Bioorganic & Medicinal Chemistry Letters最新文献_第3页

Design and synthesis of guanidino derivatives of benzoate esters as SIRT6 inhibitors 苯甲酸酯类胍类衍生物SIRT6抑制剂的设计与合成。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-10-07 DOI: 10.1016/j.bmcl.2025.130430

Yongzhi Ma , Minni Ding , Kewang Yu , Siyu Wang , Siyuan Wang , Hao Cao , Huiming Hua , Dahong Li

{"title":"Design and synthesis of guanidino derivatives of benzoate esters as SIRT6 inhibitors","authors":"Yongzhi Ma , Minni Ding , Kewang Yu , Siyu Wang , Siyuan Wang , Hao Cao , Huiming Hua , Dahong Li","doi":"10.1016/j.bmcl.2025.130430","DOIUrl":"10.1016/j.bmcl.2025.130430","url":null,"abstract":"<div><div>SIRT6 is a key member of the Sirtuin family and plays a crucial role in regulating cellular metabolism, maintaining genomic stability, and influencing the aging process. SIRT6 inhibitors have garnered significant attention due to their potential therapeutic value in treating cancer, inflammation, and metabolic diseases. In this study, a high-throughput virtual screening approach, combined with FLUOR DE LYS detection, was employed to identify the guanidino benzoate ester compound <strong>Hit 13</strong>, which exhibits SIRT6 inhibitory activity. Subsequent structural optimization yielded a series of analogs. Among these, compounds <strong>15</strong>, <strong>25</strong>, and <strong>27</strong> demonstrated SIRT6 inhibitory activity and selectivity. Combination therapy, an emerging strategy in cancer treatment, has demonstrated promising efficacy. The combination of SIRT6 inhibitors with chemotherapy drugs can produce synergistic cytotoxic effects, reverse drug resistance, and has the potential to reduce chemotherapy doses while mitigating side effects. When compound <strong>15</strong> or <strong>25</strong> was combined with chemotherapy agents, they significantly enhanced the anti-proliferative effects of these drugs on tumor cells. This sensitization effect was particularly pronounced with doxorubicin, which reduced its IC<sub>50</sub> value against MCF-7 cells from 11 μM to 4 μM. Compounds <strong>15</strong> and <strong>25</strong> may serve as promising lead compounds for drug development targeting SIRT6.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130430"},"PeriodicalIF":2.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249077","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}

引用次数: 0

In vitro comparison of the glycosidase inhibitory profile of isoiminosugars with their 1- and 5a-modified derivatives 异亚糖及其1-和5a修饰衍生物的糖苷酶抑制谱的体外比较。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-10-06 DOI: 10.1016/j.bmcl.2025.130426

Solveig Auranaune Markussen , Óscar López , Emil Lindbäck

引用次数: 0

Privileged scaffold repurposed: the evolving role of quinolone derivatives in antiviral therapy 特权支架的重新利用：喹诺酮类衍生物在抗病毒治疗中的演变作用。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-10-04 DOI: 10.1016/j.bmcl.2025.130427

Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan

{"title":"Privileged scaffold repurposed: the evolving role of quinolone derivatives in antiviral therapy","authors":"Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan","doi":"10.1016/j.bmcl.2025.130427","DOIUrl":"10.1016/j.bmcl.2025.130427","url":null,"abstract":"<div><div>Significant advancements have been made in the field of antiviral drug development; however, existing therapies still face considerable challenges regarding safety and efficacy. Moreover, with the frequent emergence of outbreaks caused by viruses such as SARS-CoV-2, monkeypox virus, and Chikungunya virus in recent years, there is an urgent need to develop novel antiviral drugs that are highly effective, low-toxic, and possess broad-spectrum activity against drug-resistant strains. Exploring antiviral agents from privileged structures has long been a tacit shortcut for researchers, and quinolone derivatives, as a class of privileged structures with diverse antiviral activities, have attracted extensive attention in recent years, providing a crucial material basis for the development of next-generation antiviral drugs. This review focuses on the discovery, mechanisms of action, potential clinical applications, and research progress of quinolone derivatives with typical structural characteristics or potent antiviral activity, aiming to provide insights for current and future antiviral drug research.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130427"},"PeriodicalIF":2.2,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237464","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}

