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}
Pub Date : 2025-01-17DOI: 10.1016/j.bmc.2025.118078
Zhiwen Wu, Guoqiang Zhang, Yifan Shang, Jiaxin Huang, Yongqian Liu, Huixian Zhou, Tao Wang
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 β-diketone moiety. Further antiproliferative activities against five cancer cell lines (Hela, A549, HepG2, MCF-7 and HT-29) in vitro showed that compound 4a-4e displayed remarkable anti-tumor effect against A549, HepG2, MCF-7 and HT-29. Of them, compound 4d is particularly prominent against MCF-7, with IC50 of 1.39 μM. Preliminary mechanism found that compound 4d 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 4d decreased the ratio of SLC7A11 to GAPDH and GPX4 to β-actin. Docking results indicated that compound 4d had good binding affinity to the active site of GPX4 (PDB ID: 7u4n and 7u4k). In conclusion, compound 4d may be potential anti-tumor agent, which induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis.
{"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":"https://doi.org/10.1016/j.bmc.2025.118078","url":null,"abstract":"<p><p>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 β-diketone moiety. Further antiproliferative activities against five cancer cell lines (Hela, A549, HepG2, MCF-7 and HT-29) in vitro showed that compound 4a-4e displayed remarkable anti-tumor effect against A549, HepG2, MCF-7 and HT-29. Of them, compound 4d is particularly prominent against MCF-7, with IC<sub>50</sub> of 1.39 μM. Preliminary mechanism found that compound 4d 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 4d decreased the ratio of SLC7A11 to GAPDH and GPX4 to β-actin. Docking results indicated that compound 4d had good binding affinity to the active site of GPX4 (PDB ID: 7u4n and 7u4k). In conclusion, compound 4d may be potential anti-tumor agent, which induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":" ","pages":"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}
Pub Date : 2025-01-15DOI: 10.1016/j.bmc.2025.118067
Zhiheng Jin , Gang Li , Dengqin He , Jiaxin Chen , Yali Zhang , Mengjie Li , Hongliang Yao
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.
{"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}
Pub Date : 2025-01-12DOI: 10.1016/j.bmc.2025.118069
Dumitrela Diaconu , Marius Savu , Catalina Ciobanu , Violeta Mangalagiu , Ionel I. Mangalagiu
In the last decades fungal infections became a major threat to human health having an unacceptably occurrence, a high rate of mortality and the number of patients at risk for these infections continue to increase every year. An effective, modern and very useful strategy in antifungal therapy is represented by the use of chimeric and hybrid drugs, most of them being with azaheterocycle skeleton. In this review, we present an overview from the last five years of the most representative achievements in the field of chimeric and hybrid diazine derivatives with antifungal properties. Within this work we emphasize the most relevant data concerning the synthesis, design, Structure Activity Relationships (SAR) correlations and antifungal activity of the main classes of diazine: 1,2-diazine (pyridazine), 1,3-diazine (pyrimidine), 1,4-diazine (pyrazine) and their fused derivatives.
{"title":"Current strategies in design and synthesis of antifungals hybrid and chimeric diazine derivatives","authors":"Dumitrela Diaconu , Marius Savu , Catalina Ciobanu , Violeta Mangalagiu , Ionel I. Mangalagiu","doi":"10.1016/j.bmc.2025.118069","DOIUrl":"10.1016/j.bmc.2025.118069","url":null,"abstract":"<div><div>In the last decades fungal infections became a major threat to human health having an unacceptably occurrence, a high rate of mortality and the number of patients at risk for these infections continue to increase every year. An effective, modern and very useful strategy in antifungal therapy is represented by the use of chimeric and hybrid drugs, most of them being with azaheterocycle skeleton. In this review, we present an overview from the last five years of the most representative achievements in the field of chimeric and hybrid diazine derivatives with antifungal properties. Within this work we emphasize the most relevant data concerning the synthesis, design, Structure Activity Relationships (SAR) correlations and antifungal activity of the main classes of diazine: 1,2-diazine (pyridazine), 1,3-diazine (pyrimidine), 1,4-diazine (pyrazine) and their fused derivatives.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"119 ","pages":"Article 118069"},"PeriodicalIF":3.3,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1016/j.bmc.2025.118065
Long Yan , Yanan Sun , Ke Ding, Tao Peng
Vitamin A and its primary active derivative, all-trans 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.
