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

Design, synthesis and anti-GBM activities of amide-modified Curcumol derivatives 酰胺修饰莪术酚衍生物的设计、合成及抗gbm活性研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-06 DOI: 10.1016/j.bmcl.2025.130265

Shiqi Hu , Yuhang Fan , Yumo Zhao, Zhengyang Gao, Jie Lu, Jian Li, Jinlian Wei, Yongqiang Zhang

引用次数: 0

Overcoming CK1α liability in the discovery of a series of isoIndolinone Glutarimides as selective IKZF2 molecular glue degraders 克服CK1α倾向性，发现一系列异吲哚酮戊二酰亚胺作为选择性IKZF2分子胶降解剂

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-05 DOI: 10.1016/j.bmcl.2025.130263

Xuqing Zhang, Qiaolin Deng, Harshil Dhruv, Matthew Tudor, Rakesh Nagilla, Larry J. Jolivette, Cory T. Rice, Peter Orth, Elham Behshad, Corey O. Strickland, Helai P. Mohammad, Zhihua Sui, E. Scott Priestley

{"title":"Overcoming CK1α liability in the discovery of a series of isoIndolinone Glutarimides as selective IKZF2 molecular glue degraders","authors":"Xuqing Zhang, Qiaolin Deng, Harshil Dhruv, Matthew Tudor, Rakesh Nagilla, Larry J. Jolivette, Cory T. Rice, Peter Orth, Elham Behshad, Corey O. Strickland, Helai P. Mohammad, Zhihua Sui, E. Scott Priestley","doi":"10.1016/j.bmcl.2025.130263","DOIUrl":"10.1016/j.bmcl.2025.130263","url":null,"abstract":"<div><div>IKZF2 (Ikaros Family Zinc Finger 2) is a transcription factor implicated in immune regulation and hematologic malignancies, where its dysregulation drives oncogenic programs, immune evasion, and therapy resistance. While targeted protein degradation (TPD) has emerged as a promising strategy, achieving selective IKZF2 degradation remains challenging due to off-target effects on structurally related neosubstrates such as IKZF1/3, SALL4, CK1α, and GSPT1. Here, we report the discovery of a novel series of isoindolinone glutarimide-based molecular glue degraders that selectively degrade IKZF2 while sparing CK1α and other neosubstrates. Through a structure-guided medicinal chemistry campaign, we identified divergent structure-activity relationships (SARs) enabling potent IKZF2 degradation with minimal off-target activity. The lead degrader (<strong>31</strong>) demonstrated high selectivity between IKZF2 and CK1α with acceptable oral bioavailability in mice. Our findings highlight the feasibility of developing precise IKZF2 degraders and provide a framework for optimizing selectivity in molecular glue design, offering a potential therapeutic strategy for IKZF2-dependent cancers.</div><div>2025 Elsevier Ltd. All rights reserved.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130263"},"PeriodicalIF":2.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923267","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 N-methylguanidine derivatives as a new type of potent pyruvate kinase M2 inhibitor 新型丙酮酸激酶M2抑制剂n -甲基胍衍生物的发现

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-05 DOI: 10.1016/j.bmcl.2025.130264

Weiguo Zhang , Zhenjiao Yang , Xingxing Li , Danfang Li , Jingyan Liu , Wanyi Liu , Wei Xie , Jian Liu , Yunzhang Cheng , Hao Yang , Xiuhong Lu

