{"title":"Prodrug activation by 4,4’-bipyridine-mediated aromatic nitro reduction","authors":"Qing Wang, Yikang Song, Shuowei Yuan, Yaoji Zhu, Wenjing Wang, Ling Chu","doi":"10.1038/s41467-024-52604-y","DOIUrl":null,"url":null,"abstract":"<p>Unleashing prodrugs through nitro-reduction is a promising strategy in cancer treatment. In this study, we present a unique bioorthogonal reaction for aromatic nitro reduction, mediated by 4,4‘-bipyridine. The reaction is a rare example of organocatalyst-mediated bioorthogonal reaction. This bioorthogonal reaction demonstrates broad substrate scope and proceeds at low micromolar concentrations under biocompatible conditions. Our mechanistic study reveals that water is essential for the reaction to proceed at biorelevant substrate concentrations. We illustrate the utility of our reaction for controlled prodrug activation in mammalian cells, bacteria, and mouse models. Furthermore, a nitro-reduction-annulation cascade is developed for the synthesis of indole derivatives in living cells.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":null,"pages":null},"PeriodicalIF":14.7000,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-024-52604-y","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Unleashing prodrugs through nitro-reduction is a promising strategy in cancer treatment. In this study, we present a unique bioorthogonal reaction for aromatic nitro reduction, mediated by 4,4‘-bipyridine. The reaction is a rare example of organocatalyst-mediated bioorthogonal reaction. This bioorthogonal reaction demonstrates broad substrate scope and proceeds at low micromolar concentrations under biocompatible conditions. Our mechanistic study reveals that water is essential for the reaction to proceed at biorelevant substrate concentrations. We illustrate the utility of our reaction for controlled prodrug activation in mammalian cells, bacteria, and mouse models. Furthermore, a nitro-reduction-annulation cascade is developed for the synthesis of indole derivatives in living cells.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.