Electron-induced Single Strand Break in the Nucleotide of 5- and 6-Bromouridine. A DFT Study

We studied electron-induced O-P bond breakage in 5- and 6-bromo-2'-deoxyuridine 3',5'-diphosphates at the B3LYP/6-31++G** level of theory. Electron attachment to the 6-bromo derivative causes debromination, resulting in 6-radical that can abstract a hydrogen atom from the sugar residue. For 5-radical, H abstraction and conversion to 6-radical are kinetically prevented, suggesting that the radiosensitizing properties of 5-bromo-2'-deoxyuridine cannot be explained by intranucleotide reaction. The radicals, produced by hydrogen abstraction may undergo breakage at the O-P bond, forming carbonyl compounds. This reaction is thermodynamically favored for the 3'-site. Identification of 3'-ketone in radiolytic experiments with 6-bromo-2'-deoxyuridine labeled DNA would confirm our mechanism. (C) 2014 Elsevier B.V. All rights reserved.