Journal of the American Chemical Society p. 2235 - 2242 (1994)
Update date:2022-08-18
Topics:
Wagner
Van Lier
Berger
Cadet
The primary products of DNA oxidation by free radicals are thymidine hydroperoxides, which include eight diastereomers of 5(6)-hydroxy-6(5)-hydroperoxy-5,6-dihydrothymidine and 5-(hydroperoxymethyl)-2'-deoxyuridine. The hydroperoxides were prepared by trifluoroperacetic acid oxidation of thymidine, which gave the four trans and ics diastereomers of 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine, and sensitized photooxidation of thymidine with 2-methyl-l,4-naphthoquinone and near-UV light, which gave the four trans and cis diasteromers of 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine as well as 5-(hydroperoxymethyl)-2'-deoxyuridine. 1H and 13C NMR analyses suggested that the pyrimidine ring of thymidine 5,6-hydroxyhydroperoxides adopts four puckered conformations in which the orientations of the C6 hydroxy or hydroperoxy substituents are predominantly axial. The kinetics of decomposition of 5(6)-hydroxy-6(5)-hydroperoxy-5,6-dihydrothymidine were studied at 22, 37, and 55°C in ultrapure water. The cis diastereomers of each group were generally found to more stable than the corresponding trans diastereomers. The enthalpy (ΔH≠) and entropy (ΔS≠) of decomposition were in the range of 22.9-25.2 kcal mol-1 (ΔH≠) and -7.4-+3.7 cal mol-1 deg-1 (ΔS≠) for 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine and in the range 28.5-35.2 kcal mol-1 (ΔH≠) and +9.7-+30 cal mol-1 deg-1 (ΔS≠) for 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine. The mechanism of decomposition was studied by analysis of stable and intermediate products: the major decomposition products of the trans and cis diasteromers of 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine were N-(2-deoxy-β-D-erythro-pentofuranosyl)-5-hydroxy-5-methylbarbituric acid and N1-(2-deoxy-β-D-erythro-pentofuranosyl-N3-tartronoylurea in neutral aqueous solutions; in contrast, the trans and cis diastereomers of 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine were observed to undergo isomerization and ultimately decomposed into the 5R* and 5S* diastereomers of N-(2-deoxy-β-d-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin. On the basis of the above results, the mechanism of decomposition was proposed to involve either dehydration for 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine or ring-chain tautomerism followed by α-cleavage of an intermediate hydroperoxy aldehyde and subsequent ring closure for 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine.
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