Simpson Mathew M, Lam Ching Ching, Goodman Jonathan M, Balasubramanian Shankar
Yusuf Hamied Department of Chemistry University of Cambridge Lensfield Road CB2 1EW Cambridge UK.
Cancer Research UK Cambridge Institute Li Ka Shing Centre University of Cambridge Robinson Way CB2 0RE Cambridge UK.
Angew Chem Weinheim Bergstr Ger. 2023 Jun 26;135(26):e202304756. doi: 10.1002/ange.202304756. Epub 2023 May 15.
The epigenetic modification 5-methylcytosine plays a vital role in development, cell specific gene expression and disease states. The selective chemical modification of the 5-methylcytosine methyl group is challenging. Currently, no such chemistry exists. Direct functionalisation of 5-methylcytosine would improve the detection and study of this epigenetic feature. We report a xanthone-photosensitised process that introduces a 4-pyridine modification at a C(sp)-H bond in the methyl group of 5-methylcytosine. We propose a reaction mechanism for this type of reaction based on density functional calculations and apply transition state analysis to rationalise differences in observed reaction efficiencies between cyanopyridine derivatives. The reaction is initiated by single electron oxidation of 5-methylcytosine followed by deprotonation to generate the methyl group radical. Cross coupling of the methyl radical with 4-cyanopyridine installs a 4-pyridine label at 5-methylcytosine. We demonstrate use of the pyridination reaction to enrich 5-methylcytosine-containing ribonucleic acid.
表观遗传修饰5-甲基胞嘧啶在发育、细胞特异性基因表达和疾病状态中起着至关重要的作用。对5-甲基胞嘧啶甲基基团进行选择性化学修饰具有挑战性。目前，尚无此类化学方法。5-甲基胞嘧啶的直接功能化将改善对这种表观遗传特征的检测和研究。我们报道了一种呫吨酮光敏化过程，该过程在5-甲基胞嘧啶甲基基团的C(sp)-H键处引入4-吡啶修饰。我们基于密度泛函计算提出了此类反应的机理，并应用过渡态分析来解释氰基吡啶衍生物之间观察到的反应效率差异。该反应由5-甲基胞嘧啶的单电子氧化引发，随后去质子化生成甲基自由基。甲基自由基与4-氰基吡啶的交叉偶联在5-甲基胞嘧啶上安装了一个4-吡啶标签。我们展示了吡啶化反应在富集含5-甲基胞嘧啶核糖核酸中的应用。
