Cleavage of Single-Stranded 4'-Oligonucleotide Radicals in the Presence of O2

Giese, Bernd; Beyrich-Graf, Xenia; Erdmann, Peter; Giraud, Luc; Imwinkelried, Petra; Mueller, Stephan N.; Schwitter, Urs

doi:10.1021/ja00127a038

Cited by 60 publications

(65 citation statements)

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“…In addition to initiating DNAstrand damage as described, 4 has also been shown to trap deoxyribosyl radicals by forming covalent adducts at the N-oxide oxygen. This adduct subsequently undergoes cytotoxic oxidative fragmentation to products similar to those from deoxyribose under aerobic conditions [56,57] (Fig. (10)).…”

Section: B Tirapazaminementioning

confidence: 99%

Mechanisms of Anti-Cancer Agents Emphasis on Oxidative Stress and Electron Transfer

Kovacic

Osuna²

2000

CPD

150

105

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A large body of evidence has accumulated indicating involvement of oxidative stress (OS) in the mode of action of various bioactive substances, including those of the immune system. The data for anticancer drugs (main and miscellaneous) are summarized herein. Although diverse origins pertain, reactive oxygen species (ROS) are frequently generated by redox cycling via electron transfer (ET) groups, such as quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced products) and conjugated imines (or iminium species). We believe it is not coincidental that these functionalities are frequently found in anticancer agents or their metabolites. Generally, the ET moieties display reduction potentials in the physiologically active range. Often ROS are also implicated in more traditional rationales, namely, enzyme inhibition, membrane or DNA insult, and interference with DNA or protein synthesis. A multi-faceted approach to mechanism appears to be the most logical. Significantly, the unifying theme of ET-OS also applies to other drug categories, as well as to toxins, carcinogens, hormones, and enzymes. Since this theoretical framework aids in our understanding of drug action, it can serve as a useful tool in the design of more active and safer pharmaceuticals.

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Section: B Tirapazaminementioning

confidence: 99%

Mechanisms of Anti-Cancer Agents Emphasis on Oxidative Stress and Electron Transfer

Kovacic

Osuna²

2000

CPD

150

105

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“…The products 347 and 348, characteristic of the anaerobic cleavage (Scheme 41), were identified together with two new products assigned the structures 371 and 372 (Scheme 47). 161 These were thought to arise from cleavage of the initial radical 349 to the radical cation 350 followed by trapping with water to give a new C4′ radical 373, which itself was quenched by oxygen, giving a peroxy radical 374, and after further reduction the hydroperoxide 371. The phosphoglycolate 372 would then arise by Grob-type fragmentation of 371 (Scheme 48).…”

Section: Aerobic Conditionsmentioning

confidence: 99%

Chemistry of β-(Acyloxy)alkyl and β-(Phosphatoxy)alkyl Radicals and Related Species: Radical and Radical Ionic Migrations and Fragmentations of Carbon−Oxygen Bonds

et al. 1997

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ContentsI. Introduction 3273 II. Rearrangements 3275 A. β-(Acyloxy)alkyl Rearrangement 3275 1. Esters 3275 2. Lactones 3280 3. Thiocarbonyl Esters 3280 B. β-(Phosphatoxy)alkyl Rearrangement 3282 C. β-(Nitroxy)alkyl and β-(Sulfonatoxy)alkyl Rearrangements 3285 D. (Acyloxyalkyl)silyl Radical Rearrangement 3285 III. Fragmentation Reactions 3286 A. β-(Acyloxy)alkyl Radicals and Their Thiocarbonyl Analogues 3286 B. β-(Phosphatoxy)alkyl Radicals 3288 1. Anaerobic Conditions 3288 2. Aerobic Conditions 3293 C. β-(Sulfonatoxy)alkyl and Related Radicals 3294 IV. Mechanism 3294 A. β-(Ester)alkyl Radicals Susceptible to Neither Rearrangement Nor Fragmentation 3294 B. Fragmentation Reactions 3295 C. Rearrangement Reactions 3295 1. Noncage Dissociative Pathways 3296 2. Stepwise Pathways via Five-Membered Cyclic Intermediate Radicals 3296 3. Use of Isotopic and Stereochemical Labeling as Probes of Mechanism 3296 4. Quantitative Structure Activity Relationships 3298 5. Computational Studies and ESR Considerations 3299 V. Overview of β-(Ester)alkyl Radical Reactions 3303 VI. Related Reactions Involving Radical C−O Bond Shift and Cleavage 3305 A. Rearrangement and Fragmentation of β-Hydroxyalkyl Radicals 3305 B. Schenck or Allylperoxy Radical Rearrangement 3307 C. β-(Vinyloxy)alkyl to 4-Ketobutyl Rearrangement 3308 VII. Acknowledgments 3309 VIII. References 3309 Scheme 6

