The Mechanism of Anaerobic, Radical‐Induced DNA Strand Scission

Giese, Bernd; Beyrich-Graf, Xenia; Burger, Jutta; Kesselheim, Christoph; Senn, Martin; Schäfer, Thomas

doi:10.1002/anie.199317421

Cited by 72 publications

(49 citation statements)

References 13 publications

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“…Since the efficiency of the DNA damage is not significantly influenced by the presence of oxygen, a mechanism that involves the generation of singlet oxygen may be excluded. No alkaline work-up of the reaction mixture is required to detect the strand breaks, thus the DNA damage is likely to be introduced by hydrogen abstraction at the deoxyribose moiety of the DNA, for example, according to the mechanism proposed by Schulte-Frohlinde et al [39] and further elucidated by Giese et al [40] An alternative pathway involves oxidative transformations of the DNA bases by an intercalated dye. However, in this case alkaline work-up is usually necessary to detect DNA strand breaks in the pBR322 assay.…”

Section: Discussionmentioning

confidence: 99%

Indolo[2,3-b]-Quinolizinium Bromide: An Efficient Intercalator with DNA-Photodamaging Properties

et al. 2002

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The associative interactions of indolo[2,3-b]-quinolizinium bromide with DNA and its DNA photocleavage properties were studied in detail. Absorption and emission spectroscopy, linear dichroism, and energy-transfer measurements indicate that the indoloquinolizinium binds to DNA primarily by intercalation, with a preference for GC base pairs. In agreement with this data, the results of primer extension analysis indicate that photocleavage occurrs prevalently at the GC nucleotides. Molecular modeling studies confirm that intercalative stacking between adjacent base pairs is energetically favorable. However, it is also observed that the location of the dye in the minor groove of the DNA is energetically even more favorable. Upon UVA irradiation, the indoloquinolizinium causes single-strand cleavage with an efficiency that varies with the dye-DNA ratio. This observation is rationalized in terms of more efficient photocleavage by the externally bound dye compared with the intercalated one. The kinetics of strand degradation under aerobic and anaerobic conditions suggest that a Type I reaction occurs, that is, radical-mediated DNA damage.

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Section: Discussionmentioning

confidence: 99%

Indolo[2,3-b]-Quinolizinium Bromide: An Efficient Intercalator with DNA-Photodamaging Properties

et al. 2002

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“…134 Trapping experiments, impossible with 299, 300, and 309 owing to the high rate of electron transfer from the thiol(ate) to the radical cation, were conducted in methanol solution using the reaction of the selenide 315 with tributyltin hydride as the source of C4′ radical. The spectrum of products observed (Scheme 36) is fully consonant with a pathway involving the formation of a C4′ radical 316, its fragmentation to a radical cation 317, and trapping by methanol.…”

Section: Anaerobic 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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“…At the present stage, the time-resolved absorption measurements did not show the presence of any other transient formed upon laser excitation of drugs. However, it cannot exclude the occurrence of parallel processes, such as hydrogen abstraction already proposed to explain "franck" DNA-strand breaks [108][109][110], which involve low concentration of other transient species. The hypothesis that the photoinduced electron transfer is an important stage in the DNA damage is supported by the assessment of the cleavage sites.…”

Section: Mechanism(s) Of Dna Photocleavagementioning

confidence: 99%

Photosensitization of Biomolecules by Phenothiazine Derivatives

Viola¹,

Dall’Acqua

2006

CDT

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It is well known that many drugs act as photosensitizers towards cells by interacting with various cellular components such as lipids, proteins and nucleic acids. The structural modifications of the cellular components may occur by direct interactions of the excited states (singlets or triplets) of the drugs with the biological substrate or indirectly, through reactive species of oxygen sensitised by the drug themselves. In particular, the phototoxic activity of various drugs correlated with their potential photomutagenic and photocarcinogenic effects, takes place through DNA modification. Phenothiazines, a class of antihistaminic (anti-H1) or neuroleptic drugs used in the therapy of mental illness, such as schizophrenia, organic psychoses and other mental disorders, are known to induce photosensitization of the skin by systemic use or by topical applications as antiallergic drugs. In this review we have focused our attention on the photosensitizing property of phenothiazines and related compounds both in vitro and in vivo systems. Particular attention has been given to the mechanism of photo reaction with biomolecules such as lipids, proteins and DNA. Moreover there is a growing interest in drugs having photobiological effects because of their possible application as phototherapeutics. It has been interesting in this context to mention briefly the possible application of phenothiazine derivatives as new photosensitizers for their therapeutic application in photodynamic therapy (PDT) or in the light inactivation of viruses and bacteria.

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The Mechanism of Anaerobic, Radical‐Induced DNA Strand Scission

Cited by 72 publications

References 13 publications

Indolo[2,3-b]-Quinolizinium Bromide: An Efficient Intercalator with DNA-Photodamaging Properties

Indolo[2,3-b]-Quinolizinium Bromide: An Efficient Intercalator with DNA-Photodamaging Properties

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

Photosensitization of Biomolecules by Phenothiazine Derivatives

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