引用次数: 0

Design and validation of the first-in-class PROTACs for targeted degradation of the immune checkpoint LAG-3 针对免疫检查点LAG-3靶向降解的同类首个PROTACs的设计和验证。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-10-04 DOI: 10.1016/j.bmcl.2025.130428

Nelson García Vázquez , Somaya A. Abdel-Rahman , Hossam Nada , Moustafa Gabr

{"title":"Design and validation of the first-in-class PROTACs for targeted degradation of the immune checkpoint LAG-3","authors":"Nelson García Vázquez , Somaya A. Abdel-Rahman , Hossam Nada , Moustafa Gabr","doi":"10.1016/j.bmcl.2025.130428","DOIUrl":"10.1016/j.bmcl.2025.130428","url":null,"abstract":"<div><div>Lymphocyte activation gene-3 (LAG-3) is an inhibitory immune checkpoint receptor that plays a central role in T cell exhaustion and immune evasion in cancer. While monoclonal antibodies targeting LAG-3 have entered clinical development, small molecule approaches remain largely unexplored. Here, we report the design and validation of the first-in-class PROTACs for targeted degradation of LAG-3. In this study, we repurposed a LAG-3-binding small molecule identified through DNA-encoded library (DEL) screening as the targeting ligand for a series of CRL4<sup>CRBN</sup>-based PROTACs designed with varied linker lengths. Western blot analysis in Raji-LAG3 cells demonstrated that <strong>LAG-3 PROTAC-1</strong> and <strong>LAG-3 PROTAC-3</strong> induce potent, dose-dependent degradation of LAG-3, with DC<sub>50</sub> values of 0.27 μM and 0.42 μM, respectively. Molecular docking and molecular dynamics (MD) simulations revealed the LAG-3 binding mode of designed PROTACs and provided structural insights into PROTAC-mediated ternary complex formation. Collectively, this work establishes a proof-of-concept for chemical degradation of LAG-3 for the first time and paves the way for novel immunotherapeutic strategies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130428"},"PeriodicalIF":2.2,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237450","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}

引用次数: 0

Development and bio-evaluation of novel indolizine derivatives in FLT3 mutant acute myeloid leukemia cells 新型吲哚嗪衍生物在FLT3突变型急性髓系白血病细胞中的开发和生物评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-10-04 DOI: 10.1016/j.bmcl.2025.130429

Qianlu Xing , Jiangdong Li , Yanjiao Shen , Lu He , Xiaojuan Ma , Pei Huang , Qiang Huang , Yan Chen

{"title":"Development and bio-evaluation of novel indolizine derivatives in FLT3 mutant acute myeloid leukemia cells","authors":"Qianlu Xing , Jiangdong Li , Yanjiao Shen , Lu He , Xiaojuan Ma , Pei Huang , Qiang Huang , Yan Chen","doi":"10.1016/j.bmcl.2025.130429","DOIUrl":"10.1016/j.bmcl.2025.130429","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is a highly malignant blood tumor, and FLT3 serves as an important molecular target for the treatment of AML. Currently, FLT3 inhibitors still have issues of drug resistance and unsatisfactory clinical efficacy in the treatment of AML. Indolizine derivatives exhibit good antibacterial and antitumor biological activities. Based on the synthesis and identification of a library of multiple indolizine lead compounds and screening of their antitumor activities, we evaluated a novel indolizine derivative, <strong>8h</strong>, which exhibited more sensitivity in inhibiting FLT3-mutated AML cells MV4-11 and MOLM13. <strong>8h</strong> concentration-dependently induced apoptosis of MV4-11 cells, as well as cell cycle arrest and mitochondrial membrane potential reduction. Treatment with <strong>8h</strong> downregulated the expression levels of FLT3 protein and downstream signaling proteins, and induced the activation of apoptosis-related proteins Caspase-3 and Caspase-9. The novel indolizine derivative <strong>8h</strong> has a good inhibitory effect on FLT3-mutated AML cells and has the potential to become a FLT3 inhibitor.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130429"},"PeriodicalIF":2.2,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237476","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}

