Electron-induced single strand break in the nucleotide of 5- and 6-bromouridine. A DFT study

Golon, Łukasz; Chomicz, Lidia; Rak, Janusz

doi:10.1016/j.cplett.2014.08.049

Cited by 15 publications

(19 citation statements)

References 41 publications

(10 reference statements)

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“…In the subsequent step, the sugar radical may undergo either heterolytic dissociation 5 at the CX′-O (X = 3 or 5) bond or homolytic dissociation at the O-P bond. 42,43 The former process produces the X′-OH on the deoxyribose (see 7 in Fig. 2), while the latter produces an aldehyde group on C5′ (see 6 in Fig.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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“…Such bond breakages, which have not been studied up to now to our best knowledge, may be involved in radiation induced damage to DNA modified by 5XdU. On the other hand, hydrogen abstraction from the C 3′ site was predicted to be feasible in radiosensitizing studies of 6-bromo-2-deoxyuridine 3′,5′-diphosphate, 6-bromo-2-deoxycytidine 3′,5′-diphosphate, 8-bromo-2′-deoxyadenosine 3′,5′-diphosphate, and 8-bromo-2′-deoxyguanine 3′,5′-diphosphate . Similarly, the uracil-5-yl radical may abstract the hydrogen atom located at the C 3′ position of a neighboring nucleotide leading to subsequent P–O 3′ bond cleavage.…”

Section: Introductionmentioning

confidence: 99%

“…The radiosensitivity of 5XdU has been extensively investigated in different DNA fragments − and cancer cells. − Impressive single- and double-stranded breaks, − intra- and interstrand cross-links, − alkali-labile lesions, chromosomal aberrations, and base releases were detected. Moreover, the potential anticancer applications of 5XdU were further demonstrated in clinical trials. − The radiosensitizing character of 5XdU is attributed to their considerable electron affinities having enough ability to bind a radiation-produced secondary electron. , The estimated electron affinities of 5-halogenated uracil derivatives lie in a range 0.37–0.64 eV in the gas phase and 2.21–2.60 eV in aqueous solution, − which are separately much higher than those of native nucleobase derivatives (−0.37 to 0.44 eV in the gas phase and 0.95 to 2.18 eV in aqueous solution). , Experimental studies showed that the anions formed by 5-halogenated uracil derivatives interacting with secondary electrons are only metastable intermediates, which can go through a rapid halide anion elimination reaction producing the uracil-5-yl radical. − Theoretical calculations − , and simulations , predicted that the halide anion elimination process is spontaneous or needs surmounting only a small kinetic barrier in both the gas phase and aqueous solution, demonstrating the experimental observations. The produced uracil-5-yl radical is highly reactive, thereby being considered to be able to attack surrounding molecular fragments (such as the 2′-deoxyribose moiety of the same or an adjacent nucleotide) or molecules leading to diverse DNA lesions.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Responsible for High Energy Radiation Induced Damage to Single-Stranded DNA Modified by Radiosensitizing 5-Halogenated Deoxyuridines

et al. 2016

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Experimental studies showed that high energy radiation induced base release and DNA backbone breaks mainly occur at the neighboring 5' nucleotide when a single-stranded DNA is modified by radiosensitizing 5-halogenated deoxyuridines. However, no mechanism can be used to interpret these experimental observations. To better understand the radiosensitivity of 5-halogenated deoxyuridines, mechanisms involving hydrogen abstraction by the uracil-5-yl radical from the C2' and C3' positions of an adjacent nucleotide separately followed by the C3'-O3' or N-glycosidic bond rupture and the P-O3' bond breakage are investigated in the DNA sequence 5'-TU(•)-3' employing density functional theory calculations in the present study. It is found that hydrogen abstractions from both positions are comparable with the one from the C2' site slightly more favorable. The N-glycosidic bond cleavage in the neighboring 5' nucleotide following the internucleotide C2'-Ha abstraction is estimated to have the lowest activation free energies, indicating that the adjacent 5' base release dominates electron induced damage to single-stranded DNA incorporated by 5-halogenated deoxyuridines. Relative to the P-O3' bond breakage after the internucleotide C3'-H abstraction, the C3'-O3' bond rupture in the neighboring 5' nucleotide following the internucleotide C2'-Ha abstraction is predicted to have a lower activation free energy, implying that single-stranded DNA backbone breaks are prone to occur at the C3'-O3' bond site. The 5'-TU(•)-3' species has substantial electron affinity and can even capture a hydrated electron, forming the 5'-TU(-)-3' anion. However, the electron induced C3'-O3' bond rupture in 5'-TU(-)-3' anion via a pathway of internucleotide proton abstraction is only minor in both the gas phase and aqueous solution. The present theoretical predictions can interpret rationally experimental observations, thereby demonstrating that the mechanisms proposed here are responsible for high energy radiation induced damage to single-stranded DNA incorporated by radiosensitizing 5-halogenated deoxyuridines. By comparing with previous results, our work proves that the radiosensitizing action of 5-bromo-2-deoxyuridine is not weaker but stronger than its isomer 6-bromo-2-deoxyuridine on the basis of the available data.

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“…The dissociation of the 5BrdU anion radical takes place once an electron is attached to 5BrdU, which results in the reactive nucleobase radical and bromide anion . If the radical is formed in DNA, it is capable of abstracting a hydrogen atom from the adjacent deoxyribose to produce a strand break after several secondary steps …”

Section: Introductionmentioning

confidence: 99%

“…[19][20][21] If the radicali sf ormed in DNA, it is capable of abstracting ah ydrogen atom from the adjacent deoxyribose to produce as trand break after severals econdary steps. [22] Whereas the efficacy of radiation-induced damage to DNA labeled with 5BrdU has been proved in vitro, the in vivo case remains unclear.S ome studies have shown that radiotherapy with the employment of 5BrdU gives better results (e.g. longer survival rate) than radiotherapy alone, whereas others have found no significant survival difference betweenp atients treated with RT and RT/5BrdU.…”

Section: Introductionmentioning

confidence: 99%

Electrophilic 5‐Substituted Uracils as Potential Radiosensitizers: A Density Functional Theory Study

2016

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Although 5-bromo-2'-deoxyuridine (5BrdU) possesses significant radiosensitizing power in vitro, clinical studies do not confirm any advantages of radiotherapy employing 5BrdU. This situation calls for a continuous search for efficient radiosensitizers. Using the proposed mechanism of radiosensitization by 5BrdU, we propose a series of 5-substituted uracils, XYU, that should undergo efficient dissociative electron attachment. The DFT-calculated thermodynamic and kinetic data concerning the XYU degradations induced by electron addition suggests that some of the scrutinized derivatives have much better characteristics than 5BrdU itself. Synthesis of these promising candidates for radiosensitizers, followed by studies of their radiosensitizing properties in DNA context, and ultimately in cancer cells, are further steps to confirm their potential applicability in anticancer treatment.

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Electron-induced single strand break in the nucleotide of 5- and 6-bromouridine. A DFT study

Cited by 15 publications

References 41 publications

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

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

Mechanisms Responsible for High Energy Radiation Induced Damage to Single-Stranded DNA Modified by Radiosensitizing 5-Halogenated Deoxyuridines

Electrophilic 5‐Substituted Uracils as Potential Radiosensitizers: A Density Functional Theory Study

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