Dissociative electron attachment to halogenated nucleotides: a quest for better radiosensitizers.

Tumor hypoxia hampers radiotherapy efficacy, necessitating radiosensitizers. Substituted nucleobases offer advantages as radiosensitizers. They can be incorporated into DNA with minimal gene-expression alteration, selectively targeting tumor cells and having lower toxicity to normal tissues. They possess higher electron affinity than native DNA, facilitating rapid electron attachment for cancer-cell damage. Despite advancements, exploration beyond uracil nucleobases remains limited. Herein, we investigated electron attachment to potential radiosensitizers, specifically 5-halo-2'-deoxycytidine-3'-monophosphates (5X-3'-dCMPH). Our findings indicate that 5X-3'-dCMPH nucleotides possess higher electron affinity than unsubstituted 3'-dCMPH, suggesting halogenated nucleotides are better electron acceptors. Moreover, the high vertical detachment energy (VDE) implies minimal auto-detachment, and the dissociative electron attachment (DEA) pathways suggest that dehalogenation is the favored process for halogenated systems, supported by low dissociation barriers. Notably, 5Br-3'-dCMPH and 5I-3'-dCMPH exhibit nearly barrier-free dissociation after electron attachment, and thus, they may preferentially act as superior radiosensitizers.