Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
J Am Chem Soc. 2020 Dec 23;142(51):21484-21492. doi: 10.1021/jacs.0c10616. Epub 2020 Dec 11.
Selective chemistry that modifies the structure of DNA and RNA is essential to understanding the role of epigenetic modifications. We report a visible-light-activated photocatalytic process that introduces a covalent modification at a C(sp)-H bond in the methyl group of N6-methyl deoxyadenosine and N6-methyl adenosine, epigenetic modifications of emerging importance. A carefully orchestrated reaction combines reduction of a nitropyridine to form a nitrosopyridine spin-trapping reagent and an exquisitely selective tertiary amine-mediated hydrogen-atom abstraction at the N6-methyl group to form an α-amino radical. Cross-coupling of the putative α-amino radical with nitrosopyridine leads to a stable conjugate, installing a label at N6-methyl-adenosine. We show that N6-methyl deoxyadenosine-containing oligonucleotides can be enriched from complex mixtures, paving the way for applications to identify this modification in genomic DNA and RNA.
选择性地修饰 DNA 和 RNA 的结构对于理解表观遗传修饰的作用至关重要。我们报告了一种可见光激活的光催化过程，该过程可以在 N6-甲基脱氧腺苷和 N6-甲基腺苷的甲基 C(sp)-H 键上引入共价修饰，这些修饰是新兴的重要修饰。精心设计的反应将硝基吡啶还原为亚硝吡啶自旋捕获试剂，并通过精细选择性的叔胺介导的 N6-甲基氢原子提取形成α-氨基自由基。假定的α-氨基自由基与亚硝吡啶的交叉偶联导致形成稳定的轭合物，在 N6-甲基-腺苷上安装一个标记。我们表明，含有 N6-甲基脱氧腺苷的寡核苷酸可以从复杂混合物中富集，为在基因组 DNA 和 RNA 中鉴定这种修饰铺平了道路。
