Bioorganic & Medicinal Chemistry最新文献_第4页

Design, synthesis and biological evaluation of benzo[b]thiophene analogues as novel ferroptosis inhibitor that inhibit fibrosarcoma cell proliferation

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-28 DOI: 10.1016/j.bmc.2025.118089

Hua Yang , Mingmei Guo , Sumeng Guan, Yuanyuan Chang, Xiaoya Wu, Yinuo Wang, Ling Zhu, Moran Sun

{"title":"Design, synthesis and biological evaluation of benzo[b]thiophene analogues as novel ferroptosis inhibitor that inhibit fibrosarcoma cell proliferation","authors":"Hua Yang , Mingmei Guo , Sumeng Guan, Yuanyuan Chang, Xiaoya Wu, Yinuo Wang, Ling Zhu, Moran Sun","doi":"10.1016/j.bmc.2025.118089","DOIUrl":"10.1016/j.bmc.2025.118089","url":null,"abstract":"<div><div>While apoptosis activation has traditionally been considered as an anti-cancer mechanism, current research points to ferroptosis stimulation as a potentially effective cancer therapy. Glutathione peroxidase 4 (GPX4), an essential antioxidant enzyme, serves as a negative regulator of ferroptosis, and its targeted inhibition or degradation can efficiently induce this process. In this study, a potent ferroptosis inducer <strong>III-4</strong> that bearing a benzo[<em>b</em>]thiophene moiety was developed by employing a sequential structure optimization process based on RSL-3 to inhibit cancer cells proliferation. At the same time, this cytotoxic activity could be reversed by ferroptosis inducer Fer-1, suggesting that <strong>III-4</strong> functions as a ferroptosis inducer. The structure–activity relationship (SAR) of these compounds was also explored. At the cellular level, compound <strong>III-4</strong> could block the generation of GSH, cause the accumulation of ROS and MDA, down-regulate GPX4 level, and finally trigger the Fe<sup>2+</sup>-mediated ferroptosis in HT1080 cell lines. Further biological investigation revealed that <strong>III-4</strong> arrested the cell cycle at the S phase and inhibited HT1080 cell lines migration. These results indicated that compound <strong>III-4</strong> is a candidate for the identification of novel ferroptosis inducer for fibrosarcoma cells.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118089"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Proteolysis targeting chimera of BI-2536 induces potent dual degradation of PLK1 and BET proteins

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-28 DOI: 10.1016/j.bmc.2025.118087

Shiwei Song, Wanrong Yang, Wanyi Tai

{"title":"Proteolysis targeting chimera of BI-2536 induces potent dual degradation of PLK1 and BET proteins","authors":"Shiwei Song, Wanrong Yang, Wanyi Tai","doi":"10.1016/j.bmc.2025.118087","DOIUrl":"10.1016/j.bmc.2025.118087","url":null,"abstract":"<div><div>Polo-like kinase 1 (PLK1) and bromodomain 4 (BRD4) are well-known oncoproteins that drive tumor cell growth in many cancer types. Simultaneously targeting these protein targets has been intently pursued by scientists to enhance anti-cancer effect in chemotherapy. However, it is rare to design proteolytic targeting chimeras (PROTAC) to degrade these oncoproteins simultaneously by one single molecule. Herein, we designed and synthesized seven PROTAC molecules based on BI-2536, a dual-target inhibitor of BRD4 and PLK1. Among these, compound 17b demonstrated the best ability to degrade PLK1, BRD4 and other BET family proteins. The dual targeting PROTAC 17b induces the almost complete degradation of BET proteins and PLK1 at concentration as low as 3 nM, but proteolysis of PLK1 takes place a lot later than BET proteins (36 h <em>vs</em> 4 h). Compound 17b exhibited strong anti-proliferative activities across multiple cancer cell lines. Furthermore, 17b was able to regulate the expression of downstream genes involved in key cellular processes and exert the prolonged suppression of cancer cell growth. These findings suggest that 17b is a highly potent and efficacious dual-targeting degrader.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118087"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 spirocyclic derivates as potent androgen receptor antagonists

