Silyl ether is particularly attractive for application in drug development for its easy preparation, non-toxicity and remarkable biocompatibility. Earlier studies relied on the use of intracellular acidic conditions to induce the cleavage of alkoxy silyl ethers. However, acidic conditions are not suitable to trigger the release of phenoxy silyl ethers, since they are more stable under acidic conditions compared with neutral conditions. We explored the vulnerability of the phenoxy silyl ether towards biological nucleophilic reagents and found that glutathione (GSH) could effectively and selectively induce the cleavage of phenoxy silyl ether. We also demonstrated that the rate of cleavage was controllable by adjusting the substituents on the phenyl ring. Phenoxy silyl ether-based prodrugs and antibody–drug conjugates (ADCs) were designed and synthesized, which could be effectively activated in cells with high GSH levels and there was an obvious therapeutic window between cells with different GSH levels.
{"title":"Fine-tuning phenoxy silyl scaffolds for the development of glutathione-responsive prodrugs and antibody–drug conjugates","authors":"Ding Wei , Huihui Wang , Shangwei Huangfu , Cheng Qi , Yuecheng Jiang , Xianqiang Yu , Biao Jiang , Hongli Chen","doi":"10.1016/j.bmc.2025.118088","DOIUrl":"10.1016/j.bmc.2025.118088","url":null,"abstract":"<div><div>Silyl ether is particularly attractive for application in drug development for its easy preparation, non-toxicity and remarkable biocompatibility. Earlier studies relied on the use of intracellular acidic conditions to induce the cleavage of alkoxy silyl ethers. However, acidic conditions are not suitable to trigger the release of phenoxy silyl ethers, since they are more stable under acidic conditions compared with neutral conditions. We explored the vulnerability of the phenoxy silyl ether towards biological nucleophilic reagents and found that glutathione (GSH) could effectively and selectively induce the cleavage of phenoxy silyl ether. We also demonstrated that the rate of cleavage was controllable by adjusting the substituents on the phenyl ring. Phenoxy silyl ether-based prodrugs and antibody–drug conjugates (ADCs) were designed and synthesized, which could be effectively activated in cells with high GSH levels and there was an obvious therapeutic window between cells with different GSH levels.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118088"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147543","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}
Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Based on their structures, we designed and synthesized a novel BACE1 inhibitor with a hydroxyproline-derived N-amidinopyrrolidine scaffold. The initially synthesized derivative 7a showed a weak but detectable inhibitory activity against recombinant BACE1, which suggested that this novel scaffold was a viable BACE1 inhibitor. To enhance its activity, 22 derivatives with various substituents on the terminal benzene rings of the two biphenyl groups were synthesized and evaluated. Structure–activity relationship studies showed that introducing a substituent at the meta position of the biphenyl group on the hydroxy terminal improved the activity, and we identified the highly active derivative 12f. In contrast, substituents at the para position of the biphenyl group on the carboxy terminal increased activity. Additionally, we investigated the absolute configuration of the substituted pyrrolidine ring, which showed that the (2S,4R)-derivative exhibited the highest activity. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors.
{"title":"Development of novel BACE1 inhibitors with a hydroxyproline-derived N-amidinopyrrolidine scaffold","authors":"Kazuya Kobayashi , Chinami Taniguchi , Misaki Tanaka , Rani Kimura , Kaho Komurasaki , Meguru Kuwano , Mayu Ikemoto , Natsuki Kawakami , Shinya Oishi , Yasunao Hattori , Kenichi Akaji","doi":"10.1016/j.bmc.2025.118086","DOIUrl":"10.1016/j.bmc.2025.118086","url":null,"abstract":"<div><div>Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Based on their structures, we designed and synthesized a novel BACE1 inhibitor with a hydroxyproline-derived <em>N</em>-amidinopyrrolidine scaffold. The initially synthesized derivative <strong>7a</strong> showed a weak but detectable inhibitory activity against recombinant BACE1, which suggested that this novel scaffold was a viable BACE1 inhibitor. To enhance its activity, 22 derivatives with various substituents on the terminal benzene rings of the two biphenyl groups were synthesized and evaluated. Structure–activity relationship studies showed that introducing a substituent at the <em>meta</em> position of the biphenyl group on the hydroxy terminal improved the activity, and we identified the highly active derivative <strong>12f</strong>. In contrast, substituents at the <em>para</em> position of the biphenyl group on the carboxy terminal increased activity. Additionally, we investigated the absolute configuration of the substituted pyrrolidine ring, which showed that the (2<em>S</em>,4<em>R</em>)-derivative exhibited the highest activity. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118086"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143287857","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}
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. In vivo 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 in vivo toxicity. Lysosomal escape and cell transfection data verify the in vitro 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.
{"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}
Pub Date : 2025-01-28DOI: 10.1016/j.bmc.2025.118089
Hua Yang , Mingmei Guo , Sumeng Guan, Yuanyuan Chang, Xiaoya Wu, Yinuo Wang, Ling Zhu, Moran Sun
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 III-4 that bearing a benzo[b]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 III-4 functions as a ferroptosis inducer. The structure–activity relationship (SAR) of these compounds was also explored. At the cellular level, compound III-4 could block the generation of GSH, cause the accumulation of ROS and MDA, down-regulate GPX4 level, and finally trigger the Fe2+-mediated ferroptosis in HT1080 cell lines. Further biological investigation revealed that III-4 arrested the cell cycle at the S phase and inhibited HT1080 cell lines migration. These results indicated that compound III-4 is a candidate for the identification of novel ferroptosis inducer for fibrosarcoma cells.
