Bioorganic & Medicinal Chemistry最新文献_第7页

Janus dendritic ionizable lipids with fine designed headgroup and tails to improve mRNA delivery efficiency

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-28 DOI: 10.1016/j.bmc.2025.118080

Chao Liu, Yuhao Jiang, Wenliang Xue, Jinyu Liu, Zihao Wang, Xinsong Li

{"title":"Janus dendritic ionizable lipids with fine designed headgroup and tails to improve mRNA delivery efficiency","authors":"Chao Liu, Yuhao Jiang, Wenliang Xue, Jinyu Liu, Zihao Wang, Xinsong Li","doi":"10.1016/j.bmc.2025.118080","DOIUrl":"10.1016/j.bmc.2025.118080","url":null,"abstract":"<div><div>Lipid nanoparticles (LNP) are recognized as the most efficient non-viral carriers for the delivery of nucleic acids including small interfering RNA (siRNA) and messenger RNA (mRNA). Ionizable lipid within the system is pivotal component influencing encapsulation, endosomal escape, delivery efficiency and immunogenicity. Accordingly, the precision design of ionizable lipids is a key step in the development of LNP. In this report, we constructed sixteen Janus dendritic ionizable lipids by varying numbers and alkyl chain length of tails based on different ionizable head containing hydroxyl and tertiary amine groups. The corresponding LNP were prepared by using microfluidic mixing device, with all samples exhibiting particle size around 100 nm and polydispersity index (PDI) below 0.2. <em>In vivo</em> validation demonstrates that two optimized ionizable lipids containing two hydroxy groups, two tertiary amines and six hydrophobic chain tails (U-502, U-503) show superior delivery efficiency compared to lipids with less tails and commercial ALC-0315. Hematoxylin and Eosin (H&E) staining of tissues, immunogenicity, liver and kidney function tests additionally confirm that both ionizable lipids have favorable biocompatibility and low <em>in vivo</em> toxicity. Lysosomal escape and cell transfection data verify the <em>in vitro</em> delivery efficacy of these LNP. Taken together, Janus dendritic lipids with fine designed ionizable head and multiple hydrophobic tails have improved mRNA delivery efficiency and biosafety, which may be promise in the development of delivery system.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118080"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077867","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 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

New curcumin derivative induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2025-01-17 DOI: 10.1016/j.bmc.2025.118078

Zhiwen Wu , Guoqiang Zhang , Yifan Shang , Jiaxin Huang , Yongqian Liu , Huixian Zhou , Tao Wang

{"title":"New curcumin derivative induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis","authors":"Zhiwen Wu , Guoqiang Zhang , Yifan Shang , Jiaxin Huang , Yongqian Liu , Huixian Zhou , Tao Wang","doi":"10.1016/j.bmc.2025.118078","DOIUrl":"10.1016/j.bmc.2025.118078","url":null,"abstract":"<div><div>Previous experiments have revealed that curcumin exerts potential antitumor effect by inducing apoptosis and ferroptosis of tumor cells. However, its low solubility and bioavailability, as well as fast metabolism limit its clinical use. The structural modification of curcumin is beneficial for the discovery of potential candidate drugs for cancer treatment. Here, three new series of curcumin derivatives including 25 compounds were synthesized at active sites on benzene ring and <em>β</em>-diketone moiety. Further antiproliferative activities against five cancer cell lines (Hela, A549, HepG2, MCF-7 and HT-29) <em>in vitro</em> showed that compound <strong>4a–4e</strong> displayed remarkable anti-tumor effect against A549, HepG2, MCF-7 and HT-29. Of them, compound <strong>4d</strong> is particularly prominent against MCF-7, with IC<sub>50</sub> of 1.39 μM. Preliminary mechanism found that compound <strong>4d</strong> could trigger ferrous ions and ROS accumulation, increase MDA level in MCF-7 cells, while significantly down-regulate GPX4 level in dose-dependent manner. Western Blot results discovered that compound <strong>4d</strong> decreased the ratio of SLC7A11 to GAPDH and GPX4 to <em>β</em>-actin. Docking results indicated that compound <strong>4d</strong> had good binding affinity to the active site of GPX4 (PDB ID: 7u4n and 7u4k). In conclusion, compound <strong>4d</strong> may be potential anti-tumor agent, which induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118078"},"PeriodicalIF":3.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447599","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