{"title":"从丹参中发现天然 Ah 受体拮抗剂并合成用于肿瘤免疫疗法的类似物","authors":"Zhenyuan Li, Shuying Li, Zeyu Xing, Quanchang Gu, Rongrong Du, Jianshuang Jiang, Xiang Yuan, Xu Zhang, Xiaoguang Chen, Nina Xue*, Peicheng Zhang*, Jing Jin* and Yanan Yang*, ","doi":"10.1021/acs.jmedchem.3c01740","DOIUrl":null,"url":null,"abstract":"<p >IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A–D (<b>1–4</b>), the first adducts composed of <i>ortho</i>-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of <i>Salvia miltiorrhiza</i> Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a <i>cis</i>-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both <i>in</i> <i>vitro</i> and <i>in</i> <i>vivo</i> experiments, (±)-<b>13e</b> demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8<sup>+</sup> T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Natural Ah Receptor Antagonists from Salvia miltiorrhiza Bunge and Synthesis of Analogs for Tumor Immunotherapy\",\"authors\":\"Zhenyuan Li, Shuying Li, Zeyu Xing, Quanchang Gu, Rongrong Du, Jianshuang Jiang, Xiang Yuan, Xu Zhang, Xiaoguang Chen, Nina Xue*, Peicheng Zhang*, Jing Jin* and Yanan Yang*, \",\"doi\":\"10.1021/acs.jmedchem.3c01740\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A–D (<b>1–4</b>), the first adducts composed of <i>ortho</i>-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of <i>Salvia miltiorrhiza</i> Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a <i>cis</i>-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both <i>in</i> <i>vitro</i> and <i>in</i> <i>vivo</i> experiments, (±)-<b>13e</b> demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8<sup>+</sup> T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-01-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01740\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01740","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of Natural Ah Receptor Antagonists from Salvia miltiorrhiza Bunge and Synthesis of Analogs for Tumor Immunotherapy
IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A–D (1–4), the first adducts composed of ortho-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of Salvia miltiorrhiza Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a cis-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both invitro and invivo experiments, (±)-13e demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8+ T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.