Bioorganic & Medicinal Chemistry Letters最新文献_第5页

Synthesis of substrate peptides incorporating non-natural amino acids and screening study using BACE1 含非天然氨基酸的底物肽的合成及BACE1筛选研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-28 DOI: 10.1016/j.bmcl.2025.130290

Shinji Katsuoka, Ryo Watanabe, Yuma Uchida, Masaki Midorikawa, Reo Yamada, Taeko Kakizawa

引用次数: 0

Design, synthesis, and activity evaluation of Asiatic acid derivatives as Survivin inhibitors 亚洲酸衍生物作为Survivin抑制剂的设计、合成和活性评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-23 DOI: 10.1016/j.bmcl.2025.130288

Heng Wu , Liangfeng Zhang , Xuehao Lu , Yuting Han , Zan Wang , Yanqiu Meng

{"title":"Design, synthesis, and activity evaluation of Asiatic acid derivatives as Survivin inhibitors","authors":"Heng Wu , Liangfeng Zhang , Xuehao Lu , Yuting Han , Zan Wang , Yanqiu Meng","doi":"10.1016/j.bmcl.2025.130288","DOIUrl":"10.1016/j.bmcl.2025.130288","url":null,"abstract":"<div><div>Asiatic acid, a triterpenoid isolated from <em>Centella asiatica</em>, putatively functions through inhibition of Survivin—a member of the Inhibitor of Apoptosis Protein (IAP) family that modulates tumor survival. Taking <em>GDP366</em> and <em>LQZ-7I</em>, two Survivin inhibitors of preclinical stage, as reference compounds, two classes of novel Asiatic acid derivatives (24 compounds in total) were designed and synthesized. These compounds demonstrated favorable docking capabilities and binding modes with the three-dimensional crystal structure of Survivin. The MTT assay demonstrated that these compounds exhibited anti-proliferative effects against <em>A549</em> and <em>MCF-7</em> cell lines, with compounds <strong>I</strong><sub><strong>3</strong></sub>, <strong>I</strong><sub><strong>9</strong></sub>, <strong>II</strong><sub><strong>3</strong></sub>, <strong>II</strong><sub><strong>5</strong></sub>, and <strong>II</strong><sub><strong>12</strong></sub> showing potency comparable to the positive control drug. Furthermore, Western blot analysis revealed that compound <strong>II</strong><sub><strong>3</strong></sub> dose-dependently reduced Survivin protein levels. Compound <strong>II</strong><sub><strong>3</strong></sub> provides a valuable reference for further research on Survivin inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130288"},"PeriodicalIF":2.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141019","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 nonpungent Transient Receptor Potential Vanilloid (TRPV1) agonist antedrugs for treatment of dysphagia 发现非刺激性瞬时受体电位香草样蛋白（TRPV1）激动剂治疗吞咽困难

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-22 DOI: 10.1016/j.bmcl.2025.130287

Hiroyuki Kitano , Yuki Mizukami, Masanori Miyauchi, Itaru Natsutani, Kozo Yoshida

{"title":"Discovery of nonpungent Transient Receptor Potential Vanilloid (TRPV1) agonist antedrugs for treatment of dysphagia","authors":"Hiroyuki Kitano , Yuki Mizukami, Masanori Miyauchi, Itaru Natsutani, Kozo Yoshida","doi":"10.1016/j.bmcl.2025.130287","DOIUrl":"10.1016/j.bmcl.2025.130287","url":null,"abstract":"<div><div>Transient Receptor Potential Vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel that functions as a cellular sensor for heat and chemical stimuli, such as vanilloids. In recent years, TRPV1 has gained attention as a therapeutic target for treating dysphagia, with both preclinical and clinical trials utilizing capsaicin, a member of the vanilloid family. However, TRPV1 agonists often have pronounced irritant properties and may potentially induce hypothermia upon systemic exposure. Here, we describe the synthesis and characterization of a series of nonpungent TRPV1 agonists with antedrug properties. The discovered compounds exhibit similar agonistic properties to capsaicin, while demonstrating low irritancy in animal models and showing no systemic exposure when administered orally. As these compounds selectively act within the oral cavity without causing a sensation of spiciness, they offer a useful alternative to address the challenges associated with TRPV1 agonists as therapeutic agents for improving dysphagia.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130287"},"PeriodicalIF":2.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134186","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

