNA-based proteolysis-targeting chimeras (DNA-PROTACs), which harness the exceptional specificity and binding affinity of DNA to substantially expand the targetable protein repertoire beyond conventional small molecule PROTACs. Through extensive literature analysis encompassing mechanistic studies, preclinical evaluations, and clinical investigations, we demonstrate that DNA-PROTACs effectively target previously undruggable proteins, including transcription factors, cell membrane proteins, and DNA damage response mediators. These innovative chimeric constructs exhibit superior catalytic efficiency through E3 ubiquitin ligase recruitment via the proteasomal degradation pathway, with unique advantages in linker optimization enabled by precise nucleotide-level control during DNA synthesis. Cell-based assays consistently reveal enhanced selectivity profiles and expanded therapeutic windows compared to traditional PROTAC modalities and alternative RNA-based approaches. Despite promising preclinical outcomes and advancing clinical development timelines, challenges in delivery optimization, molecular stability enhancement, and clinical translation persist. The integration of artificial intelligence-assisted drug design platforms and in vivo aptamer evolution technologies presents unprecedented opportunities for accelerating DNA-PROTACs development toward sub-nanomolar potency targets, positioning this technology as a paradigm-shifting approach in precision medicine across oncology, immunotherapy, and neurodegeneration therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118297"},"PeriodicalIF":3.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144536024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Jolkinolide B inhibits mycobacterial growth by down-regulating ribosomal proteins and interfering with protein synthesis Jolkinolide B通过下调核糖体蛋白和干扰蛋白合成抑制分枝杆菌生长

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-06-26 DOI: 10.1016/j.bmc.2025.118294

Renxiang Zhao , Xiuyan Han , Changming Chen , Shujing Zhang , Yuzhuo Wu , Chao Wang , Xiaochi Ma

{"title":"Jolkinolide B inhibits mycobacterial growth by down-regulating ribosomal proteins and interfering with protein synthesis","authors":"Renxiang Zhao , Xiuyan Han , Changming Chen , Shujing Zhang , Yuzhuo Wu , Chao Wang , Xiaochi Ma","doi":"10.1016/j.bmc.2025.118294","DOIUrl":"10.1016/j.bmc.2025.118294","url":null,"abstract":"<div><div>The traditional Chinese medicine <em>Euphorbia fischeriana</em> Steud (<em>E. fischeriana</em>) has been used for treating lymph node tuberculosis (TB) for a long time. This study demonstrates that Jolkinolide B, a component of <em>E. fischeriana,</em> exhibits antimycobacterial activity with a minimum inhibitory concentration (MIC) of 3 μg/mL against <em>M. tuberculosis</em> H37Ra. Additionally, it shows bactericidal effect on RAW264.7 macrophages infected with <em>M. tuberculosis</em> at a concentration of 2 × MIC. Mechanistic study via transcriptome revealed that Jolkinolide B significantly reduced the transcription of 17 ribosomal proteins, thereby inhibiting protein synthesis in <em>M. tuberculosis</em>. RT-qPCR confirmed that Jolkinolide B decreased the expression of mycobacterial ribosomal proteins in a concentration-dependent manner. Finally, morphological observations indicated that Jolkinolide B caused the tubercle bacilli to become shorter and deformed. This study highlights a natural compound from <em>E. fischeriana</em> and clarifies its mechanism of action against TB, supporting the rational use of traditional Chinese medicine (TCM) and antibiotics in TB treatment.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118294"},"PeriodicalIF":3.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144557053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis, anticancer activity, and in silico computational studies of new imidazolone-based derivatives with potential multi-target kinase inhibitory activity 具有潜在多靶点激酶抑制活性的新型咪唑酮衍生物的设计、合成、抗癌活性和计算机计算研究

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-06-25 DOI: 10.1016/j.bmc.2025.118292

Nesreen S. Ahmed , Somaia S. Abd El-Karim , Manal M. Anwar , Neama A. Mohamed , Ahmed F. El-Sayed , Nagy M. Khalifa

{"title":"Design, synthesis, anticancer activity, and in silico computational studies of new imidazolone-based derivatives with potential multi-target kinase inhibitory activity","authors":"Nesreen S. Ahmed , Somaia S. Abd El-Karim , Manal M. Anwar , Neama A. Mohamed , Ahmed F. El-Sayed , Nagy M. Khalifa","doi":"10.1016/j.bmc.2025.118292","DOIUrl":"10.1016/j.bmc.2025.118292","url":null,"abstract":"<div><div>A novel class of 5-(3,5-dimethoxybenzylidene)-2-thioxoimidazolidin-4-one-based derivatives, linked to various alkyl and aryl substituents <strong>1a-d</strong> and <strong>2a-h</strong>, was designed and synthesized as promising candidates for anti-colon cancer therapy with multi-targeting kinase suppression activity. The antiproliferative effect of the new compounds was assessed against HT-29 using the MTT assay. The congeners <strong>1c</strong> and <strong>2h</strong> demonstrated the most potent suppressive effects, with IC<sub>50</sub> values 1.828 and 2.197 μg/mL, respectively. The latter derivatives were evaluated as multi-kinase inhibitors against VEGFR-2, c-Met, and PIM-1, exhibiting promising activity with IC<sub>50</sub> values ranging from 0.081 ± 0.003 to 0.433 ± 0.017 μg/mL. Moreover, <strong>2h</strong> induced an apoptotic effect and cell cycle arrest at G0/G1 of the mitotic cycle in HT-29 cells. Furthermore, <strong>2h</strong> upregulated the oncogenic parameters, including caspase-3, caspase-9, and the Bax/Bcl-2 ratio. The docking results showed that compounds <strong>1c</strong>, <strong>2h</strong>, and <strong>2e</strong> had strong binding energies and effectively interacted with the active sites of the VEGFR-2, c-Met, and PIM-1 receptors. According to the <em>in-silico</em> ADMET analysis the new compounds are anticipated to exhibit promising oral bioavailability, desirable drug-like qualities, and minimal toxicity risks. Molecular dynamics (MD) simulations indicated that <strong>2h</strong> interacts consistently with the c-MET, PIM-1, and VEGFR-2 receptors. These results reinforce the potential of these compounds as candidates for further drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118292"},"PeriodicalIF":3.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144536025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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