Photochemical and Single Electron Transfer Generation of 2′-Deoxycytidin-N4-yl Radical from Oxime Esters,The Journal of Organic Chemistry

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Photochemical and Single Electron Transfer Generation of 2′-Deoxycytidin-N4-yl Radical from Oxime Esters
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2023-05-23 , DOI: 10.1021/acs.joc.3c00646
Haihui Peng ₁ , Son Vu ₁ , Parker Retes ₂ , Samuel Ward ₂ , Anil Kumar ₂ , Michael D Sevilla ₂ , Amitava Adhikary ₂ , Marc M Greenberg ₁

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A 2′-deoxycytidin-N4-yl radical (dC·), a strong oxidant that also abstracts hydrogen atoms from carbon–hydrogen bonds, is produced in a variety of DNA damaging processes. We describe here the independent generation of dC· from oxime esters under UV-irradiation or single electron transfer conditions. Support for this σ-type iminyl radical generation is provided by product studies carried out under aerobic and anaerobic conditions, as well as electron spin resonance (ESR) characterization of dC· in a homogeneous glassy solution at low temperature. Density functional theory (DFT) calculations also support fragmentation of the corresponding radical anions of oxime esters 2d and 2e to dC· and subsequent hydrogen atom abstraction from organic solvents. The corresponding 2′-deoxynucleotide triphosphate (dNTP) of isopropyl oxime ester 2c (5) is incorporated opposite 2′-deoxyadenosine and 2′-deoxyguanosine by a DNA polymerase with approximately equal efficiency. Photolysis experiments of DNA containing 2c support dC· generation and indicate that the radical produces tandem lesions when flanked on the 5′-side by 5′-d(GGT). These experiments suggest that oxime esters are reliable sources of nitrogen radicals in nucleic acids that will be useful mechanistic tools and possibly radiosensitizing agents when incorporated in DNA.

中文翻译：

肟酯光化学和单电子转移生成 2′-脱氧胞苷-N4-基自由基

2′-脱氧胞苷-N 4-基自由基 (dC·) 是一种强氧化剂，也能从碳氢键中夺取氢原子，在多种 DNA 损伤过程中产生。我们在此描述了在紫外线照射或单电子转移条件下从肟酯独立生成dC·。在有氧和无氧条件下进行的产物研究以及低温均匀玻璃状溶液中 dC· 的电子自旋共振 (ESR) 表征为这种 σ 型亚氨基自由基的生成提供了支持。密度泛函理论 (DFT) 计算还支持肟酯2d和2e的相应自由基阴离子裂解为 dC· 以及随后从有机溶剂中提取氢原子。异丙肟酯2c ( 5 ) 的相应 2'-脱氧核苷酸三磷酸 (dNTP) 通过 DNA 聚合酶以大致相同的效率与 2'-脱氧腺苷和 2'-脱氧鸟苷相对掺入。含有2c的 DNA 的光解实验支持 dC· 的产生，并表明当 5'-d(GGT) 位于 5' 侧时，自由基会产生串联损伤。这些实验表明，肟酯是核酸中氮自由基的可靠来源，当其掺入DNA中时，氮自由基将成为有用的机械工具，并可能成为放射增敏剂。

更新日期：2023-05-23

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