Bioorganic & Medicinal Chemistry Letters最新文献_第2页

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

Structure-guided development of Quinoline derivatives targeting kinesin spindle protein 以激酶纺锤体蛋白为靶点的喹啉衍生物的结构导向研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-15 DOI: 10.1016/j.bmcl.2025.130278

Rohini S. Kavalapure , Shankar G. Alegaon , Shankar Gharge , Shriram D. Ranade , Sachin Gudasi , U. Venkatasubramanian , Soundarya Priya A.

引用次数: 0

1,2,3-Triazole‑gold(I)-triethylphosphine derivatives of nutrients as new antimicrobials against antibiotic resistant Gram-positive pathogens 1,2,3-三唑金(I)-三乙基膦营养物衍生物作为抗革兰氏阳性耐药病原体的新抗生素。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-14 DOI: 10.1016/j.bmcl.2025.130276

Mathieu Michaut , Françoise Hoegy , Alexandre Steffen , Jean-Marie Contreras , Christophe Morice , Patrick Plésiat , Gaëtan L.A. Mislin

引用次数: 0

The discrepancies in amino acid sequence of the phosphate-binding loop lead to distinctive binding modes of a covalent inhibitor for MAP2K1 and MAP2K6: Structural insights for producing selective inhibitors 磷酸结合环氨基酸序列的差异导致MAP2K1和MAP2K6共价抑制剂的不同结合模式：生产选择性抑制剂的结构见解

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-14 DOI: 10.1016/j.bmcl.2025.130277

Seigo Yumura , Kei Moritsugu , Daisuke Kitagawa , Masaaki Sawa , Takayoshi Kinoshita

{"title":"The discrepancies in amino acid sequence of the phosphate-binding loop lead to distinctive binding modes of a covalent inhibitor for MAP2K1 and MAP2K6: Structural insights for producing selective inhibitors","authors":"Seigo Yumura , Kei Moritsugu , Daisuke Kitagawa , Masaaki Sawa , Takayoshi Kinoshita","doi":"10.1016/j.bmcl.2025.130277","DOIUrl":"10.1016/j.bmcl.2025.130277","url":null,"abstract":"<div><div>Mitogen-activated protein kinase kinase 6 (MAP2K6) plays a crucial role in activating the p38 MAPK pathway, and dysregulation of this pathway is associated with serious diseases including autoimmune diseases. 5Z-7-oxozeaenol (5Z7O), a covalent-binding inhibitor, inhibits MAP2K6 approximately ten times more strongly than MAP2K1, a common off-target kinase of MAP2K6. Here, we determined the crystal structure of the 5Z7O-MAP2K6 complex and carefully compared it with that of the 5Z7O-MAP2K1 complex previously reported. The binding orientation of 5Z7O is slightly different between the MAP2K1 and MAP2K6 complexes, resulting in different hydrogen-bond networks and thereby the higher potency of 5Z7O for MAP2K6 than MAP2K1. 5Z7O formed hydrogen bonds with the arginine residue in the catalytic HRD motif of MAP2K6 and asparagine residue in the solvent-accessible region but not with the corresponding residues of MAP2K1. Structural comparison implied that these differences in hydrogen bonding were attributable to differences in the phosphate-binding loop (P-loop) between MAP2K6 and MAP2K1. Molecular dynamics simulation revealed the above-mentioned and further structural features of MAP2K1 and MAP2K6. These distinct structural features are potentially useful for producing selective inhibitors for MAP2K1 and MAP2K6.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130277"},"PeriodicalIF":2.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072167","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 DC20 as a potential non-nucleoside reverse transcriptase inhibitor with excellent pharmacokinetic properties 发现DC20作为一种潜在的非核苷类逆转录酶抑制剂，具有良好的药代动力学特性。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-13 DOI: 10.1016/j.bmcl.2025.130267

Jia-Yu Liu , Meng-Di Ma , Yi-Ming Li , Cong-Qiang Xie , Jia-Rui Wu , Kai-Ting Yan , Deng-Yu Niu , Rong-Hua Luo , Yue-Ping Wang , Yong-Tang Zheng , Zhen-nan She , Hong-Bing Zhang , Liu-Meng Yang , Yan-Ping He

{"title":"Discovery of DC20 as a potential non-nucleoside reverse transcriptase inhibitor with excellent pharmacokinetic properties","authors":"Jia-Yu Liu , Meng-Di Ma , Yi-Ming Li , Cong-Qiang Xie , Jia-Rui Wu , Kai-Ting Yan , Deng-Yu Niu , Rong-Hua Luo , Yue-Ping Wang , Yong-Tang Zheng , Zhen-nan She , Hong-Bing Zhang , Liu-Meng Yang , Yan-Ping He","doi":"10.1016/j.bmcl.2025.130267","DOIUrl":"10.1016/j.bmcl.2025.130267","url":null,"abstract":"<div><div><em>S</em>-DACOs are a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) known for their effective antiviral activity and low cytotoxicity, although their water solubility and bioavailability have been suboptimal. In this study, we synthesized and evaluated 25 novel compounds, most of which demonstrated a CLogP below 5 and exhibited potent antiviral activity against HIV-1<sub>IIIB</sub> with EC<sub>50</sub> values ranging from 0.86 to 0.004 μmol/L. Among them, compound <strong>DC20</strong> (EC<sub>50</sub> = 0.004 μM, CC<sub>50</sub> = 134.21 ± 0.78 μM, SI = 33,552) emerged as particularly promising, it effectively targets reverse transcriptase and maintains high efficacy against mutant strains V106M, K103N, and Y181C. Particularly notable is that <strong>DC20</strong> possesses excellent pharmacokinetic properties, with an oral bioavailability reaching up to 89.1 %. Given its high potency and low toxicity, <strong>DC20</strong> holds significant potential for drug development and may serve as a critical candidate for future clinical applications. Further investigations will focus on its pharmaceutical viability.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130267"},"PeriodicalIF":2.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075043","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