Telomerase reverse transcriptase degradation via a rationally designed covalent proteolysis targeting chimera 端粒酶逆转录酶降解通过合理设计的共价蛋白水解靶向嵌合体。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-22 DOI: 10.1016/j.bmcl.2025.130286

Grant B. Frost , Yue Liu , Stephen J. Kron , Karl A. Scheidt

{"title":"Telomerase reverse transcriptase degradation via a rationally designed covalent proteolysis targeting chimera","authors":"Grant B. Frost , Yue Liu , Stephen J. Kron , Karl A. Scheidt","doi":"10.1016/j.bmcl.2025.130286","DOIUrl":"10.1016/j.bmcl.2025.130286","url":null,"abstract":"<div><div>Expression of telomerase reverse transcriptase (TERT) is a hallmark of cancer, maintaining telomere integrity to enable replicative immortality. However, TERT also serves multiple enzyme-dependent and -independent functions to support cancer growth and survival, including enhanced DNA damage response. Agents that inhibit TERT reverse transcriptase activity prevent telomere elongation but may fail to limit other TERT functions that mediate cancer therapy resistance. Thus, we applied structure-based design, modular synthesis, and biochemical assays towards developing a proteolysis targeting chimera (PROTAC) to drive proteasomal degradation of TERT in cancer cells. This yielded <strong>NU-PRO-1</strong>, a PROTAC linking the TERT active site-targeted covalent inhibitor <strong>NU-1</strong> to the VHL E3-ligase ligand (<em>S</em>,<em>R</em>,<em>S</em>)-AHPC. Applied to cancer cells, <strong>NU-PRO-1</strong> induced transient VHL- and proteasome-dependent TERT degradation. <strong>NU-PRO-1</strong> did not induce DNA damage on its own but acted to further delay DNA repair after irradiation compared to <strong>NU-1</strong>. TERT-degrading PROTACs provide novel chemical probes of TERT's non-catalytic functions and may overcome the limitations of current telomerase inhibitors as cancer therapeutics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130286"},"PeriodicalIF":2.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141024","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 characterization of N-oxide cinnamanilide derivative PX5–9: Improved solubility and BDNF upregulation n -氧化物肉桂苯胺衍生物PX5-9的设计和表征：改善溶解度和上调BDNF

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-22 DOI: 10.1016/j.bmcl.2025.130266

Zhixian Zhang , Qianhui Shen , Yanping Chen , Zhi Liang , Yuan Liu , Yu Ren , Cailv Wei , Kang Jia , Chao Ding , Shisong Wang , Rongbiao Pi

{"title":"Design and characterization of N-oxide cinnamanilide derivative PX5–9: Improved solubility and BDNF upregulation","authors":"Zhixian Zhang , Qianhui Shen , Yanping Chen , Zhi Liang , Yuan Liu , Yu Ren , Cailv Wei , Kang Jia , Chao Ding , Shisong Wang , Rongbiao Pi","doi":"10.1016/j.bmcl.2025.130266","DOIUrl":"10.1016/j.bmcl.2025.130266","url":null,"abstract":"<div><div>Compound <strong>5</strong>, a cinnamanilide derivative, upregulates brain derivated neurotrophic factor (BDNF) expression but with low soluablity. In this study, <strong>PX5–9</strong>, a N-oxide derivative of <strong>5</strong>, demonstrated significant protective effects in the HT22 glutamate-induced toxicity model and showed no significant toxicity at 30 μM. Western blot analysis confirmed that <strong>PX5–9</strong> increased BDNF levels similar to <strong>5</strong>. Solubility tests revealed a significant improvement in <strong>PX5–9</strong> (37.10 ± 0.33 μg/mL) compared to <strong>5</strong> (< 15 ng/mL). Pharmacokinetic studies of <strong>PX5–9</strong> revealed favorable properties, fast absorption and also can be transformated into parent compound <strong>5</strong>, suggesting it is a potential candidate for these diseases involving with BDNF. The N-oxide modification might be a good prodrug design to enhance solubility while preserving biological activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130266"},"PeriodicalIF":2.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144125083","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 of novel pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as potent noncovalent Bruton's tyrosine kinase (BTK) inhibitors 新型吡咯[1,2-a]喹啉-4(5H)- 1衍生物作为有效的非共价布鲁顿酪氨酸激酶（BTK）抑制剂的结构设计

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-19 DOI: 10.1016/j.bmcl.2025.130285

