Oxidation of 2'-deoxycytidine to four inter-converting diastereomers of N-1-carbamoyl-4,5-dihydroxy-2-oxo-imidazolidine nucleosides

Modification of 2'-deoxycytidine (dCyd) by hydroxyl radicals and direct ionization leads to the formation of various oxidation products, including dCyd 5,6-glycols, 5-hydroxy-2'-deoxycytidine, and ring fragmentation products. The mechanism of oxidation is complex and poorly understood. In the present work, we have prepared four cis- and trans-diastereomers of N-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1-carbamoyl-2-oxo-4,5-dihydro oxy-imidazolidine by bromination of dCyd followed by peroxidation of the resulting dCyd bromo-hydrins. The structure and stereochemistry of each product were determined by 1H NMR, 13C NMR, and 2D NOE analyses. The formation of imidazolidine products involves rearrangement of initial 5(6)-hydroxy-6(5)-hydro-peroxides to C6-C2 endo-peroxides, which subsequently decompose by a concerted pathway to imidazolidine products. A remarkable feature of the four diastereomers was their ability to inter-convert via single and successive cycles of ring-chain tautomerism at N1-C5 and N3-C4, leading to epimerization of C5 and C4, respectively. The rate of isomerization was greater for cis-diastereomers compared to trans-diastereomers, and the rate sharply increased with pH (pH 9.0 ≥ 7.0 ≥ 5.5). (authors)