Bioorganic & Medicinal Chemistry Letters最新文献

Discovery of novel pyridine skeleton derivatives as potent CLK2/3 inhibitors.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-29 DOI: 10.1016/j.bmcl.2025.130212

Jie Wei, Guochuang Zheng, Tingting Yu, Qi Liu, Wenying Yu, Cheng Jiang, Xu Quan

{"title":"Discovery of novel pyridine skeleton derivatives as potent CLK2/3 inhibitors.","authors":"Jie Wei, Guochuang Zheng, Tingting Yu, Qi Liu, Wenying Yu, Cheng Jiang, Xu Quan","doi":"10.1016/j.bmcl.2025.130212","DOIUrl":"https://doi.org/10.1016/j.bmcl.2025.130212","url":null,"abstract":"<p><p>The CLK family plays a crucial role in regulating the transcript splicing, catalyzing the molecular mechanism of spliceosomes. It also regulates the activity or expression of non-spliced proteins by phosphorylating SR proteins. Hence, CLKs are promising therapeutic targets for a variety of diseases, especially in tumors. Several small molecule CLK2/3 inhibitors were under the clinical studies, while most of these molecule possessed N-containing bicyclic heteroaryl as the skeleton. The goal of this work was to introduce a novel skeleton as well as provide structure diversity to the development of CLK2/3 inhibitors. Herein, a series of pyridine derivatives (5a-5h, 6a-6e, and 7a-7g) were designed, synthesized and evaluated. Among them, compound 7c was identified to have good inhibitory activities against both CLK2/3 and proliferation of SW480 tumor cell. Additionally, pharmacokinetic study in mice as well as the stability assay were performed to investigate the druggability of 7c. The good in vitro activity and promising pharmacokinetic properties indicated that the 7c was a reliable lead compound for further development.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130212"},"PeriodicalIF":2.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750571","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 and biological evaluation of novel 4-Arylaminoquinolines derivatives as EGFR/HDAC inhibitors

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-29 DOI: 10.1016/j.bmcl.2025.130214

Keke Yao , Yaxin Li , Wei Wei , Sisi Liu , Xiaoli Wang , Jiamin Xu , Ranran Zhang , Zhigang Wu , Chunyan Guo , Leifu Yang , Liming Hu

{"title":"Synthesis and biological evaluation of novel 4-Arylaminoquinolines derivatives as EGFR/HDAC inhibitors","authors":"Keke Yao , Yaxin Li , Wei Wei , Sisi Liu , Xiaoli Wang , Jiamin Xu , Ranran Zhang , Zhigang Wu , Chunyan Guo , Leifu Yang , Liming Hu","doi":"10.1016/j.bmcl.2025.130214","DOIUrl":"10.1016/j.bmcl.2025.130214","url":null,"abstract":"<div><div>Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality worldwide. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the role of epigenetic modifications, such as histone deacetylation, in cancer progression underscore the need for novel therapeutic strategies. This study reports the design, synthesis, and biological evaluation of novel 4-arylaminoquinoline derivatives as dual inhibitors targeting EGFR and histone deacetylase (HDAC). Leveraging structure-activity relationship insights, a series of compounds were synthesized by integrating pharmacophoric elements of EGFR-TKIs and HDAC inhibitors and their kinase and cellular activities were evaluated. Compound <strong>22c2</strong> exhibited the highest inhibitory activities against EGFR (IC<sub>50</sub> = 4.81 nM) and HDAC (IC<sub>50</sub> = 119.4 nM and 354.8 nM for HDAC1 and HDAC3, respectively). Moreover, <strong>22c2</strong> demonstrated excellent anti-proliferative effects on four human cancer cell lines. These findings provide a foundation for developing dual EGFR/HDAC inhibitors as potential anticancer therapeutics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130214"},"PeriodicalIF":2.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747689","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

A small-molecule pretargeting approach for PSMA-targeted conjugates

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-28 DOI: 10.1016/j.bmcl.2025.130213

Nooshin Mesbahi, Hosog Yoon, Melody D. Fulton, Clifford E. Berkman

引用次数: 0

Discovery of 4-((quinolin-8-ylthio)methyl)benzamide derivatives as a new class of SARS-CoV-2 nsp13 inhibitors

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-25 DOI: 10.1016/j.bmcl.2025.130207

Danchen Fan , Yuanting Huang , Rui Yao , Guo Zhang , Shengyong Yang , Linli Li

引用次数: 0

Redox-responsive ferulic acid-biotin conjugate: Design, synthesis, and enhanced anticancer efficacy

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-25 DOI: 10.1016/j.bmcl.2025.130209