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-27 DOI: 10.1016/j.bmc.2025.118082

Wenqiang Zhang , Xiaoyu Zhou , Hao Zhu , Yawen Fan , Zhuolin Chen , Chenxiao Wang , Xingru Chen , Hongmei Li , Tao Lu , Xian Wei , Yadong Chen , Caiping Chen , Yu Jiao

引用次数: 0

Discovery of maleimide derivatives as m6A demethylase ALKBH5 inhibitors

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-27 DOI: 10.1016/j.bmc.2025.118083

Luxia Liang , Wenlong Fei , Yingzhe Wang , Ze Zhang , Qidong You , Xiaoke Guo

引用次数: 0

A peptide-based fluorescent bioprobe for EphA2-overexpressing tumor targeting and image-guided surgical resection

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-27 DOI: 10.1016/j.bmc.2025.118090

Xudong Yu , Jianfei Jin , Yun Si , Huanmin Zhang , Zhegang Song

{"title":"A peptide-based fluorescent bioprobe for EphA2-overexpressing tumor targeting and image-guided surgical resection","authors":"Xudong Yu , Jianfei Jin , Yun Si , Huanmin Zhang , Zhegang Song","doi":"10.1016/j.bmc.2025.118090","DOIUrl":"10.1016/j.bmc.2025.118090","url":null,"abstract":"<div><div>Fluorescence-guided surgery (FGS) is an emerging and highly promising surgical technique in clinic. Owing to its real-time and visual characteristics, it assists in achieving clear pictures on lesion site, tumor boundary and degree of metastasis, which will definitely improve surgery accuracy and minimize cancer recurrence as much as possible. Herein, we report a near-infrared fluorescent bioprobe, YK80, which utilizes a modified heptamethine cyanine dye as the fluorophore and a self-assembling peptide targeting Ephrin receptor A2 (EphA2) proteins as the ligand. The design strategy and the synthetic route to YK80 are described, and then optical properties, pharmacokinetics, binding affinity between YK80 and the protein are further investigated. YK80 shows high affinity (<em>K</em><sub>D</sub> ≈ 100 nM) with EphA2-expressing cancer cells and excellent targeting ability in mouse models bearing colorectal tumors. Meanwhile, indocyanine green (ICG), the commonly used non-targeted fluorescent contrast agent is employed as the comparison for <em>in vivo</em> experiments. However, ICG owns no such capability towards cancer cells or solid tumors. Thus, YK80 could potentially serve as a targeted contrast agent for image-guided surgery and this successful example will boost the development of medical imaging, surgical methods as well as translational medicine.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118090"},"PeriodicalIF":3.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Rational design of AIEgens through π-bridge engineering for dual-modal photodynamic and photothermal therapy

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-23 DOI: 10.1016/j.bmc.2025.118081

Yanwen Liu , Shunzhi Gou , Hongchao Wang , Yumei Wu , Mingyan Yang , Xinmin Li , Hongyu Li , Zhe Zheng , Zeli Yuan , Jie Gao

