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

  • J Phys Chem B. 2023 Feb 23;127(7):1563-1571. doi: 10.1021/acs.jpcb.2c08257.
Daniel Adjei  1 ,  Yahaira Reyes  2 ,  Anil Kumar  3 ,  Samuel Ward  3 ,  Sergey A Denisov  1 ,  Moaadh Alahmadi  3 ,  Michael D Sevilla  3 ,  Stanislaw F Wnuk  2 ,  Mehran Mostafavi  1 ,  Amitava Adhikary  3
Affiliations
  • 1. Institut de Chimie Physique, UMR 8000 CNRS, Bât. 349, Université Paris-Saclay, 91405 Orsay Cedex, France.
  • 2. Department of Chemistry and Biochemistry, Florida International University, Miami, Florida 33199, United States.
  • 3. Department of Chemistry, Oakland University, 146 Library Drive, Rochester, Michigan 48309, United States.
PMID: 36780335 DOI: 10.1021/acs.jpcb.2c08257
Abstract

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.

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