Oxidation of 2'-deoxycytidine to four interconverting diastereomers of N1-carbamoyl-4,5-dihydroxy-2-oxoimidazolidine 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 N1-(2-deoxy-beta-D-erythro-pentofuranosyl)-1-carbamoyl-2-oxo-4,5-dihydroxyimidazolidine by bromination of dCyd followed by peroxidation of the resulting dCyd bromohydrins. 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)-hydroperoxides to C6-C2 endoperoxides, which subsequently decompose by a concerted pathway to imidazolidine products. A remarkable feature of the four diastereomers was their ability to interconvert 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).
Tremblay
Sébastien
S
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Science, University of Sherbrooke, Quebec, Canada J1H 5N4.
Gantchev
Tsvetan
T
Tremblay
Luc
L
Lavigne
Pierre
P
Cadet
Jean
J
Wagner
J Richard
JR
D000438:Alcohols / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000138:chemical synthesis / Q000737:chemistry*; D048289:Imidazolidines / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013237:Stereoisomerism
D000438:Alcohols; D048289:Imidazolidines; C520701:N1-carbamoyl-4,5-dihydroxy-2-oxoimidazolidine; C023963:bromohydrins; D003841:Deoxycytidine