引用次数: 0

Targeting NFE2L1 signalling with small molecules to protect against Ferroptosis 利用小分子靶向NFE2L1信号传导预防铁下垂。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-10-03 DOI: 10.1016/j.bmcl.2025.130425

Lucie Svobodová , Jindřich Sedláček , Zuzana Šmahelová , Pavel Majer , Aleš Machara , Klára Grantz Šašková

引用次数: 0

Discovery of novel VEGFR-2 inhibitors through virtual screening, synthesis and bioactivity evaluation 通过虚拟筛选、合成和生物活性评价发现新的VEGFR-2抑制剂

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-10-03 DOI: 10.1016/j.bmcl.2025.130423

Xi Gu , Linquan Li , Jianquan Yin , Zhili Zuo

{"title":"Discovery of novel VEGFR-2 inhibitors through virtual screening, synthesis and bioactivity evaluation","authors":"Xi Gu , Linquan Li , Jianquan Yin , Zhili Zuo","doi":"10.1016/j.bmcl.2025.130423","DOIUrl":"10.1016/j.bmcl.2025.130423","url":null,"abstract":"<div><div>Vascular endothelial growth factor receptor 2 (VEGFR-2) is an attractive antitumor target. By effectively inhibiting the overexpression of VEGFR-2, it suppresses the abnormal angiogenesis occurring within tumors. Although some inhibitors targeting VEGFR-2 have been identified, the drug resistance is an unignorable disadvantage to make the urgent need of new structure inhibitors. In this study, an innovative approach involving vast chemical space similarity searching was applied using sunitinib as a template to generate a series of structurally novel and synthetically accessible small molecules. A series robust virtual screening methods were employed to discover promising compounds for synthesis and evaluation of their kinase inhibitory activity against VEGFR-2. The results demonstrated that two of these compounds, <strong>GL-3</strong> (IC<sub>50</sub> = 5.44 μM) and <strong>GL-1</strong> (IC<sub>50</sub> = 13.4 μM), exhibited inhibitory activity against VEGFR-2. Subsequently, molecular dynamics simulations were conducted to investigate the interaction mechanisms of these active molecules with VEGFR-2. In summary, this study offers novel perspectives on the development of VEGFR-2 inhibitors and offers an innovative strategy for discovering novel anticancer drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130423"},"PeriodicalIF":2.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218259","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}

引用次数: 0

Discovery of a macrocyclic FAK inhibitor GZD-257 for treatment of glioblastoma 发现治疗胶质母细胞瘤的大环FAK抑制剂GZD-257。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-10-02 DOI: 10.1016/j.bmcl.2025.130424

