American Chemical Society
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Pathways of the Dissociative Electron Attachment Observed in 5- and 6‑Azidomethyluracil Nucleosides: Nitrogen (N2) Elimination vs Azide Anion (N3) Elimination

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journal contribution
posted on 2023-02-13, 18:38 authored by Daniel Adjei, Yahaira Reyes, Anil Kumar, Samuel Ward, Sergey A. Denisov, Moaadh Alahmadi, Michael D. Sevilla, Stanislaw F. Wnuk, Mehran Mostafavi, Amitava Adhikary
5-Azidomethyl-2′-deoxyuridine (5-AmdU, 1) has been successfully employed for the metabolic labeling of DNA and fluorescent imaging of live cells. 5-AmdU also demonstrated significant radiosensitization in breast cancer cells via site-specific nitrogen-centered radical (π-aminyl (U-5-CH2–NH), 2, and σ-iminyl (U-5-CHN), 3) formation. This work shows that these nitrogen-centered radicals are not formed via the reduction of the azido group in 6-azidomethyluridine (6-AmU, 4). Radical assignments were performed using electron spin resonance (ESR) in supercooled solutions, pulse radiolysis in aqueous solutions, and theoretical (DFT) calculations. Radiation-produced electron addition to 4 leads to the facile N3 loss, forming a stable neutral C-centered allylic radical (U-6-CH2, 5) through dissociative electron attachment (DEA) via the transient negative ion, TNI (U-6-CH2-N3•–), in agreement with DFT calculations. In contrast, TNI (U-5-CH2–N3•–) of 1, via facile N2 loss (DEA) and protonation from the surrounding water, forms radical 2. Subsequently, 2 undergoes rapid H-atom abstraction from 1 and produces the metastable intermediate α-azidoalkyl radical (U-5-CH-N3). U-5-CH-N3 converts facilely to radical 3. N3 loss from U-6-CH2–N3•– is thermodynamically controlled, whereas N2 loss from U-5-CH2–N3•– is dictated by protonation from the surrounding waters and resonance conjugation of the azidomethyl side chain at C5 with the pyrimidine ring.