To learn more about Prof. Adhikary: https://sites.google.com/site/adhikaryamitava/
"Azido-substituted Nucleosides as Radiation Damage Enhancement Agents: Role of Electrons"
Organic azides, first identified over 160 years ago, now play major roles in biochemistry. Azido(N3)-modified nucleosides have been used in click chemistry, bioconjugation, aminonucleoside synthesis, metabolic labeling, live-cell imaging, and enzyme inhibition. Systematic studies of N₃-compounds have also revealed their potential as radiosensitizers. Since ionizing radiation produces copious extent of free electrons-highly reactive and strongest reducing agents; electron-induced reactions can enhance DNA damage. EPR studies have shown that electron transfer from protein radicals to electron-affinic pyrimidine bases (T (thymine) and C (cytosine), T preferred) is efficient, making C5-modified thymidine a promising design strategy. Classic examples such as 5-bromodeoxyuridine undergo dissociative electron attachment (DEA) to form reactive radical intermediates that increase DNA-strand breaks, but clinical toxicity limits their use. Therefore, newer C5-modified thymidine analogs are sought that show strong DEA reactivity yet retain their substituents after cellular incorporation. Our work demonstrated that C5-azido derivatives maintain cell viability and that azidothymidine (AZT) enhances radiosensitization across multiple tumor cell lines, though potential metabolic issues remain.
Other azido-modified nucleosides, such as C5-azidomethyl and C5-azidovinyl derivatives, also sensitize cancer cells to radiation, and EPR, pulse radiolysis, and DFT studies have shown that these compounds typically undergo DEA to form nitrogen-centered radicals (NCRs). DEA proceeds via a transient negative ion (R–N₃•⁻), followed by N₂ loss to yield a nitrene anion radical (RN•⁻), which rapidly protonates to form RNH• before tautomerizing to R=N• depending on substitution. A notable exception is 6-azidomethyluridine, which forms a C-centered radical instead of an NCR. This work began at Oakland University (Sevilla-Adhikary) and now this has become a strong collaborative work among the University of Iowa (Radiation and EPR and overall supervision - Adhikary), Florida International University (Wnuk – synthesis), Mostafavi (University of Paris-Saclay, Paris, France), and quantum chemical calculations (Sevilla and Kumar – Oakland University).