5-Azidomethyl-2'-deoxyuridine (5-AmdU, 1) has been utilized for metabolic labeling of DNA and fluorescent imaging of live cells. The addition of radiation-produced electrons to 1 leads to the formation of π-aminyl radicals 2. 2, via rapid H-atom abstraction from 1, leads to the intermediate α-azidoalkyl radical (dU-5-CH●N3) that undergoes facile conversion to σ-iminyl radicals 3. 5-AmdU demonstrates effective radiosensitization in EMT6 breast cancer cells. We have now prepared 6-azidomethyluridine (6-AmU, 4) to expand our studies on the properties and reactivity of the site-specific formation of nitrogen-centered (aminyl and iminyl) radicals generated from the azido modified nucleobases. 6-AmU was synthesized form 2',3'-O-isopropylidene-5'-O-TBDMS-6-iodouridine by successive methylation, oxidation, and conversion of the allylic alcohol into the azido. Contrary to our results with 1 where radiation-mediated prehydrated electrons, formed in homogeneous aqueous glassy solution (7.5 M LiCl, 77 K) in the absence of oxygen, led to radicals 2 and 3, radiation-produced electron addition to 4 leads to the unexpected loss of azide as an anion via dissociative electron attachment, from the initially formed azide anion radical intermediate (U-6-CH2-N3●–), to generate the allylic radical 5.

Distinct pathways of dissociative electron attachment observed in 5- and 6-azidomethyl uracil nucleosides: N2 elimination vs. azide anion elimination

ACS Spring 2022

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