{"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}
Pub Date : 2025-01-07DOI: 10.1016/j.bmc.2025.118066
Chao Liu , Xiaohong Zhu , Wenjing Shi , Qionglu Duan , Min Yuan , Yifan Zheng , Yuanjuan Wei , Baoqing You , Jing Zhang , Shuyi Si , Yan Li
Infectious diseases caused by drug-resistant bacteria represent one of the most significant global public challenges of this century. There is an urgent need for the treatment of drug-resistant Gram-negative bacterial infections. A series of 3,4-dihydro-2H-[1,3]oxazino[5,6-h]quinoline derivatives were synthesized and evaluated for their antibacterial activity against Gram-negative bacteria including strains from ATCC and clinical isolates, initially revealing the structure–activity relationship. Among them, 22 compounds demonstrated inhibitory activity (MICs: 3.125–12.5 μg/mL) against Escherichia coli (E. coli) ATCC 25922 and Acinetobacter baumannii (A. baumannii) ATCC 19606. Among these, 7 compounds exhibited good inhibitory activity against MDR A. baumannii clinical isolates, with MICs ranging from 3.125 to 12.5 μg/mL. Most of these compounds also showed lower cytotoxicity than IMB-881. Notably, 2 compounds, 4n1 and 4b3, significantly extended the survival of Galleria mellonella larvae infected with E. coli. Mechanism studies have revealed that compounds 4n1 and 4b3 might disrupt the interaction between LptA and LptC, showing moderate affinity for LptA protein. These compounds also induce abnormal bacterial morphology and cause outer membrane damage. This finding provides a novel class of antibiotic sensitizers with the potential to effectively fight against E. coli and A. baumannii.
{"title":"Synthesis, biological evaluation and validation of IMB-881 derivatives as anti-Gram-negative bacterial agents","authors":"Chao Liu , Xiaohong Zhu , Wenjing Shi , Qionglu Duan , Min Yuan , Yifan Zheng , Yuanjuan Wei , Baoqing You , Jing Zhang , Shuyi Si , Yan Li","doi":"10.1016/j.bmc.2025.118066","DOIUrl":"10.1016/j.bmc.2025.118066","url":null,"abstract":"<div><div>Infectious diseases caused by drug-resistant bacteria represent one of the most significant global public challenges of this century. There is an urgent need for the treatment of drug-resistant Gram-negative bacterial infections. A series of 3,4-dihydro-2H-[1,3]oxazino[5,6-<em>h</em>]quinoline derivatives were synthesized and evaluated for their antibacterial activity against Gram-negative bacteria including strains from ATCC and clinical isolates, initially revealing the structure–activity relationship. Among them, 22 compounds demonstrated inhibitory activity (MICs: 3.125–12.5 μg/mL) against <em>Escherichia coli</em> (<em>E. coli</em>) ATCC 25922 and <em>Acinetobacter baumannii</em> (<em>A. baumannii</em>) ATCC 19606. Among these, 7 compounds exhibited good inhibitory activity against MDR <em>A. baumannii</em> clinical isolates, with MICs ranging from 3.125 to 12.5 μg/mL. Most of these compounds also showed lower cytotoxicity than IMB-881. Notably, 2 compounds, <strong>4n1</strong> and <strong>4b3</strong>, significantly extended the survival of <em>Galleria mellonella</em> larvae infected with <em>E. coli</em>. Mechanism studies have revealed that compounds <strong>4n1</strong> and <strong>4b3</strong> might disrupt the interaction between LptA and LptC, showing moderate affinity for LptA protein. These compounds also induce abnormal bacterial morphology and cause outer membrane damage. This finding provides a novel class of antibiotic sensitizers with the potential to effectively fight against <em>E. coli</em> and <em>A. baumannii</em>.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"119 ","pages":"Article 118066"},"PeriodicalIF":3.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968976","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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