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Nucleic Acids Research, 1992, Vol. 20, No. 18 4839-4845
© 1992

CHEMISTRY

Synthesis of the diastereomers of thymidine glycol, determination of concentrations and rates of interconversion of their cis-trans epimers at equilibrium and demonstration of differential alkali lability within DNA

Mark J. Lustig, Jean Cadet1, Robert J. Boorstein and W. Teebor*

Departments of Pathology and Environmental Medicine and Rtia and Stanley Kaplan Cancer Center New York University Medical Center, New York, NY 10016, USA 1Laboratories de Chimie Department de Recherche Fondamentale, Centre d'Etudes Nucleaires de Grenoble 85X, 38041 Greno Cedex, France

To whom correspondence should be addressed

Received June 8, 1992. Revised August 14, 1992. Accepted August 14, 1992.

5,6-dihydroxy-5,6-dihydrothymldine (thymidine glycol) is a major product of the reaction of thymidine with reactive oxygen species, including those generated by ionizing radiation. Thymidine giycol exists as 2 diastereomeric pairs by virtue of the chirality of the C(5) and C(6) atoms. A simple procedure is described for synthesizing and purifying each of the diastereomeric pairs separately. After brominating thymidine, the two trans 5-bromo-6-hydroxy-5,6-dihydrothymidlne (thymidine bromohydrin) C(5) diastereomers were easily separated by High Performance Liquid Chromatography. Each thymidine bromohydrin was quantitatively converted to the corresponding diastereomeric thymidine glycol pair by refiux in aqueous solution. The concentrations at equiiibtlum of the cis (5S,6R),(5R,6S)and trans (5S,6S),(5R,6R) forms of the thymidine glycol diastereomers were determined and were 80% cis and 20% trans for the 5S pair and 87% cis and 13% trans for the 5R pair. At equilibrium, the rate of cis-trans epimerization of the two sets of diastereomers was essentially identical. The 5S diastereomeric pair was significantly more alkali labile than the 5R pair due to the higher concentration of the 5S trans epimer at equilibrium. This differential alkali lability was also manifest when the thymine glycol moiety was present in chemically oxidized poly(dA dT). poly(dA-dT) indicating that the chemical differences between the diastereomeric pairs are preserved in DNA. These chemical differences may affect the biological properties of this important oxidative derivative of thymine in DNA.


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