{"title":"Discovery of N-methylguanidine derivatives as a new type of potent pyruvate kinase M2 inhibitor","authors":"Weiguo Zhang , Zhenjiao Yang , Xingxing Li , Danfang Li , Jingyan Liu , Wanyi Liu , Wei Xie , Jian Liu , Yunzhang Cheng , Hao Yang , Xiuhong Lu","doi":"10.1016/j.bmcl.2025.130264","DOIUrl":"10.1016/j.bmcl.2025.130264","url":null,"abstract":"<div><div>Lung cancer is the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for 80–85 % of all cases. Thus, while challenging, the exploration of novel therapeutic agents for NSCLC treatment is highly desirable. Pyruvate kinase M2 (PKM2) has been closely associated with disease progression and metastasis in NSCLC, making it a promising therapeutic target. Herein, we report the discovery of a series of <em>N</em>-methylguanidine derivatives that demonstrated potent PKM2 inhibitory activity. In particular, <em>N′</em>-phenanthroline-substituted <em>N</em>-methyl guanidine exhibited notable PKM2 inhibition. Further testing demonstrated that compound <strong>16</strong> exhibited excellent inhibitory effects on A549 and HCC1833 NSCLC cell lines, with IC<sub>50</sub> values of 3.36 μM and 9.20 μM, respectively. <em>In vivo</em> antitumor studies further showed that compound <strong>16</strong> significantly inhibited tumor growth in human-derived NSCLC models and mouse lung adenocarcinoma models. Based on these findings, we propose <em>N′</em>-phenanthroline-substituted <em>N</em>-methylguanidine <strong>16</strong> as a promising novel PKM2 inhibitor with potential therapeutic applications for NSCLC.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130264"},"PeriodicalIF":2.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923266","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 TNG-6132, a potent, selective, and orally bioavailable USP1 inhibitor 发现TNG-6132，一种有效的，选择性的，口服生物可利用的USP1抑制剂

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-30 DOI: 10.1016/j.bmcl.2025.130262

Scott Throner, Tianshu Feng, Jannik N. Andersen, Madhavi Bandi, Justin L. Engel, Shanzhong Gong, Deepali Gotur, Lina Gu, Alan Huang, Katherine Lazarides, John P. Maxwell, Patrick McCarren, Brian J. McMillan, Truc V. Pham, Antoine Simoneau, Alice Tsai, Douglas A. Whittington, Erik Wilker, Minjie Zhang, Wenhai Zhang

{"title":"Discovery of TNG-6132, a potent, selective, and orally bioavailable USP1 inhibitor","authors":"Scott Throner, Tianshu Feng, Jannik N. Andersen, Madhavi Bandi, Justin L. Engel, Shanzhong Gong, Deepali Gotur, Lina Gu, Alan Huang, Katherine Lazarides, John P. Maxwell, Patrick McCarren, Brian J. McMillan, Truc V. Pham, Antoine Simoneau, Alice Tsai, Douglas A. Whittington, Erik Wilker, Minjie Zhang, Wenhai Zhang","doi":"10.1016/j.bmcl.2025.130262","DOIUrl":"10.1016/j.bmcl.2025.130262","url":null,"abstract":"<div><div>USP1 (ubiquitin-specific peptidase 1) is a deubiquitinating enzyme that has been identified as essential in <em>BRCA1/2</em> mutant cells and implicated in the DNA damage response. Inhibition of USP1 by small molecule inhibitors disrupts DNA repair and replication and is being pursued as a potential anticancer therapeutic in <em>BRCA1/2</em> mutant cancers. We report the discovery of an <em>in vitro</em> and <em>in vivo</em> USP1 inhibitor tool compound TNG-6132 (<strong>18</strong>), a reversible, allosteric inhibitor of USP1, which strongly inhibits USP1 enzymatic activity. This inhibitory effect translates into <em>in vitro</em> cellular viability defects in a <em>BRCA1</em>-mutant breast cancer cell line, as well as an <em>in vivo</em> pharmacodynamic (PD) response and tumor growth suppression in a mouse xenograft efficacy model. Additionally, we report an X-ray co-crystal structure of TNG-6132 (<strong>18</strong>) bound in the USP1-UAF1 complex, a result that furthered our understanding of the role played by key elements of the pharmacophore of this chemotype as well as its mechanism of inhibition of USP1.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130262"},"PeriodicalIF":2.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912686","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

Synthesis of Isosteviol derivatives as potential anticancer agents, especially for ovarian Cancer: In vitro cytotoxicity, cell cycle arrest, network pharmacology and molecular docking study 异甜菊醇衍生物作为潜在抗癌药物的合成，特别是卵巢癌：体外细胞毒性、细胞周期阻滞、网络药理学和分子对接研究

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-29 DOI: 10.1016/j.bmcl.2025.130261

