title: Stereospecific synthesis of oligonucleotides containing crotonaldehyde adducts of deoxyguanosine.
abstract: Crotonaldehyde reacts with DNA to form two diastereomeric 1,N(2) cyclic adducts of deoxyguanosine. A synthesis of the two diastereomeric deoxynucleosides has been achieved by reaction of mixed diastereomers of 4-amino-1,2-pentanediol with 2-fluoro-O(6)-(trimethylsilylethyl)-deoxyinosine. The resulting N(2)-(1-methyl-3,4-dihydroxybutyl)-deoxyguanosine was treated with NaIO(4), cleaving the vicinal diol to the aldehyde. Spontaneous cyclization gave the two diastereomers of the crotonaldehyde-adducted nucleoside that were readily separated by HPLC. The absolute configurations were assigned by an enantiospecific synthesis of one diastereomer from (S)-3-aminobutanoic acid. The synthetic strategy has been extended to preparation of a site-specifically adducted oligonucleotide by reaction of the mixed diastereomers of 4-amino-1,2-pentanediol with an 8-mer oligonucleotide containing 2-fluoro-O(6)-(trimethylsilylethyl)-deoxyinosine. The diastereomeric oligonucleotides were separated by HPLC and absolute configurations of the adducts were established by enzymatic digestion to the adducted nucleosides.
authors.affiliation: Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: L V
authors.initials: LV
authors.lastname: Nechev
authors.forename: I
authors.initials: I
authors.lastname: Kozekov
authors.forename: C M
authors.initials: CM
authors.lastname: Harris
authors.forename: T M
authors.initials: TM
authors.lastname: Harris
mesh_terms: D000447:Aldehydes / Q000009:adverse effects / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000138:chemical synthesis / Q000737:chemistry*; D003849:Deoxyguanosine / Q000737:chemistry*; D006801:Humans; D008968:Molecular Conformation; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000447:Aldehydes; D018736:DNA Adducts; D009841:Oligonucleotides; C012796:2-butenal; D003849:Deoxyguanosine