Synthesis and Characterization of Nucleosides and Oligonucleotides with a Benzo[a]pyren-6-ylmethyl Adduct at Adenine N6 or Guanine N2

Benzo[a]pyrene (1) can be converted to reactive electrophilic species by a number of metabolic pathways, of which the route to the mutagenic and carcinogenic diol epoxide(s) is the best studied. An alternative and interesting pathway to a highly genotoxic electrophile is through alkylation at the 6 position to 6-methylbenzo[a]pyrene (2) followed by oxidation of the methyl group to give 6-hydroxymethylbenzo[a]pyrene (3). Esterification of 3, especially to sulfate ester 4, gives compounds which are both mutagenic and carcinogenic. The major DNA adduct identified from exposure of rats and mice to 4 is the guanine N(2) adduct [2'-deoxy-N(2)-(benzo[a]pyren-6-ylmethyl)guanosine, 5] which is also formed via activation of 2 to a radical cation species by horseradish peroxidase/H(2)O(2) or iodine. To study the biological and structural properties of this adduct and the analogous adenine N(6) adduct (6), a nonbiomimetic synthesis of the adducted nucleosides 5 and 6 has been developed and has been extended to preparation of oligonucleotides containing 5 or 6 at a single site.