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“…This approach offers a distinctive advantage over the use of ionizing radiation, Fenton reaction or other oxidative DNA damage agents, in which multiple reactive intermediates are formed. A number of radical intermediates, such as the 5,6-dihydrothymid-5-yl radical (16–18), the 5,6-dihydrourid-6-yl radical (19,20), the 5-hydroxy-5,6-dihydrothymid-6-yl radical (21,22), the 5-(pyrimidyl)methyl radical (12–14,23) and radicals on C 1′ (24,25), C 3′ (26) and C 4′ (27,28), have been synthesized and their reactivities have been examined. Recently, we reported the efficient generation of the 5-methyl radical of mC from the 254 nm irradiation of 5-phenylthiomethyl-2′-deoxycytidine (14).…”

Section: Introductionmentioning

confidence: 99%

Generation of 5-(2'-deoxycytidyl)methyl radical and the formation of intrastrand cross-link lesions in oligodeoxyribonucleotides

Zhang

Wang

2005

Nucleic Acids Research

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Hydroxyl radical is one of the major reactive oxygen species (ROS) formed from γ-radiolysis of water or Fenton reaction, and it can abstract one hydrogen atom from the methyl carbon atom of thymine and 5-methylcytosine to give the 5-methyl radical of the pyrimidine bases. The latter radical can also be induced from Type-I photo-oxidation process. Here, we examined the reactivity of the independently generated 5-(2′-deoxycytidyl)methyl radical (I) in single- and double-stranded oligodeoxyribonucleotides (ODNs). It was found that an intrastrand cross-link lesion, in which the methyl carbon atom of 5-methylcytosine and the C8 carbon atom of guanine are covalently bonded, could be formed from the independently generated radical at both GmC and mCG sites, with the yield being much higher at the former site. We also showed by LC-MS/MS that the same cross-link lesions were formed in mC-containing duplex ODNs upon γ irradiation under both aerobic and anaerobic conditions, and the yield was ∼10-fold higher under the latter conditions. The independently generated radical allows for the availability of pure, sufficient and well-characterized intrastrand cross-link lesion-bearing ODN substrates for future biochemical and biophysical characterizations. This was also the first demonstration that the coupling of radical I with its 5′ neighboring guanine can occur in the presence of molecular oxygen, suggesting that the formation of this and other types of intrastrand cross-link lesions might have important implications in the cytotoxic effects of ROS.

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Cleavage of Single-Stranded 4'-Oligonucleotide Radicals in the Presence of O2

Cited by 60 publications

References 0 publications

Mechanisms of Anti-Cancer Agents Emphasis on Oxidative Stress and Electron Transfer

Mechanisms of Anti-Cancer Agents Emphasis on Oxidative Stress and Electron Transfer

Chemistry of β-(Acyloxy)alkyl and β-(Phosphatoxy)alkyl Radicals and Related Species: Radical and Radical Ionic Migrations and Fragmentations of Carbon−Oxygen Bonds

Generation of 5-(2'-deoxycytidyl)methyl radical and the formation of intrastrand cross-link lesions in oligodeoxyribonucleotides

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