Electron-Mediated Aminyl and Iminyl Radicals from C5 Azido-Modified Pyrimidine Nucleosides Augment Radiation Damage to Cancer Cells

Abstract

Two classes of azido-modified pyrimidine nucleosides were synthesized as potential radiosensitizers; one class is 5-azidomethyl-2′-deoxyuridine (AmdU) and cytidine (AmdC), while the second class is 5-(1-azidovinyl)-2′-deoxyuridine (AvdU) and cytidine (AvdC). The addition of radiation-produced electrons to C5-azido nucleosides leads to the formation of π-aminyl radicals followed by facile conversion to σ-iminyl radicals either via a bimolecular reaction involving intermediate α-azidoalkyl radicals in AmdU/AmdC or by tautomerization in AvdU/ AvdC. AmdU demonstrates effective radiosensitization in EMT6 tumor cells.

Quasi-Free Electron-Mediated Radiation Sensitization by C5-Halopyrimidines

“…Thus, some groups are synthesizing halopyridine-like molecules with similar or even better DEA efficiency, but without the drawbacks of dehalogenation by thymidylate synthetase. In other words, new base and nucleoside derivatives are synthesized that have similar or better DEA yields in the 0–3 eV region than the haloprimidines; in addition, these derivatives would not lose the C5-modification of the thymine base by thymidylate synthetase. − Based on our previous works and on the current work, our work predicts that the DEA process of these halopyridine-like molecules in solution should predominantly be governed by e qf – .…”

Azide‐Modified Nucleosides as Versatile Tools for Bioorthogonal Labeling and Functionalization

“…[54] The similar but more stable 5-azidomethyl-2'deoxyuridine (AmdU) derivative can be obtained from thymidine after halogenation of the 5-methyl group followed by reaction with NaN 3 . [55] Moreover, the respective cytidine derivative AmdC can be obtained from AmdU by treatment with TIPBSÀ Cl (Scheme 5 A). [55] Furthermore, 6-azidouridine (6-AzU) has been described to be obtained by iodination of the C6-position and subsequent substitution with NaN 3 (Scheme 5 B).…”

“…[55] Moreover, the respective cytidine derivative AmdC can be obtained from AmdU by treatment with TIPBSÀ Cl (Scheme 5 A). [55] Furthermore, 6-azidouridine (6-AzU) has been described to be obtained by iodination of the C6-position and subsequent substitution with NaN 3 (Scheme 5 B). [56,57] In theory, it should be possible to obtain the 6-azide-modified cytidine derivative by TIPBSÀ Cl treatment as well.…”

Reaction of Electrons with DNA: Radiation Damage to Radiosensitization

“…We have extended our work to various pyrimidine nucleosides with azido modification at the C5-site of the pyrimidine base; e.g., C5-azidomethyl-2′-deoxyuridine (5-AZmdU; and our results show that radiation-produced electrons can be converted to the highly damaging RNH• at 77 K [128]. Based on these results, we hypothesize that site-specific incorporation of azido-modified nucleosides into genomic DNA would augment radiation-induced damage in cells owing to the reactions of aminyl radicals under a reductive environment.…”

“…3′-AZT substantially enhanced γ-irradiation killing of EBV (Epstein-Barr virus)-transformed lymphoblastoid cells in vitro [133]. In addition, our very recent studies employing a number of C5-azidomethyl and C5-azidovinyl pyrimidine nucleosides show that 5-AZmdU caused significant radiosensitization against EMT-6 breast cancer cells [128]. These results offer an opportunity to investigate the potential use of azido-DNA-models as site-specific radiation sensitizers.…”