Electron-Induced Decomposition of 5-Bromo-4-thiouracil and 5-Bromo-4-thio-2′-deoxyuridine: The Effect of the Deoxyribose Moiety on Dissociative Electron Attachment

Abstract

When modified uridine derivatives are incorporated into DNA, radical species may form that cause DNA damage. This category of molecules has been proposed as radiosensitizers and is currently being researched. Here, we study electron attachment to 5-bromo-4-thiouracil (BrSU), a uracil derivative, and 5-bromo-4-thio-2′-deoxyuridine (BrSdU), with an attached deoxyribose moiety via the N-glycosidic (N1-C) bond. Quadrupole mass spectrometry was used to detect the anionic products of dissociative electron attachment (DEA), and the experimental results were supported by quantum chemical calculations performed at the M062X/aug-cc-pVTZ level of theory. Experimentally, we found that BrSU predominantly captures low-energy electrons with kinetic energies near 0 eV, though the abundance of bromine anions was rather low compared to a similar experiment with bromouracil. We suggest that, for this reaction channel, proton-transfer reactions in the transient negative ions limit the release of bromine anions.

Dissociative Electron Attachment to 5-Iodo-4-thio-2′-deoxyuridine: A Potential Radiosensitizer of Hypoxic Cells

“…It should be noted that in their DEA study with IU, Abdoul-Carime et al reported also the formation of two fragment anions, (C 3 H 2 NO) − and NCO – , associated with the cleavage of the uracil ring . We observed the latter anion also in our recent study with BrSdU, however, with a reduced relative intensity compared to that of brominated nucleoside BrdU . This quenching of NCO – formation in halogenated thio-2′-deoxyuracils/uridines like ISdU may be explained by the simple argument that one site of formation is not available due to the presence of the sulfur atom.…”

“…The calculated adiabatic electron affinity of ISdU at the M06-2X/DGDZVP++ level is ∼1.43 eV (see Figure 2), which is close to that very recently reported for BrSdU (for details of the computational methods see section S.2). 38 Thus, the parent anion of ISdU decays by either fast spontaneous emission of the excess electron or, more likely, molecular bond cleavages (DEA) (see the discussion below). To the best of our knowledge, no previous work on electron attachment to the IdU in the gas phase has been published.…”

Interaction of low-energy electrons with radiosensitizers

“…for 5-bromo-4-thio-uracil. 115 An additional explanation for the observed dissociation near 0 eV can be the creation of stable neutral HX molecules during the TNI lifetime, where X is halogen, which was suggested in the mentioned study of 5-bromo-4-thio-uracil as well as several other TNIs. 116–118…”

“…More recently, 5-bromo-4-thio-uracil was studied showing strong effects of intramolecular proton transfer on reaction dynamics, partially stabilizing the parent anion and allowing for HBr formation and release during the TNI decay. 115 It is worth repeating that the formation of hydrohalic acids seems to be an important process upon LEE interaction with many halogenated molecules 116,118,135 however, the biological consequences of this process are not well explored.…”

“…The environmental effects such as solubility and buffer reactivity will be critical for the transfer of further halogen-based radiosensitizers into applications such as 5-iodo-4-thio-2-deoxyuridine 154 or 5-bromo-4-thio--deoxyuridine. 115…”