Irreversible electron attachment – a key to DNA damage by solvated electrons in aqueous solution

Abstract

The TYT and TXT trimeric oligonucleotides, where X stands for a native nucleobase, T (thymine), C (cytosine), A (adenine), or G (guanine), and Y indicates a brominated analogue of the former, were irradiated with ionizing radiation generated by a (60)Co source in aqueous solutions containing Tris as a hydroxyl radical scavenger. In the past, these oligomers were bombarded with low energy electrons under an ultra-high vacuum and significant damage to TXT trimers was observed. However, in aqueous solution, hydrated electrons do not produce serious damage to TXT trimers although the employed radiation dose exceeded many times the doses used in radiotherapy. Thus, our studies demonstrate unequivocally that hydrated electrons, which are the major form of electrons generated during radiotherapy, are a negligible factor in damage to native DNA. It was also demonstrated that all the studied brominated nucleobases have a potential to sensitize DNA under hypoxic conditions. Strand breaks, abasic sites and the products of hydroxyl radical attachment to nucleobases have been identified by HPLC and LC-MS methods. Although all the bromonucleobases lead to DNA damage under the experimental conditions of the present work, bromopyrimidines seem to be the radiosensitizers of choice since they lead to more strand breaks than bromopurines.

5-Selenocyanato and 5-trifluoromethanesulfonyl derivatives of 2′-deoxyuridine: synthesis, radiation and computational chemistry as well as cytotoxicity

“…9 To harness solvated electrons, which are inactive toward native DNA, 10 2 0 -deoxyuridine derivatives substituted with an electrophilic residue in the C5-position might be used for DNA damage. 11 Beside the necessity of undergoing enzymatic triphosphorylation and incorporation into DNA by enzymatic machinery of a cell, these derivatives should possess high electron affinity and should undergo dissociative electron attachment (DEA) that leads to reactive radicals inside the genome.…”

COST Action CM1201 “Biomimetic Radical Chemistry”: free radical chemistry successfully meets many disciplines

“…Moreover, the extent of damage, especially the formation of cytotoxic single-strand breaks induced by hydrated electrons is doubled in the trimeric oligonucleotides labeled with IdU or IdC compared to their counterparts labeled with BrdU or BrdC [78]. Our studies showed unequivocally that hydrated electrons are a negligible factor in damage to native DNA even for a ionizing radiation dose exceeded many times the doses used in radiotherapy [77]. Therefore, some kind of radiosensitization seems to be an indispensable component of any efficient radiotherapy.…”

“…Using HPLC and LC-MS techniques, it was demonstrated that beside the substitution of bromine atom by 2-hydroxypropyl radical (OHisop ), electron transfer from OHisop to BrdX takes place only for 5-bromo-2 0 -deoxyuridine (BrdU) and 5-bromo-2 0 -deoxycytydine (BrdC) due to larger electron affinity (EA) of pyrimidines than purines [76]. The larger EA of brominated pyrimidines also accounts for more efficient damage induced by hydrated electrons in the trimeric oligonucleotides, TBrdXT, labeled with BrdU or BrdC [77]. Moreover, the extent of damage, especially the formation of cytotoxic single-strand breaks induced by hydrated electrons is doubled in the trimeric oligonucleotides labeled with IdU or IdC compared to their counterparts labeled with BrdU or BrdC [78].…”

Molecular features of thymidine analogues governing the activity of human thymidine kinase

“…Their radiosensitising action is related to the irreversible and swift elimination of halide anions (X − ) from the modified nucleobase anion [7,8] that is formed due to solvated electron (e − hyd ) attachment. The latter species, the second (beside hydroxyl radicals) most abundant product of water radiolysis [9], are amply stable under hypoxia, but native DNA is not sensitive to them [5]. This situation is different for the DNA with incorporated radiosensitiser, where the elimination of X − leaves a reactive nucleoside radical in the biopolymer.…”

“…In order to overcome this therapeutically undesirable effect, radiosensitisation is necessary. One may mention several classes of cellular radiosensitisers that have been investigated so far [3], of which thymine analogues as 5-bromouracil (BrU)/5-iodouracil (IU) [4] and other halogenated nucleobases [5,6] seem to be especially promising since they work under hypoxia. Their radiosensitising action is related to the irreversible and swift elimination of halide anions (X − ) from the modified nucleobase anion [7,8] that is formed due to solvated electron (e − hyd ) attachment.…”