Xiaoshuang Dai , Ke Mei , Jianpeng Liu , Bin Sun , Neng Qiu

{"title":"Redox-responsive ferulic acid-biotin conjugate: Design, synthesis, and enhanced anticancer efficacy","authors":"Xiaoshuang Dai , Ke Mei , Jianpeng Liu , Bin Sun , Neng Qiu","doi":"10.1016/j.bmcl.2025.130209","DOIUrl":"10.1016/j.bmcl.2025.130209","url":null,"abstract":"<div><div>In this study, ferulic acid (FA) was conjugated with biotin via a disulfide bond to improve its anticancer activity. The resulting conjugate (FA-SS-Bio) was characterized by proton nuclear magnetic resonance (<sup>1</sup>H NMR) and exhibited an amorphous structure, in contrast to the crystalline nature of FA. FA-SS-Bio demonstrated accelerated drug release under reductive and oxidative conditions. Biotinylation significantly increased cell uptake of the drug in biotin receptor (BR)-positive HeLa and MCF-7 cells, as confirmed by cellular uptake studies and molecular docking, which revealed strong biotin-BR interactions. Additionally, the cytotoxicity of FA-SS-Bio was significantly improved, with IC<sub>50</sub> values that were 2.94-fold and 2.95-fold lower than those of free FA against HeLa and MCF-7 cells, respectively. BR blockade with biotin reduced FA-SS-Bio cytotoxicity in a concentration-dependent manner, confirming biotin-mediated targeting. Apoptosis assays showed enhanced FA-induced apoptosis due to biotin and disulfide bonds. FA-SS-Bio demonstrated excellent blood compatibility, with a hemolysis rate below 0.5 %, compared to ∼1.5 % for FA. Additionally, FA-SS-Bio exhibited higher cell viability in MCF-10 A cells than in cancer cells, highlighting its favorable safety profile. These findings provide a novel perspective on the design of prodrug conjugates for improved cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130209"},"PeriodicalIF":2.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715530","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

PEG-ASO conjugates for efficient targeted delivery and migration inhibition in Cancer cell

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-24 DOI: 10.1016/j.bmcl.2025.130208

Chunhui Zhao , Xiangjun Li , Zixin He , Chun Ye , Feng Chen , Jia Cheng

引用次数: 0

Design, synthesis, molecular docking and ADME of novel phenylalanine derivatives as mushroom tyrosinase inhibitors

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-24 DOI: 10.1016/j.bmcl.2025.130211

Longhao Wang, Shunshun Lei, Liyun Du, Chengyao Lai, Weijie Yang, Liqin Qiu, Rihui Cao

{"title":"Design, synthesis, molecular docking and ADME of novel phenylalanine derivatives as mushroom tyrosinase inhibitors","authors":"Longhao Wang, Shunshun Lei, Liyun Du, Chengyao Lai, Weijie Yang, Liqin Qiu, Rihui Cao","doi":"10.1016/j.bmcl.2025.130211","DOIUrl":"10.1016/j.bmcl.2025.130211","url":null,"abstract":"<div><div>Tyrosinase is the key rate-limiting enzyme for melanin synthesis. The accumulation and excessive production of melanin lead to skin pigmentation. Therefore, tyrosinase is the target of tyrosinase inhibitors to control melanin synthesis. Only a few TYR inhibitors have been proven to be effective and safe to treat skin pigmentation. This highlights the importance of developing new tyrosinase inhibitors. Based on the reported tyrosinase inhibitors with phenylalanine structure, a series of novel phenylalanine derivatives were synthesized and investigated as mTYR inhibitors. The results demonstrated that most of these derivatives had more potent mTYR inhibitory activities than positive controls. Compound <strong>3e</strong> was found to be the strongest inhibitor with an IC<sub>50</sub> value of 4.86 ± 0.026 μM. The Lineweaver-Burk plots of mTYR inhibition kinetics revealed that the selected compounds <strong>2d</strong> and <strong>3e</strong> were reversible and competitive inhibitors. In addition, molecular docking results of compounds <strong>2d</strong> and <strong>3e</strong> show they could compete with the substrate for the active center, including mTYR and hTYR. And the ADME prediction of selected derivatives assess the potential druglikeness. These results indicated that this class of compounds could be used as leads for developing new TYR inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130211"},"PeriodicalIF":2.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725539","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 and biological evaluation of amino-conjugated bile acid derivatives against non-alcoholic steatohepatitis

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-24 DOI: 10.1016/j.bmcl.2025.130210

Zhitao Wu , Mingge Zhang , Meng Kun Yan , Chenyue Li , Guoyu Pan , Lijiang Xuan

引用次数: 0

Imide-based enones: A new scaffold that inhibits biofilm formation in Gram-negative pathogens

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-23 DOI: 10.1016/j.bmcl.2025.130206

J. Israel Barrera-Hernández , Jesús R. Pérez-Velázquez , Ángel Ramírez-Trinidad , Jesús Oria-Hernández , Eduardo Hernández-Vázquez

引用次数: 0

Design, synthesis, and evaluation of a novel protein degrader FPFT-2216.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-22 DOI: 10.1016/j.bmcl.2025.130193

Yasuyuki Ueda, Takashi Ando, Yoshiteru Eikyu, Takumi Okamoto, Hironori Yokoyama, Naoshi Kunimura, Daiki Kanaoka, Shotaro Izuno, Mayumi Watanabe

引用次数: 0