Synthesis of Multiply-Labeled [15N3,13C1]-8-Oxo-Substituted Purine Bases and Their Corresponding 2′-Deoxynucleosides

Richard H. Stadler, Andreas A. Staempfli, Laurent B. Fay, Robert J. Turesky, Dieter H. Welti

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Abstract

Stable isotope-labeled analogues of oxidatively modified purine bases are required as internal standards for accurate quantitation of free radical induced damage in DNA using the isotopedilution GC/MS technique. For this reason, we report on a facile and expedient method to synthesize the isotope-labeled oxidized DNA bases 8-oxoguanine (8-oxo-Gua, 5a) and 8-oxoadenine (8-oxo-Ade, 5b). Both routes have in common the introduction of two exocyclic 15N isotopes simultaneously by halogen displacement of chlorine-substituted pyrimidines with [15N]- benzylamine. Debenzylation is achieved by either catalytic hydrogenation or treatment with aluminium chloride in benzene. An additional isotope is incorporated by nitrosation with 15N-labeled sodium nitrite. Cyclocondensation of the triamines with 13C-labeled urea then affords 5a and 5b in overall yields of 34% and 27%, respectively, and each with four isotope labels and at least 99 atom % excess. A further one-step enzyme catalyzed coupling of the C8 adducted purines with 2′-deoxyribose furnishes the isotope-labeled 2′-deoxynucleosides 2′-deoxy-7,8- dihydro-8-oxoguanosine (8-oxo-dGuo) and 2′-deoxy-7,8-dihydro-8-oxoadenosine (8-oxo-dAdo).

Original languageEnglish (US)
Pages (from-to)784-791
Number of pages8
JournalChemical Research in Toxicology
Volume7
Issue number6
DOIs
StatePublished - Nov 1 1994

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