Yuxin Ding , Enxiao Wang , Lin Xing , Chaoyan Zhang , Ruilong Sheng , Wenhui Wu , Ruihua Guo

{"title":"Synthesis of Isosteviol derivatives as potential anticancer agents, especially for ovarian Cancer: In vitro cytotoxicity, cell cycle arrest, network pharmacology and molecular docking study","authors":"Yuxin Ding , Enxiao Wang , Lin Xing , Chaoyan Zhang , Ruilong Sheng , Wenhui Wu , Ruihua Guo","doi":"10.1016/j.bmcl.2025.130261","DOIUrl":"10.1016/j.bmcl.2025.130261","url":null,"abstract":"<div><div>Isosteviol is a tetracyclic diterpenoid from the hydrolysis of steviosidic acid, it exhibits a moderate inhibitory impact on tumor proliferation across various cancer types. Herein, we improved antitumor efficacy of isosteviol by modifying its reactive groups at C-16 and C-19 positions. A series of isosteviol derivatives <strong>2</strong>–<strong>17</strong>, were synthesized and characterized. Their anti-proliferative activities were evaluated in three human cancer cell lines (HCT116, SKOV3 and HepG2) by CCK-8 assay. The results showed that derivative <strong>10</strong> has strong cancer cell inhibitory activities (with IC<sub>50</sub> = 24.98 ± 1.82 μM for HCT116, IC<sub>50</sub> = 26.15 ± 0.05 μM for SKOV3 and IC<sub>50</sub> = 23.09 ± 0.31 μM for HepG2 cells). Accordingly, structure-activity relationships (SARs) of these isosteviol derivatives in ovarian cancer SKOV3 cells were discussed in detail. Moreover, derivative <strong>10</strong> has concentration-dependent cell cycle arrest at S-G2/M phases in SKOV3 cells, and it could greatly induce apoptosis. In addition, the targets of isosteviol against ovarian cancer were predicted and analyzed <em>via</em> network pharmacology. Then, molecular docking analysis showed that derivative <strong>10</strong> could interact with HSP90AA1 through its LYS-58 residues (docking energy: −8.96 kal/mol). The results suggested that derivative <strong>10</strong> might be employed as a promising drug candidate for anticancer chemotherapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130261"},"PeriodicalIF":2.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908269","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, synthesis and evaluation of novel cycloalkylthiophene-based aminopyrimidine derivatives as potent PLK1 inhibitors 新型环烷基噻吩基氨基嘧啶衍生物作为PLK1抑制剂的设计、合成和评价

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-29 DOI: 10.1016/j.bmcl.2025.130260

Meixue Ai , Yukang Lin , Xiaoyu Zhong , Zhongkai Zou , Pengcheng Diao , Yanting Zhang , Jingkao Chen , Peiliang Zhao , Zhibo Zhu

{"title":"Design, synthesis and evaluation of novel cycloalkylthiophene-based aminopyrimidine derivatives as potent PLK1 inhibitors","authors":"Meixue Ai , Yukang Lin , Xiaoyu Zhong , Zhongkai Zou , Pengcheng Diao , Yanting Zhang , Jingkao Chen , Peiliang Zhao , Zhibo Zhu","doi":"10.1016/j.bmcl.2025.130260","DOIUrl":"10.1016/j.bmcl.2025.130260","url":null,"abstract":"<div><div>PLK1 plays a pivotal role in cell-cycle regulation and has been well-characterized as a promising target for cancer therapy. Here, we synthesized a series of fused-thiophene based aminopyrimidine derivatives, and discovered a novel and potent PLK1 inhibitor compound <strong>7n</strong> with an IC<sub>50</sub> value of 38.5 nM. Analogue <strong>7n</strong> exhibited remarkable antiproliferative efficacy toward HepG2, Huh7, H1299, and A549 cells, and hasn't any noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies indicated <strong>7n</strong> arrested the cell cycle at the G2/M phase and induced apoptosis in HepG2 cells with a concentration-dependent manner. Molecular docking presented that <strong>7n</strong> could occupy well the ATP-binding site of PLK1 with a U-shaped conformation. Collectively, these results provide new insights into the further development of fused-thiophene based aminopyrimidines as PLK1 inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130260"},"PeriodicalIF":2.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908268","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

