Oxidation of 5-Hydroxypyrimidine Nucleosides to 5-Hydroxyhydantoin and Its -Hydroxy-ketone Isomer

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• 作者：Johann Rivi&egrave ; re ; Klaus Klarskov ; and J. Richard Wagner
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：August 2005
• 年：2005
• 卷：18
• 期：8
• 页码：1332 - 1338
• 全文大小：133K
• 年卷期：v.18,no.8(August 2005)
• ISSN：1520-5010

文摘

The reaction of hydroxyl radicals with 2'-deoxycytidine (dCyd), as well as the decompositionof dCyd radical cations, leads to a complex mixture of oxidation products in aqueous aeratedsolutions. The oxidation of dCyd gives products with a relatively low oxidation potential thatare highly susceptible to further oxidation, including 5-hydroxy-2'-deoxycytidine (5-oh-dCyd)and 5-hydroxy-2'-deoxyuridine (5-oh-dUrd). Previously, we showed that the oxidation of 2'-deoxyuridine (dUrd) involves the formation of dialuric acid and isodialuric acid intermediates,followed by ring contraction to N¹-(2-deoxy--D-erythro-pentofuranosyl)-5-hydroxyhydantoin(5-oh-dHyd). In this work, we have examined the oxidation of 5-oh-dCyd and 5-oh-dUrd ingreater detail. The oxidation of these substrates by Br₂ led to a similar profile of intermediateand stable products indicating that the dialuric and isodialuric acid derivatives of dCyd largelyundergo deamination before they transform into 5-oh-dHyd. Analysis of the final mixture ofoxidation products by HPLC revealed the formation of two novel products. On the basis ofNMR and MS, these products were identified as the diastereomers of N¹-(2-deoxy--D-erythro-pentofuranosyl)-5-hydroxyimidazolidine-2,5-dione (iso-4-oh-dHyd). These products arise from-hydroxy-ketone isomerization of 5-oh-dHyd. The isomerization of 5-oh-dHyd to iso-4-oh-dHydwas reversible, and each diastereomer produced a specific diastereomer of the other structuralisomer. The rate of isomerization was accelerated in going from pH 5 to pH 9, whereas allisomers decomposed at higher pH. In contrast, interconversion between each pair of diastereomers was minor. Thus, we conclude that the oxidation of 5-oh-dCyd or 5-oh-dUrd gives amixture of four isomers of 5-oh-dHyd and iso-4-oh-dHyd as final products. The biologicalconsequences of dCyd oxidation may ultimately depend on the effects of these products.