Chaoquan Tian , Wenjie Liao , Zhixiao Yu , Husheng Du , Haoming Song , Wenyi Mei , Zhenjiang Zhao , Yanyan Diao , Zhuo Chen , Honglin Li

{"title":"Structure-based design of novel pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as potent noncovalent Bruton's tyrosine kinase (BTK) inhibitors","authors":"Chaoquan Tian , Wenjie Liao , Zhixiao Yu , Husheng Du , Haoming Song , Wenyi Mei , Zhenjiang Zhao , Yanyan Diao , Zhuo Chen , Honglin Li","doi":"10.1016/j.bmcl.2025.130285","DOIUrl":"10.1016/j.bmcl.2025.130285","url":null,"abstract":"<div><div>Bruton's tyrosine kinase (BTK) is a promising target for the treatment of B cell malignancies. Developing noncovalent BTK inhibitors is a promising strategy to address the treatment limitations of covalent BTK inhibitors including off-target toxicity and acquired resistance. Our group previously discovered a novel noncovalent BTK inhibitor <strong>S2</strong> with pyrrolo[1,2-<em>α</em>]quinoxalin-4(5<em>H</em>)-one as the scaffold. To further reduce the synthetic difficulty and improve physicochemical properties, we designed and synthesized a new series of ring-opening pyrrolo[1,2-<em>α</em>]quinoxalin-4(5<em>H</em>)-one derivatives based on the docking mode of <strong>S2</strong> with BTK. Among them, the representative compound <strong>10</strong> exhibited potent BTK inhibitory activity (IC<sub>50</sub> = 24.7 nM). Compared with <strong>S2</strong>, compound <strong>10</strong> had lower structural rigidity, lipophilicity (cLogP: 4.2 <em>vs</em> 5.5), and molecular weight (MW: 490 <em>vs</em> 510), and was easier to prepare. Further study showed that compound <strong>10</strong> exhibited potent antitumor activities in lymphoma cells. The favorable physicochemical properties and <em>in vitro</em> activities suggested that compound <strong>10</strong> was a promising noncovalent BTK inhibitors worthy of further exploration.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130285"},"PeriodicalIF":2.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099361","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 novel coumarin-sulfonates as tubulin polymerization inhibitors targeting the colchicine-binding site with potent anticancer activities 发现新的香豆素磺酸盐作为微管蛋白聚合抑制剂，靶向秋水仙碱结合位点，具有有效的抗癌活性。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-18 DOI: 10.1016/j.bmcl.2025.130284

Dan Zhao , Ji Wu , Jing-Sai Song , Bing-Bing Chen , Yi-Fei Du , Meng-Bo Wu , Jin-Bo Niu , Jian Song , Yan Xu , Sai-Yang Zhang

{"title":"Discovery of novel coumarin-sulfonates as tubulin polymerization inhibitors targeting the colchicine-binding site with potent anticancer activities","authors":"Dan Zhao , Ji Wu , Jing-Sai Song , Bing-Bing Chen , Yi-Fei Du , Meng-Bo Wu , Jin-Bo Niu , Jian Song , Yan Xu , Sai-Yang Zhang","doi":"10.1016/j.bmcl.2025.130284","DOIUrl":"10.1016/j.bmcl.2025.130284","url":null,"abstract":"<div><div>A series of novel coumarin-sulfonate derivatives as potent microtubule-targeting inhibitors was constructed utilizing a molecular hybridization strategy, and their antiproliferative activities were evaluated against MGC-803, KYSE450 and HCT-116 cancer cell lines. Among them, compound <strong>C20</strong> exhibited potent antiproliferative effects on KYSE450 cells (IC<sub>50</sub> = 0.36 μM) and EC-109 cells (IC<sub>50</sub> = 0.63 μM). Mechanistic studies revealed that <strong>C20</strong> could occupied the colchicine-binding site to suppress tubulin polymerization, thereby disrupting the microtubule network integrity in KYSE450 and EC-109 cells. Notably, <strong>C20</strong> activated the Hippo signaling pathway and downregulated the expression of the oncogenic protein YAP in KYSE450 and EC-109 cells. In addition, <strong>C20</strong> effectively suppressed colony formation, induced G2/M phase cell cycle arrest, and promoted apoptosis in KYSE450 and EC-109 cells. These effects of cell apoptosis were correlated with the modulation of apoptosis related proteins cleaved PARP and cleaved Caspase3/7 level. Collectively, these findings elucidated that <strong>C20</strong>, as a tubulin polymerization inhibitor, could destroy microtubule dynamics and activate the Hippo signaling pathway, thereby exhibiting strong anti-esophageal cancer activities.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130284"},"PeriodicalIF":2.5,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109234","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 structural optimization of novel SOS1 inhibitors in KRAS-driven cancers 新型SOS1抑制剂在kras驱动癌症中的设计和结构优化。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-16 DOI: 10.1016/j.bmcl.2025.130282