Structure based design, synthesis and identification of novel covalent reversible dual TLR2/TLR9 small molecule antagonists 基于结构的新型共价可逆双TLR2/TLR9小分子拮抗剂的设计、合成与鉴定

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-26 DOI: 10.1016/j.bmcl.2025.130259

Srinivasa Reddy Natala , Agata Habas , Emily M. Stocking , Andrew Orry , Ruben Abagyan , Milan T. Makale , Wolfgang Wrasidlo

{"title":"Structure based design, synthesis and identification of novel covalent reversible dual TLR2/TLR9 small molecule antagonists","authors":"Srinivasa Reddy Natala , Agata Habas , Emily M. Stocking , Andrew Orry , Ruben Abagyan , Milan T. Makale , Wolfgang Wrasidlo","doi":"10.1016/j.bmcl.2025.130259","DOIUrl":"10.1016/j.bmcl.2025.130259","url":null,"abstract":"<div><div>Inflammation is a key driver of the onset and progression of neurodegenerative diseases and cancer and can be caused by aggregated proteins, injured neurons or synapses, dysregulation of inflammatory control mechanisms, and other factors. Tolllike receptors (TLRs) are important mediators of inflammatory pathways, and their activation leads to pro-inflammatory cytokine release by immune cells in the periphery or in the central nervous system (CNS). TLR2 and TLR9 are implicated in the inflammatory pathogenesis of CNS degenerative diseases such as Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS). They are also held to be important in the etiology of certain malignancies like inflammatory pancreatic ductal adenocarcinoma and glioblastoma. Inactivation of TLR2/9 in animal models of neurodegeneration has reduced pathological markers and diminished neuronal loss, while in animal models of cancer it has suppressed tumors. Therefore, TLR2 and TLR9 may be potential targets for the treatment of neurodegenerative disorders and cancers. We identified for the first time a key binding locus in TLR2/9 TIR domain which guided reversible covalent drug (RCD) design of a novel, first-in class series of dual TLR2/9 antagonists. Sub-micromolar antagonist concentrations potently inhibited TLR2 and TLR9 signaling induced by TLR2/9 specific agonists. Importantly, this series of antagonists did not discernably activate other TLRs and exhibited favorable in-vitro ADME and safety. The analogs described here may help realize effective TLR2/9 antagonism as a viable therapeutic strategy for inflammation driven CNS diseases and various malignancies with an inflammatory etiology.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130259"},"PeriodicalIF":2.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898811","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

Identification of hydroxyphenyl cyanovinyl thiazoles as new structural scaffold of potential antibacterial agents 羟基苯基氰乙烯基噻唑作为新型结构支架的鉴定

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-25 DOI: 10.1016/j.bmcl.2025.130258

Xing Lu , Shao-Lin Zhang , Cheng-He Zhou

{"title":"Identification of hydroxyphenyl cyanovinyl thiazoles as new structural scaffold of potential antibacterial agents","authors":"Xing Lu , Shao-Lin Zhang , Cheng-He Zhou","doi":"10.1016/j.bmcl.2025.130258","DOIUrl":"10.1016/j.bmcl.2025.130258","url":null,"abstract":"<div><div>Unique hydroxyphenyl cyanovinyl thiazoles (HCTs) as new structural scaffolds of potential antibacterial agents were developed to overcome global increasingly serious drug resistance. Some synthesized HCTs could suppress the growth of the tested strains, especially, benzothiophenyl HCT <strong>5c</strong> exhibited superior anti-<em>Escherichia coli</em> activity with a lower MIC of 0.5 μg/mL to norfloxacin (MIC = 1 μg/mL). The active benzothiophenyl HCT <strong>5c</strong> displayed no obvious hemolysis, low cytotoxicity and a much lower trend for the development of drug-resistance than norfloxacin. Further exploration revealed that benzothiophenyl HCT <strong>5c</strong> could intercalate to DNA to form a DNA–<strong>5c</strong> complex, which disturbed the biological functions to facilitate bacterial death. ADME analysis indicated that compound <strong>5c</strong> possessed favorable druggability and promising pharmacokinetic properties. This work provided an insight into further developing hydroxyphenyl cyanovinyl thiazoles as new structural scaffold of promising antibacterial candidates.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130258"},"PeriodicalIF":2.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898810","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, synthesis and evaluation of a fluorescent PI3K inhibitor as a dual-function agent toward Cancer Theranostics 一种PI3K荧光抑制剂的设计、合成及对癌症治疗双重功能的评价

