(5′<i>S</i>)- and (5′<i>R</i>)-5′,8-Cyclo-2′-deoxyguanosine: Mechanistic Insights on the 2′-Deoxyguanosin-5′-yl Radical Cyclization

Chatgilialoglu, Chryssostomos; Bazzanini, Rita; Jiménez, Liliana; Miranda, Miguel A.

doi:10.1021/tx700282x

Cited by 57 publications

(62 citation statements)

References 31 publications

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“…85 The C 5′ sugar radical is formed in significant amounts by radiation 92 and is known to undergo facile attack at C8 in guanine to produce a cyclized species, the 5′,8-cyclo-2′-deoxyguanosin-7-yl radical in two diastereoisomeric (R) and (S) forms. 50,51 The ionization potentials of these radicals (Table 4) are relatively low 6.25 eV – 6.28 eV (gas phase IP vert ) and 4.58 eV – 4.70 eV (solution IP vert ) and in keeping with these low IPs these cross-links in DNA are readily further oxidized to form the diamagnetic products, i.e., 5′,8-cyclo-2′-deoxyguanosine isomers.…”

Section: Resultsmentioning

confidence: 99%

One-Electron Oxidation of Neutral Sugar Radicals of 2′-Deoxyguanosine and 2′-Deoxythymidine: A Density Functional Theory (DFT) Study

2012

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One electron oxidation of neutral sugar radicals has recently been suggested to lead to important intermediates in the DNA damage process culminating in DNA strand breaks. In this work, we investigate sugar radicals in a DNA model system to understand the energetics of sugar radical formation and oxidation. The geometries of neutral sugar radicals C1′•, C2′•, C3′•, C4′• and C5′• of 2′-deoxyguanosine (dG) and 2′-deoxythymidine (dT) were optimized in the gas phase and in solution using the B3LYP and ωB97x functionals and 6-31++G(D) basis set. Their corresponding cations (C1′+, C2′+, C3′+, C4′+ and C5′+) were generated by removing an electron (one-electron oxidation) from the neutral sugar radicals and their geometries were also optimized using the same methods and basis set. The calculation predicts the relative stabilities of the neutral sugar radicals in the order C1′• > C4′• > C5′• > C3′• > C2′•, respectively. Of the neutral sugar radicals, C1′• has the lowest vertical ionization potential (IPvert) ca. 6.33 eV in the gas phase and 4.71 eV in solution. C2′• has the highest IPvert ca. 8.02 eV in the gas phase and the resultant C2′ cation is predicted to undergo a barrierless hydride transfer from the C1′ site to produce the C1′ cation. One electron oxidation of C2′• in dG is predicted to result in a low lying triplet state consisting of G+• and C2′•. The 5′,8-cyclo-2′-deoxyguanosin-7-yl radical formed by intramolecular bonding between C5′• and C8 of guanine transfers spin density from C5′ site to guanine and this structure has IPvert 6.25 eV and 5.48 eV in the gas phase and in solution.

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Section: Resultsmentioning

confidence: 99%

One-Electron Oxidation of Neutral Sugar Radicals of 2′-Deoxyguanosine and 2′-Deoxythymidine: A Density Functional Theory (DFT) Study

2012

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“…On the other hand, both γ-irradiation of dGuo, under hydroxyl radical generating conditions and photolysis of 8-BrdGuo in aqueous solutions leads to the formation of cdGuo in a (5'R)/(5'S) ratio of 8:1. [28] The diversity of the stereochemical outcome in both systems was rationalized in terms of steric hindrance in the protected pro(5'S) chair transition state versus favorable hydrogen bonding in the unprotected pro-(5'R) conformation, respectively, as was previously reported for the cdAdo system. [22,24] …”

Section: Purine 5'8-cyclonucleosidesmentioning

confidence: 64%

“…[28] The generation of 2'-deoxyguanosin-5'-yl radicals is effected by the photolysis of synthetic (5'R)-C(5') tert-butyl ketone derivatives of dGuo. [27] The photochemistry of the 5'R diastereomer effectively produces the 2'-deoxyguanosin-5'-yl radical which undergoes intramolecular attack at the C(8)-N(7) double bond of guanine leading ultimately to the 5',8-cyclo-2'-deoxyguanosine (cdGuo) derivative.…”

Section: Purine 5'8-cyclonucleosidesmentioning

confidence: 99%

DNA Damage and Radical Reactions: Mechanistic Aspects, Formation in Cells and Repair Studies