{"title":"Rational design of AIEgens through π-bridge engineering for dual-modal photodynamic and photothermal therapy","authors":"Yanwen Liu , Shunzhi Gou , Hongchao Wang , Yumei Wu , Mingyan Yang , Xinmin Li , Hongyu Li , Zhe Zheng , Zeli Yuan , Jie Gao","doi":"10.1016/j.bmc.2025.118081","DOIUrl":"10.1016/j.bmc.2025.118081","url":null,"abstract":"<div><div>A series of aggregation-induced emission luminogens (AIEgens) with donor–π–acceptor (D–π–A) architecture were rationally designed and synthesized through π-bridge engineering for dual-modal photodynamic and photothermal therapy. The AIEgens (TPT, TFT, and TTT) were constructed using methoxy-substituted tetraphenylene as the electron donor and tricyanofuran as the electron acceptor, connected via different π-bridges (phenyl, furan, or thiophene). These compounds exhibited red-shifted absorption (460–545 nm) and emission (712–720 nm) with remarkable aggregation-induced emission characteristics. Among them, TTT demonstrated superior photophysical properties and was successfully encapsulated into amphiphilic calixarene-based nanoparticles (T@Q NPs) with uniform morphology. The T@Q NPs showed efficient reactive oxygen species generation and photothermal conversion (η = 6.98 %), enabling effective tumor cell ablation through combined photodynamic and photothermal therapy. In vivo studies revealed that T@Q NPs achieved 70 % tumor growth inhibition in 4T1 tumor-bearing mice without obvious systemic toxicity. This work presents an effective strategy for designing AIEgens-based phototherapeutic agents through π-bridge engineering, offering promising candidates for clinical translation in tumor phototherapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"119 ","pages":"Article 118081"},"PeriodicalIF":3.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 biological evaluation of 7H-Pyrrolo[2,3-d]pyrimidines as potent HPK1 kinase inhibitors

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-21 DOI: 10.1016/j.bmc.2025.118079

Feifei Wu , Huiyu Li , Weiqiang Li , Laishun Zhang , Qi An , Jiaqi Sun , Qian Zhang , Yaoliang Sun , Lei Xu , Jinghua Yu , Xingxing Diao , Jia Li , Linghua Meng , Shilin Xu

{"title":"Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d]pyrimidines as potent HPK1 kinase inhibitors","authors":"Feifei Wu , Huiyu Li , Weiqiang Li , Laishun Zhang , Qi An , Jiaqi Sun , Qian Zhang , Yaoliang Sun , Lei Xu , Jinghua Yu , Xingxing Diao , Jia Li , Linghua Meng , Shilin Xu","doi":"10.1016/j.bmc.2025.118079","DOIUrl":"10.1016/j.bmc.2025.118079","url":null,"abstract":"<div><div>Hematopoietic progenitor kinase 1 (HPK1) has emerged as a promising target for cancer immunotherapy due to its critical role as a negative regulator of T cell receptor (TCR) signaling. Despite this potential, no HPK1 inhibitors have been approved for cancer treatment, underscoring the need for structurally novel inhibitors. Herein, we describe the design, synthesis and biological evaluation of a series of potent HPK1 inhibitors based on our previously identified hit <strong>9</strong>. Among them, compound <strong>24</strong> demonstrated strong HPK1 inhibition (IC<sub>50</sub> of 10.1 nM) and effectively suppressed phosphorylation of the downstream protein SLP76. Notably, compound <strong>24</strong> exhibited enhanced potency in promoting IL-2 secretion in Jurkat T cells, reduced cellular toxicity, and improved liver microsomal stability compared to hit <strong>9</strong>. Overall, this study provides a promising lead compound for further optimization as a candidate for cancer immunotherapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"119 ","pages":"Article 118079"},"PeriodicalIF":3.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

An overview of small-molecule agents for the treatment of psoriasis 治疗银屑病的小分子药物综述。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-15 DOI: 10.1016/j.bmc.2025.118067

Zhiheng Jin , Gang Li , Dengqin He , Jiaxin Chen , Yali Zhang , Mengjie Li , Hongliang Yao