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-24 DOI: 10.1016/j.bmcl.2025.130255

Ge Shi , Hua Tian , Shiji Chu , Dan Liu , Zheng Yan , Min Yang , Heng Xu

{"title":"Design, synthesis and evaluation of a fluorescent PI3K inhibitor as a dual-function agent toward Cancer Theranostics","authors":"Ge Shi , Hua Tian , Shiji Chu , Dan Liu , Zheng Yan , Min Yang , Heng Xu","doi":"10.1016/j.bmcl.2025.130255","DOIUrl":"10.1016/j.bmcl.2025.130255","url":null,"abstract":"<div><div>The development of PI3K-targeted therapeutics has advanced significantly, yet molecular tools capable of simultaneous kinase inhibition and real-time visualization of drug distribution remain limited. Herein, we describe the rational design, synthesis, and biological evaluation of a novel fluorescent PI3K inhibitor (compound <strong>1</strong>) that incorporates a 4-methylquinazoline pharmacophore conjugated to fluorescein isothiocyanate (FITC) through a piperazine linker. <strong>1</strong> demonstrated potent PI3K enzymatic inhibition and exhibited significant antiproliferative effects against HGC-27 and MCF-7 cancer cell lines. Mechanistic investigations revealed that <strong>1</strong> effectively suppresses DNA synthesis, triggers G0/G1 cell cycle arrest, and disrupts mitochondrial architecture. Fluorescence-based cellular and <em>in vivo</em> imaging studies demonstrated the compound's preferential cytoplasmic localization and tumor-targeting properties. This dual-function inhibitor not only advances PI3K-targeted drug discovery but also provides a valuable tool for real-time monitoring of drug distribution, representing a promising addition to the growing field of cancer theranostics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130255"},"PeriodicalIF":2.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883155","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 synthesis of novel sulfanilamide derivatives as aminopeptidase N inhibitors 新型磺胺衍生物氨基肽酶N抑制剂的设计与合成

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-23 DOI: 10.1016/j.bmcl.2025.130257

Hong Zhu , Xiaoyan Zhang , Baojun Zhang , Chunhua Ma

{"title":"Design and synthesis of novel sulfanilamide derivatives as aminopeptidase N inhibitors","authors":"Hong Zhu , Xiaoyan Zhang , Baojun Zhang , Chunhua Ma","doi":"10.1016/j.bmcl.2025.130257","DOIUrl":"10.1016/j.bmcl.2025.130257","url":null,"abstract":"<div><div>Guided by the structural architecture of the aminopeptidase N (APN) active site, we designed and synthesized a series of novel APN inhibitors featuring sulfanilamide scaffold coupled with hydroxamate zinc-binding motifs. Among the series, compound <strong>2k</strong> exhibited the inhibitory activity (IC<sub>50</sub> = 4.3 μM) as effectively as a positive control drug Bestatin. Notably, our compounds exhibited pronounced selectivity against zinc-dependent metallopeptidase MMP-2. The SAR research indicated that ortho-disubstitution in the phenyl group could lead to an order of magnitude improvement. A molecular docking study validated the novel binding mode of compound <strong>2k</strong>. The predicted ADME properties highlighted the improved hydrophilicity, cell permeability, and human oral absorption of <strong>2k</strong> than that of bestatin. These results validated simultaneously occupying S1’ and S2’ pockets as a viable design strategy for discovering APN inhibitors with a non-canonical binding modality. We anticipate that compound <strong>2k</strong> with high selectivity will be harnessed as a structurally distinctive probe candidate to investigate the pathophysiological roles of APN in tumor angiogenesis and metastasis.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130257"},"PeriodicalIF":2.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883156","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