DNA Adducts of Acrolein: Site-Specific Synthesis of an Oligodeoxynucleotide Containing 6-Hydroxy-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(3H)-one, an Acrolein Adduct of Guanine

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Abstract
3-(2-Deoxy-β-d-erythro-pentofuranosyl)-6-hydroxy-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(3H)-one is formed in low yield by the reaction of acrolein with 2‘-deoxyguanosine. The nucleoside and an oligodeoxynucleotide containing it have been synthesized. For preparation of the nucleoside 2‘-deoxyguanosine was alkylated at the N1 position using 1-bromo-3-butene to give 1-(3-butenyl)-2‘-deoxyguanosine. Oxidation with OsO4 and N-methylmorpholine-N-oxide to give the 3,4-dihydroxybutyl adduct followed by oxidation with NaIO4 gave the 1-(3-oxopropyl) adduct which cyclized spontaneously to yield the title compound as a rapidly epimerizing mixture of two diastereomers. Reduction of the nucleoside with NaBH4 gave the unfunctionalized compound plus 1-(3-hydroxypropyl)-2‘-deoxyguanosine showing that epimerization was occurring via both the imine and the 1-(3-oxopropyl) adduct. Reduction with NaCNBH3 gave exclusively unfunctionalized 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(3H)-one. The phosphoramidite reagent needed for preparation of oligonucleotides was prepared from 1-(3-butenyl)-2‘-deoxyguanosine by glycolation after protection of the 3‘ and 5‘ hydroxyl groups as silyl derivatives. Acetylation of the vicinal hydroxyl groups and the exocyclic amino group followed by removal of silyl protection gave the protected nucleoside. Protection of the 5‘ hydroxyl group as the 4,4‘-dimethoxytrityl ether followed by phosphitylation with 2-cyanoethyl-N,N,N‘,N‘-tetraisopropylphosphorodiamidite gave the prosphoramidite reagent which was used to prepare a 12-mer oligodeoxynucleotide.