{"title":"An overview of small-molecule agents for the treatment of psoriasis","authors":"Zhiheng Jin , Gang Li , Dengqin He , Jiaxin Chen , Yali Zhang , Mengjie Li , Hongliang Yao","doi":"10.1016/j.bmc.2025.118067","DOIUrl":"10.1016/j.bmc.2025.118067","url":null,"abstract":"<div><div>Psoriasis is a prevalent, chronic inflammatory disease characterized by abnormal skin plaques. To date, physical therapy, topical therapy, systemic therapy and biologic drugs are the most commonly employed strategies for treating psoriasis. Recently, many agents have advanced to clinical trials, and some anti-psoriasis drugs have been approved, including antibody drugs and small-molecule drugs. Many antibody drugs targeting cytokines and receptors, such as interleukin (IL-17 and IL-23) and tumor necrosis factor-α (TNF-α), have been approved for the treatment of psoriasis. And numerous small-molecule agents have displayed promising activities in the treatment of psoriasis. The targets of anti-psoriasis drugs encompass phosphodiesterase IV (PDE4), Janus kinase (JAK), tyrosine kinase (TYK), retinoic acid-related orphan receptors (ROR), vitamin D receptor (VDR), Interleukin (IL), Aryl hydrocarbon receptor (AhR), Interleukin-1 receptor-associated kinase 4 (IRAK), chemoattractant-like receptor 1 (ChemR23), Sphingosine-1-phosphate receptor (S1P), A3 adenosine receptor (A3AR), Heat shock protein 90 (HSP90), The Rho-associated protein kinases (ROCK), The bromodomain and extra-terminal domain (BET), FMS-like tyrosine kinase 3 (FLT3), Tumor Necrosis Factor α Converting Enzyme (TACE), Toll-like receptors (TLR), NF-κB inducing kinase (NIK), DNA topoisomerase I (Topo I), among others. Herein, this review mainly recapitulates the advancements in the structure and enzyme activity of small-molecule anti-psoriasis agents over the last ten years, and their binding modes were also explored. Hopefully, this review will facilitate the development of novel small-molecule agents as potential anti-psoriasis drugs.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"119 ","pages":"Article 118067"},"PeriodicalIF":3.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Current strategies in design and synthesis of antifungals hybrid and chimeric diazine derivatives 抗真菌杂合和嵌合嘧啶衍生物的设计和合成现状。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-12 DOI: 10.1016/j.bmc.2025.118069

Dumitrela Diaconu , Marius Savu , Catalina Ciobanu , Violeta Mangalagiu , Ionel I. Mangalagiu

引用次数: 0

Bioorthogonal chemical reporters for profiling retinoic acid-modified and retinoic acid-interacting proteins 分析维甲酸修饰蛋白和维甲酸相互作用蛋白的生物正交化学报告。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-08 DOI: 10.1016/j.bmc.2025.118065

Long Yan , Yanan Sun , Ke Ding, Tao Peng

{"title":"Bioorthogonal chemical reporters for profiling retinoic acid-modified and retinoic acid-interacting proteins","authors":"Long Yan , Yanan Sun , Ke Ding, Tao Peng","doi":"10.1016/j.bmc.2025.118065","DOIUrl":"10.1016/j.bmc.2025.118065","url":null,"abstract":"<div><div>Vitamin A and its primary active derivative, all-<em>trans</em> retinoic acid (RA), are endogenous signaling molecules essential for numerous biological processes, including cell proliferation, differentiation, and immune modulation. Owing to its differentiation-inducing effect, RA was the first differentiating agent approved for the clinical treatment of acute myeloid leukemia. While the classical mechanisms of RA signaling involve nuclear receptors, such as retinoic acid receptors (RARs), emerging evidence suggests that RA also engages in non-covalent and covalent interactions with a broader range of proteins. However, tools for thoroughly characterizing these interactions have been lacking, and a comprehensive understanding of the landscape of RA-modified and RA-interacting proteins remains limited. Here, we report the development of two RA-based chemical reporters, RA-yne and RA-diazyne, to profile RA-modified and RA-interacting proteins, respectively, in live cells. RA-yne features a clickable alkyne group for metabolic labeling of RA-modified proteins, while RA-diazyne incorporates a photoactivatable diazirine and an alkyne handle for crosslinking and capturing RA-interacting proteins. Using quantitative proteomics, we demonstrate the high-throughput identification of these proteins, revealing that non-covalent interactions are more prevalent than covalent modifications. Our global profiling also uncovers a large number of RA-interacting proteins mainly enriched in pathways related to mitochondrial processes, ER homeostasis, and lipid metabolism. Overall, this work introduces new RA-derived chemical reporters, expands the resource for studying RA biology, and enhances our understanding of RA-associated pathways in health and disease.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"119 ","pages":"Article 118065"},"PeriodicalIF":3.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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