Reactivity of Nucleic Acid Radicals

Greenberg, Marc M.

doi:10.1016/bs.apoc.2016.02.001

Cited by 20 publications

(34 citation statements)

References 284 publications

(344 reference statements)

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“…Several nucleoside carbon centered radicals have been independently generated photochemically. 11 However, examples of studies on the heteroatom radicals produced from purine oxidation are far more limited. The 2′-deoxyguanosine radical (dG•) is reported to have been produced via the N -hydroxypyrid-2(1H)-one ( 6 ) and respective thione.…”

Section: Resultsmentioning

confidence: 99%

“…10 Although independent generation of radical intermediates has been very useful for improving our understanding of nucleic acid oxidation, progress in elucidating the chemistry of purine oxidation has lagged that of other DNA and RNA components. 11 To learn more about the reactivity of 2′-deoxyadenosin- N 6-yl radical (dA•), we developed a photochemical method to produce this reactive species in aqueous solvent.…”

Section: Introductionmentioning

confidence: 99%

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Aminyl Radical Generation via Tandem Norrish Type I Photocleavage, β-Fragmentation: Independent Generation and Reactivity of the 2′-Deoxyadenosin- N6-yl Radical

et al. 2017

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Formal hydrogen atom abstraction from the nitrogen-hydrogen bonds in purine nucleosides produces reactive intermediates that are important in nucleic acid oxidation. Herein we describe an approach for the independent generation of the purine radical resulting from hydrogen atom abstraction from the N6-amine of 2′-deoxyadenosine (dA•). The method involves sequential Norrish Type I photocleavage of a ketone (7b) and β-fragmentation of the initially formed alkyl radical (8b) to form dA• and acetone. The formation of dA• was followed by laser flash photolysis, which yields a transient with λmax ~ 340 nm and a broader weaker absorption centered at ~560 nm. This transient grows in at ≥ 2 × 105 s−1; however, computations and reactivity data suggest that β-fragmentation occurs much faster, implying the consumption of dA• as it is formed. Continuous photolysis of 7b in the presence of ferrous ion or thiophenol produces good yields of dA, whereas less reactive thiols afford lower yields presumably due to a polarity mismatch. This tandem photochemical, β-fragmentation method promises to be useful for site-specific production of dA• in nucleic acid oligomers and/or polymers and also for the production of aminyl radicals, in general.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aminyl Radical Generation via Tandem Norrish Type I Photocleavage, β-Fragmentation: Independent Generation and Reactivity of the 2′-Deoxyadenosin- N6-yl Radical

et al. 2017

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“…12 Aryl sulfides have served as useful precursors to HO• radical adducts. 13–16 We envisioned capitalizing on these molecules by conjoining them with the chemistry largely developed by Crich and Newcomb to generate thymidine radical cations ( 1 , NMe- 1 , Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Independent Generation and Reactivity of Thymidine Radical Cations

2017

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Thymidine radical cation (1) is produced by ionizing radiation and has been invoked as an intermediate in electron transfer in DNA. Previous studies on its structure and reactivity have utilized thymidine as a precursor, which limits quantitative product analysis because thymidine is readily reformed from 1. In this investigation, radical cation 1 is independently generated via β-heterolysis of a pyrimidine radical generated photochemically from an aryl sulfide. Thymidine is the major product (33%) from 1 at pH 7.2. Diastereomeric mixtures of thymidine glycol and the corresponding 5-hydroxperoxides resulting from water trapping of 1 are formed. Significantly lower yields of products such as 5-formyl-2′-deoxyuridine that are ascribable to deprotonation from the C5-methyl group of 1 are observed. Independent generation of the N3-methyl analogue of 1 (NMe-1) produces considerably higher yields of products derived from water trapping, and these products are formed in much higher yields than those attributable to the C5-methyl group deprotonation in NMe-1. N3-Methyl-thymidine is, however, the major product and is produced in as high as 70% yield when the radical cation is produced in the presence of excess thiol. The effects of exogenous reagents on product distributions are consistent with the formation of diffusively free radical cations (1, NMe-1). This method should be compatible with producing radical cations at defined positions within DNA.

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“…6 Independent generation of reactive intermediates involved in nucleic acid oxidation is useful for understanding how these biopolymers are damaged. 7 We wish to report the generation of the nitrogen centered radicals, 2′-deoxyadenosin- N 6-yl radical (dA•) and 2′-deoxyguanosin- N 2-yl radical (dG(N 2 -H)•) via photodissociation of the corresponding hydrazines ( 1 , 2 ).…”

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“…6,7 Most of the nucleic acid radicals studied via photochemical generation are C-centered radicals and the Norrish Type I photocleavage reaction of ketones has been used most frequently to generate them, although aryl sulfides and aryl selenides have also been employed. 8–10 Nucleobase π-radicals (Scheme 1) also play important roles in nucleic acid oxidation, such as in electron transfer, and the direct (dG(N 1 -H)•, dG(N 2 -H)•) and indirect (dA•) effects of ionizing radiation.…”

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Independent Photochemical Generation and Reactivity of Nitrogen-Centered Purine Nucleoside Radicals from Hydrazines

Zheng

et al. 2017

Org. Lett.

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Photochemical precursors that produce dA• and dG(N2-H)• are needed to investigate their reactivity. The synthesis of two 1,1-diphenylhydrazines (1, 2) and their use as photochemical sources of dA• and dG(N2-H)• is presented. Trapping studies indicate production of these radicals with good fidelity, and 1 was incorporated into an oligonucleotide via solid phase synthesis. Cyclic voltammetric studies show that reduction potentials of 1 and 2 are lower than those of widely-used “hole sinks”, e.g., 8-oxodGuo and 7-deazadGuo, to investigate DNA-hole transfer processes. These molecules could be useful: (a) as sources of dA• and dG(N2-H)• at specific sites in oligonucleotides, and, (b) as “hole sinks” for the study of DNA-hole transfer processes.

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Reactivity of Nucleic Acid Radicals

Cited by 20 publications

References 284 publications

Aminyl Radical Generation via Tandem Norrish Type I Photocleavage, β-Fragmentation: Independent Generation and Reactivity of the 2′-Deoxyadenosin- N6-yl Radical

Aminyl Radical Generation via Tandem Norrish Type I Photocleavage, β-Fragmentation: Independent Generation and Reactivity of the 2′-Deoxyadenosin- N6-yl Radical

Independent Generation and Reactivity of Thymidine Radical Cations

Independent Photochemical Generation and Reactivity of Nitrogen-Centered Purine Nucleoside Radicals from Hydrazines

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