Fast Cationic Isomerizations which Disrupt a Cellular DNA Strand

In considering the chemistry of oxidative DNA damage, the deoxyribose-localized oxocarbenium ions C=O⁺ are accepted as cationic species resulting from 2e-oxidation of deoxyribose fragments of DNA. However, this traditional consideration is superficial – the chemistry of reactive cationic intermediates of nucleotide units in DNA is essentially more complicated. Nucleotides oxidized in this manner undergo skeletal isomerizations undiscerned previously: probably, because the final hydrolytic products are the same for the DNA strand which bears either the initial C=O⁺ or the isomerized nucleotide cation (excluding the case of oxidation of the 2’-carbon). Namely, nucleotides with 3’-, or 4’-, or 5’-oxocarbenium ion fragments are extremely unstable kinetically when adopting syn conformation: the syn conformers rapidly isomerize into cyclonucleotide cations which have another chemical functionality (e.g., amidinium cations for cytidine nucleotides) and much higher, stability-delivering delocalization. 2’-Dehydro-2’-deoxynucleotide oxocarbenium ions inconsiderately regarded in many publications and ill-modeled in some others do not exist at all, and its cyclizing isomerization is coupled with the 2’-carbon oxidation. Interception of the resulting cation by the water molecule leads to appearance of the ribonucleotide unit in the DNA strand and not to the strand disintegrity. Besides, an additional, faster isomerization is inherent to the 4ʹ-oxocarbenium ions of nucleotides: with disrupting the sugar ring, both syn and anti conformers rearrange into 1’-azocarbenium ions C=N⁺ of nucleotides.

Whether the discovery of these isomerizations cardinally changes the current view on the chemistry of the oxidized sugar-phosphate backbone in DNA remains an open question yet – experimental data from the literature provide both pro and contra arguments. Nevertheless, one can certainly claim that the rearrangement 4’-oxocarbenium ion - 1’-azocarbenium ion does occur in dsDNA. Concerning the other, nucleotide-cyclizing isomerizations, the main structural factor, which prevents these cyclizations to unfold in DNA duplexes, is absent in ssDNA.