Nanosecond-Scale Isomerization of the 4′-Carboxonium Cation Oxidatively Produced in Pyrimidine Units of DNA

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The long-standing puzzle of the chemistry producing the Stubbe-Kozarich abasic site, which is the minor product in the oxidation of 2′-deoxycytidine units of DNA by Fe(II)-bleomycin, has been computationally solved in this study. Scrupulous DFT-based calculations that included extensive screening of the potential energy surface of model-solvated nucleotides and the elucidation of the chemical structure of the located nucleotide cations via natural bond orbital analysis demonstrated that the 2′-deoxycytidine unit bearing the 2′-deoxyribose ring 2e-oxidized at the 4′-position undergoes carboxonium ion-iminium ion (C=?O+-C → C=?N+) isomerization. This 1,2-elimination of the carbonyl group 4′-C=?O from the carboxonium cation fragment is associated with minimal spatial reorganization of the molecule and appears to be an ultrafast reaction. The calculated barrier δG0# of 2.7 kcal mol-1 for this isomerization is lower than that reported for the addition of water to oxocarbenium ions. Thus, this unusual nucleotide transformation is the key chemical reaction that yields the Stubbe-Kozarich product. Such a product cannot be formed for purine nucleotide units in DNA. The isomerization of 4′-dehydro-2′-deoxyribose-4′-carboxonium cations formed in these DNA units is slower because it destroys the purine aromaticity, and the cations are intercepted by water molecules before they isomerize.

Original languageEnglish
Pages (from-to)11604-11613
Number of pages10
JournalJournal of Organic Chemistry
Issue number19
StatePublished - 5 Oct 2018

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© 2018 American Chemical Society.


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