title: New and highly efficient synthesis of cis- and trans-opened Benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the exocyclic N(2)-amino group of deoxyguanosine.
abstract: We describe a new and facile method for the synthesis of both cis- and trans-opened N(2)-deoxyguanosine (dG) adducts of (+/-)-7alpha, 8beta-dihydoxy-9beta,10beta-epoxy-7,8,9,10-tetra hydrobenzo[a]pyrene and (+/-)-7alpha,8beta-dihydoxy-9alpha,10alpha -epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene at C-10. The key step in our approach is the direct coupling of O(6)-allyl-3', 5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine with these epoxides followed by the separation of the mixtures of cis- and trans-diastereomers produced. Overall coupling yields ranged from 45 to 65%. Stereochemistry of addition of the N(2)-exocyclic amino group of dG (cis-trans, approximately 1:1) was assigned by NMR, and the absolute configuration of the dG adducts was unequivocally assigned by CD spectroscopy after separation of each individual diastereomer and cleavage of the allyl protecting group. A strong CD band at 279 nm in the O(6)-protected adduct was found to be diagnostic for configuration at C-10, with a negative band correlating with 10R configuration. The synthetic methodology described allows easy access to cis- and trans-opened N(2)-dG adducts which are valuable building blocks for the synthesis of adduct-containing oligonucleotides for physical and biochemical studies.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kroth
authors.forename: H
authors.initials: H
authors.lastname: Yagi
authors.forename: A
authors.initials: A
authors.lastname: Seidel
authors.forename: D M
authors.initials: DM
authors.lastname: Jerina
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000737:chemistry*; D018736:DNA Adducts / Q000138:chemical synthesis* / Q000737:chemistry; D003849:Deoxyguanosine / Q000737:chemistry*; D013057:Spectrum Analysis
chemical_list: D018736:DNA Adducts; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D003849:Deoxyguanosine