Pyrimidine nucleobase radical reactivity in DNA and RNA

Abstract

Nucleobase radicals are major products of the reactions between nucleic acids and hydroxyl radical, which is produced via the indirect effect of ionizing radiation. The nucleobase radicals also result from hydration of cation radicals that are produced via the direct effect of ionizing radiation. The role that nucleobase radicals play in strand scission has been investigated indirectly using ionizing radiation to generate them. More recently, the reactivity of nucleobase radicals resulting from formal hydrogen atom or hydroxyl radical addition to pyrimidines has been studied by independently generating the reactive intermediates via UV-photolysis of synthetic precursors. This approach has provided control over where the reactive intermediates are produced within biopolymers and facilitated studying their reactivity. The contributions to our understanding of pyrimidine nucleobase radical reactivity by this approach are summarized.

Degradation of Cytosine Radical Cations in 2′-Deoxycytidine and in i-Motif DNA: Hydrogen-Bonding Guided Pathways

“…DNA and other biomolecules of living systems may be oxidatively damaged by exposing them to endogenously generated oxygen species or by a large number of exogenous chemical and physical agents, which play significant roles in the pathophysiology of inflammation, cancer, and degenerative diseases. , One of the most potent sources of exogenous DNA damage is the one-electron oxidation of nucleobases, which can occur during the exposure of DNA to ionizing radiation or photosensitizers. , Numerous efforts have been made in the last two decades on the delineation of molecular mechanisms of ionizing radiation damage on cellular DNA. ,− Evidence is now accumulating that the radical cations of DNA bases generated by the ionizing radiation initiate a variety of physical and chemical alterations, constituting one of the main types of cytotoxic DNA lesions. ,− Thus, investigations on the degradation pathways of radical cations can provide guidance for understanding the mechanisms of DNA damage caused by ionizing radiation or chemical agents.…”

α-Tocopherol restores semen quality in rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…In rats, TCDD increases the ROS and MDA levels and disrupts the plasma membranes of testicular cells, including Leydig cells [27]. Excess free radicals generated due to TCDD exposure can directly damage DNA by attacking purine and pyrimidine bases [28] and initiating apoptosis, activating caspase enzymes involved in DNA fragmentation [29], and causing Leydig cell death. α-Tocopherol prevents lipid peroxidation by changing the lipid peroxyl radicals to less reactive and non-destructive [27].…”

Reaction of Electrons with DNA: Radiation Damage to Radiosensitization

“…As the pyrimidines are more electron-affinic than purines [13,92,106], modified pyrimidine derivatives, for example, the C5-halopyrimidines are well-investigated as electron-affinic radiosensitizers in cancer radiotherapy. For example, cells incorporate 5-bromo-2′-deoxyuridine (5-BrdU) in their DNA almost as readily as thymidine and depending on the extent of 5-BrdU incorporation in cells, 5-BrdU has been shown to provide up to a 3–4 fold increase in radiation-induced cell killing [13,92,107,108,109,110]. Thus, it has long been recognized as a radiosensitizing agent with potential clinical applications [13,92,107,108,109,110].…”

“…For example, cells incorporate 5-bromo-2′-deoxyuridine (5-BrdU) in their DNA almost as readily as thymidine and depending on the extent of 5-BrdU incorporation in cells, 5-BrdU has been shown to provide up to a 3–4 fold increase in radiation-induced cell killing [13,92,107,108,109,110]. Thus, it has long been recognized as a radiosensitizing agent with potential clinical applications [13,92,107,108,109,110]. However, owing to the toxicity of 5-BrdU, it did not show any increase in patient survival during phase III clinical trials and the trials were called off [107].…”

“…However, owing to the toxicity of 5-BrdU, it did not show any increase in patient survival during phase III clinical trials and the trials were called off [107]. Thus, development of non-toxic and efficient pyrimidine C5-modified analog as radiosensitizers is of great interest [108,109,110]. The C5-substituted pyrimidine, 5-(phenylselenyl)methyl-2′-deoxyuridine was shown to induce oxygen-independent benzyl-type (5-CH 2 •) radical-mediated DNA inter-strand cross-linking [111] and apoptosis in cancer cells [112].…”