Cadet¹,

Carell²,

Cellai³

et al. 2008

Chimia

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Several examples of oxidative and reductive reactions of DNA components that lead to single and tandem modifications are discussed in this review. These include nucleophilic addition reactions of the one-electron oxidation-mediated guanine radical cation and the one-electron reduced intermediate of 8-bromopurine 2'-deoxyribonucleosides that give rise to either an oxidizing guanine radical or related 5',8-cyclopurine nucleosides. In addition, mechanistic insights into the reductive pathways involved in the photolyase induced reversal of cyclobutadipyrimidine and pyrimidine (6-4) pyrimidone photoproducts are provided. Evidence for the occurrence and validation in cellular DNA of • OH radical degradation pathways of guanine that have been established in model systems has been gained from the accurate measurement of degradation products. Relevant information on biochemical aspects of the repair of single and clustered oxidatively generated damage to DNA has been gained from detailed investigations that rely on the synthesis of suitable modified probes. Thus the preparation of stable carbocyclic derivatives of purine nucleoside containing defined sequence oligonucleotides has allowed detailed crystallographic studies of the recognition step of the base damage by enzymes implicated in the base excision repair (BER) pathway. Detailed insights are provided on the BER processing of non-double strand break bistranded clustered damage that may consist of base lesions, a single strand break or abasic sites and represent one of the main deleterious classes of radiation-induced DNA damage.

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“…A similar mechanism is responsible for the formation of adenine and guanine 5′,8-cyclo-2′-deoxyribonucleoside products that occurs via the addition of C-centered 5′-hydroxylmethyl radicals produced by H-atom abstraction from 2-deoxyribose moieties (48, 49). In the presence of molecular oxygen the formation of such products is also suppressed because O 2 reacts readily with the C-centered radicals (50, 51). …”

Section: Discussionmentioning

confidence: 99%

Generation of Guanine–Thymidine Cross-Links in DNA by Peroxynitrite/Carbon Dioxide

Yun

Geacintov

Shafirovich

2011

Chem. Res. Toxicol.

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Nitrosoperoxycarbonate derived from the combination of carbon dioxide and peroxynitrite, is an important chemical mediator of inflammation. In aqueous solutions, it rapidly decomposes to the reactive species CO3•− and •NO2 radicals that are known to initiate the selective oxidation and nitration of guanine in DNA. We have previously demonstrated that the reactions of carbonate radical anions with guanine in 2′-deoxyoligoribonucleotides generate a previously unknown intrastrand cross-linked guanine-thymine product G*-T* with a covalent bond between the C8 (G*) and thymine N3 (T*) atoms (Crean et al., Nucleic Acids Res., 2008, 36, 742–755). In this work we demonstrate that G*-T* cross-linked products are also formed when peroxynitrite (0.1 mM) reacts with native DNA in aqueous solutions (pH 7.5–7.7) containing 25 mM carbon dioxide/bicarbonate, in addition to the well known nitration/oxidation products of guanine such as 8-nitroguanine (8-nitroG), 5-guanidino-4-nitroimidazole (NIm), 8-oxo-7,8-dehydroguanine (8-oxoG) and spiroiminodihydantoin (Sp). The yields of these products, after enzymatic digestion with P1 nuclease and alkaline phosphatase to the nucleotide level, and reversed phase HPLC separation, were compared with those obtained with the uniformly, isotopically labeled 15N,13C-labeled 2′-deoxy oligoribonucleotides 5′-dGpT and 5′-dGpCpT. The d(G*pT*) and d(G*-T*) cross-linked products derived from the di- and tri-oligonucleotides, respectively, were used as standards for identifying the analogous lesions in calf thymus DNA by isotope dilution LC-MS/MS methods in the selected reaction-monitoring mode. The Nim and 8nitroG are the major products formed (~ 0.05% each), and lesser amounts of 8-oxoG (~ 0.02%), and d(G*pT*) and d(G*-T*) enzymatic digestion products (~ 0.002% each) were found. It is shown that the formation of d(G*pT*) enzyme digestion product can arise only from intrastrand cross-links, whereas d(G*-T*) can arise from both interstrand and intrastrand cross-linked products.

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(5′S)- and (5′R)-5′,8-Cyclo-2′-deoxyguanosine: Mechanistic Insights on the 2′-Deoxyguanosin-5′-yl Radical Cyclization

Cited by 57 publications

References 31 publications

One-Electron Oxidation of Neutral Sugar Radicals of 2′-Deoxyguanosine and 2′-Deoxythymidine: A Density Functional Theory (DFT) Study

One-Electron Oxidation of Neutral Sugar Radicals of 2′-Deoxyguanosine and 2′-Deoxythymidine: A Density Functional Theory (DFT) Study

DNA Damage and Radical Reactions: Mechanistic Aspects, Formation in Cells and Repair Studies

Generation of Guanine–Thymidine Cross-Links in DNA by Peroxynitrite/Carbon Dioxide

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