{"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}
Pub Date : 2025-01-28DOI: 10.1016/j.bmc.2025.118087
Shiwei Song, Wanrong Yang, Wanyi Tai
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 vs 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.
polo样激酶1 （PLK1）和溴结构域4 （BRD4）是众所周知的癌蛋白，在许多癌症类型中驱动肿瘤细胞生长。同时靶向这些蛋白靶点一直是科学家们孜孜不倦地追求的，以增强化疗中的抗癌效果。然而，很少设计蛋白水解靶向嵌合体（PROTAC）通过一个单分子同时降解这些癌蛋白。本文以BRD4和PLK1双靶点抑制剂BI-2536为基础，设计合成了7个PROTAC分子。其中，化合物17b对PLK1、BRD4等BET家族蛋白的降解能力最强。双靶向的PROTAC 17b在低至3 nM的浓度下诱导BET蛋白和PLK1几乎完全降解，但PLK1的蛋白水解时间远晚于BET蛋白（36 h vs 4 h）。化合物17b在多种癌细胞系中表现出较强的抗增殖活性。此外，17b还能调控下游关键细胞过程相关基因的表达，对癌细胞生长起到长期抑制作用。这些发现表明，17b是一种高效的双靶向降解剂。
{"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}
Pub Date : 2025-01-27DOI: 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
We report herein the development of a series of novel AR antagonists characterized by a spirocyclic scaffold, employing scaffold hopping and structure-based drug design strategies. Most of the spirocyclic derivatives exhibited enhanced AR antagonistic activity and superior antiproliferative activity against LNCaP cells compared to enzalutamide. Among them, compound 21 demonstrated moderate antiproliferative activity against enzalutamide resistant prostate cancer cell lines and exhibited favorable in vitro metabolic stability. These findings offer valuable insights for the rational design of AR antagonists for the treatment of advanced prostate cancer.
{"title":"Discovery of novel spirocyclic derivates as potent androgen receptor antagonists","authors":"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","doi":"10.1016/j.bmc.2025.118082","DOIUrl":"10.1016/j.bmc.2025.118082","url":null,"abstract":"<div><div>We report herein the development of a series of novel AR antagonists characterized by a spirocyclic scaffold, employing scaffold hopping and structure-based drug design strategies. Most of the spirocyclic derivatives exhibited enhanced AR antagonistic activity and superior antiproliferative activity against LNCaP cells compared to enzalutamide. Among them, compound <strong>21</strong> demonstrated moderate antiproliferative activity against enzalutamide resistant prostate cancer cell lines and exhibited favorable <em>in vitro</em> metabolic stability. These findings offer valuable insights for the rational design of AR antagonists for the treatment of advanced prostate cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118082"},"PeriodicalIF":3.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073012","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}
Pub Date : 2025-01-27DOI: 10.1016/j.bmc.2025.118083
Luxia Liang , Wenlong Fei , Yingzhe Wang , Ze Zhang , Qidong You , Xiaoke Guo
Human AlkB homologue H5 (ALKBH5) is a crucial demethylase for N6-methyladenosine (m6A) of mRNA. Although ALKBH5 is recognized as a promising target in various cancers, especially acute myeloid leukemia (AML), research on inhibitors of ALKBH5 remains limited. Here, we reported the discovery of a series of maleimide-based small molecule inhibitors of ALKBH5, resulting in the identification of compound 18 through optimization. Comprehensive evaluations suggested that compound 18 holds significant potential as a lead compound for ALKBH5 inhibitor.
{"title":"Discovery of maleimide derivatives as m6A demethylase ALKBH5 inhibitors","authors":"Luxia Liang , Wenlong Fei , Yingzhe Wang , Ze Zhang , Qidong You , Xiaoke Guo","doi":"10.1016/j.bmc.2025.118083","DOIUrl":"10.1016/j.bmc.2025.118083","url":null,"abstract":"<div><div>Human AlkB homologue H5 (ALKBH5) is a crucial demethylase for <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A) of mRNA. Although ALKBH5 is recognized as a promising target in various cancers, especially acute myeloid leukemia (AML), research on inhibitors of ALKBH5 remains limited. Here, we reported the discovery of a series of maleimide-based small molecule inhibitors of ALKBH5, resulting in the identification of compound <strong>18</strong> through optimization. Comprehensive evaluations suggested that compound <strong>18</strong> holds significant potential as a lead compound for ALKBH5 inhibitor.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118083"},"PeriodicalIF":3.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147490","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}
Pub Date : 2025-01-27DOI: 10.1016/j.bmc.2025.118090
Xudong Yu , Jianfei Jin , Yun Si , Huanmin Zhang , Zhegang Song
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 (KD ≈ 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 in vivo 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.
{"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}
Pub Date : 2025-01-23DOI: 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
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.
{"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}
Pub Date : 2025-01-21DOI: 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
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 9. Among them, compound 24 demonstrated strong HPK1 inhibition (IC50 of 10.1 nM) and effectively suppressed phosphorylation of the downstream protein SLP76. Notably, compound 24 exhibited enhanced potency in promoting IL-2 secretion in Jurkat T cells, reduced cellular toxicity, and improved liver microsomal stability compared to hit 9. Overall, this study provides a promising lead compound for further optimization as a candidate for cancer immunotherapy.
{"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}
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