Yating Chen , Qiupei Liu , Xianghui Meng , Wenxu Cao , Lihui Duo , Xiaorong Song , Xiangchun Shen , Sze Shin Low , Wan Yong Ho , Bencan Tang , Pengli Zhang , Hua Xie , Guoqin Xia

{"title":"Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers","authors":"Yating Chen , Qiupei Liu , Xianghui Meng , Wenxu Cao , Lihui Duo , Xiaorong Song , Xiangchun Shen , Sze Shin Low , Wan Yong Ho , Bencan Tang , Pengli Zhang , Hua Xie , Guoqin Xia","doi":"10.1016/j.bmcl.2025.130282","DOIUrl":"10.1016/j.bmcl.2025.130282","url":null,"abstract":"<div><div>The development of small molecular inhibitors to target the guanine nucleotide exchange factor SOS1 has been proved to be a hopeful strategy for the treatment of various KRAS-driven cancers. Constructing novel SOS1 inhibitors is urgently needed due to the increasing drug resistance arising from structural similarity of earlier analogs. Herein, we discovered a new SOS1 inhibitor with para-dimethylaminoazetidine quinazoline scaffold. The most potent compound 10i showed superior activity to the reported SOS1 inhibitor Hit 1 in both the KRASG12C::SOS1 PPI inhibition assay and 3D proliferation inhibitory assay, and compound 10i presented enhanced aqueous solubility under physiologically relevant pH 6.8. Moreover, compound 10i could downregulate the levels of phosphorylated ERK and AKT in the NCI-H358 cancer cell line. Overall, these studies showed that 10i was a promising drug candidate for the treatment of KRAS-driven cancer.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130282"},"PeriodicalIF":2.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092362","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 of a ROS-responsive fluorescent probe for the diagnosis and imaging of breast cancer 一种用于乳腺癌诊断和成像的ros响应荧光探针的设计。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-15 DOI: 10.1016/j.bmcl.2025.130268

Chunxiao Li , Qiao Liang , Wenyun Pan , Yuyu Yang , Qianshan Shao , Baolei Fan

引用次数: 0

An overview of PROTACs targeting KRAS and SOS1 as antitumor agents 靶向KRAS和SOS1的PROTACs抗肿瘤药物综述

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-15 DOI: 10.1016/j.bmcl.2025.130283

Zhiqiu Han , Qianping Wu , Hongxin Rao , Tianfeng Xu , Chuan Zhou

{"title":"An overview of PROTACs targeting KRAS and SOS1 as antitumor agents","authors":"Zhiqiu Han , Qianping Wu , Hongxin Rao , Tianfeng Xu , Chuan Zhou","doi":"10.1016/j.bmcl.2025.130283","DOIUrl":"10.1016/j.bmcl.2025.130283","url":null,"abstract":"<div><div>KRAS is the most frequently mutated oncogene and its mutational activation drives approximately 25 % of human cancers. Son of Sevenless 1 (SOS1) plays a pivotal role in the KRAS signaling pathway through catalyzing the conversion of inactive GDP-bound KRAS to active GTP-bound KRAS, and is thus considered as a promising target for pan-KRAS inhibition. Currently, four KRAS<sup>G12C</sup>-specific inhibitors, namely sotorasib, adagrasib, fulzerasib and garsorasib, have garnered regulatory approval. However, acquired resistance to KRAS<sup>G12C</sup> inhibition rapidly emerges. In addition, the other prevalent KRAS mutations, including G12D and G12V, are still lacking effective therapeutic drugs. PROTAC-mediated KRAS and SOS1 degradation has been emerged as a promising strategy to overcome these issues, and achieved rapid progress in the recent years. This article provides an overview of the chemical structures, design strategies, structure-activity relationship (SAR) studies as well as <em>in vitro</em> and <em>in vivo</em> activities of the PROTACs degrading KRAS and SOS1, and sheds light on future challenges and opportunities to accelerate the development of new chemotherapies for KRAS-driven cancers.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130283"},"PeriodicalIF":2.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089546","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