Ting Wu, Yaqing Zuo, Kehui Chen, Ying Xu, Daili Wu, Yi Le, Li Liu, Longjia Yan

{"title":"Discovery of a macrocyclic FAK inhibitor GZD-257 for treatment of glioblastoma","authors":"Ting Wu, Yaqing Zuo, Kehui Chen, Ying Xu, Daili Wu, Yi Le, Li Liu, Longjia Yan","doi":"10.1016/j.bmcl.2025.130424","DOIUrl":"10.1016/j.bmcl.2025.130424","url":null,"abstract":"<div><div>Glioblastoma (GBM) is a primary malignant brain tumor that seriously threatens human health. Focal adhesion kinase (FAK) is an important target for GBM drug research and regulates tumor cell proliferation, invasion, and drug resistance. Although a large number of FAK inhibitors have entered clinical research, there are few reports on the treatment of GBM with FAK inhibitors. Herein, TAE-226, the earliest FAK inhibitor to enter clinical trials, was used as the lead compound, and a macrocyclization-based structural optimization strategy was adopted to develop novel FAK inhibitors. The optimized macrocyclic compound GZD-257 exhibited excellent <em>in vitro</em> anti-GBM activity. The IC<sub>50</sub> values of GZD-257 against FAK, glioblastoma cells U118-MG, and U87-MG reached 14.30 nM, 1.64 μM, and 1.40 μM, respectively. Interestingly, the IC<sub>50</sub> value of GZD-257 against Pyk2 was 68.20 nM, which performed 4.77-fold selectivity with FAK. In addition, GZD-257 showed excellent blood-brain barrier (BBB) penetration, with a Pe value of 43.85, significantly higher than that of the positive control TAE-226 (24.18). Finally, flow cytometry studies indicated that GZD-257 could significantly induce apoptosis of U118-MG cells and arrest the cell cycle at the G2/M phase. Molecular docking studies suggested that GZD-257 was a highly promising ATP-competitive FAK inhibitor</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130424"},"PeriodicalIF":2.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228334","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}

引用次数: 0

AI-assisted delivery of novel covalent WRN inhibitors from a non-covalent fragment screen. 人工智能辅助递送从非共价片段筛选的新型共价WRN抑制剂。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-30 DOI: 10.1016/j.bmcl.2025.130421

Geoffrey M T Smith, Laksh Aithani, Charlotte E Barrett, Alwin O Bucher, Christopher D O Cooper, Sébastien L Degorce, Andrew S Doré, Catherine T Fletcher, Sophie Huber, Rosemary Huckvale, Amanda J Kennedy, Abigail A Mornement, Mark Pickworth, Prakash Rucktooa, Conor C G Scully, Sarah E Skerratt

引用次数: 0

Fluorogenic rhodamine B derivatives that become brighter at neutral pH 在中性pH值下变亮的荧光罗丹明B衍生物。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-29 DOI: 10.1016/j.bmcl.2025.130422

Hidetoshi Kajino , Justin H. Kwon , Evan W. Miller

{"title":"Fluorogenic rhodamine B derivatives that become brighter at neutral pH","authors":"Hidetoshi Kajino , Justin H. Kwon , Evan W. Miller","doi":"10.1016/j.bmcl.2025.130422","DOIUrl":"10.1016/j.bmcl.2025.130422","url":null,"abstract":"<div><div>Rhodamines are useful fluorescent molecules for activity-based sensing. One powerful design strategy is to exploit changes in the open/closed equilibrium of rhodamine amides. In the context of amide derivatives of rhodamine B, a prototypical member of the rhodamine family, this strategy has been especially useful in the development of activity-based indicators for protons and metal ions. This is because at neutral pH, the closed form of rhodamine B amides dominates, making this otherwise bright and fluorescent dye non-fluorescent. At acidic pH, the equilibrium favors the open form. Despite a wealth of methods to trigger Lewis acid-mediated fluorogenicity of rhodamine B amides, there are far fewer ways to shift the open-close equilibrium to favor the open form at neutral pH. Here, we demonstrate that a simple substitution substantially shifts the native rhodamine B amide equilibrium to favor the open, fluorescent form at neutral pH. Rhodamine B derivatives with an N-(2′-carboxy)-phenyl substitution (an <em>ortho</em> anthranilic acid, RhoB-AA) show strong absorbance and emission at pH 7.2, up to ∼1500× greater than their unsubstituted <em>N</em>-phenyl derivatives (RhoB-Ph). The fluorescence of RhoB-AA at neutral pH is dependent on the free carboxylic acid. Esters of RhoB-AA are also ∼1500× less fluorescent than RhoB-AA and have optical properties nearly identical to the unsubstituted RhoB-Ph. Esters of RhoB-AA can be converted by esterases to the fully fluorescent RhoB-AA, demonstrating that the simple <em>ortho</em> anthranilic acid substitution is a powerful strategy for activity-based sensing with rhodamine amides at neutral pH.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130422"},"PeriodicalIF":2.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205039","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}

引用次数: 0