Synthesis and characterization of nucleosides and oligonucleotides with a benzo[a]pyren-6-ylmethyl adduct at adenine N-6 or guanine N-2

Benzo[alpha ]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 intere sting pathway to a highly genotoxic electrophile is through alkylation at t he 6 position to 6-methylbenzo[alpha ]pyrene (2) followed by oxidation of t he methyl group to give 6-hydroxymethylbenzo[alpha ]pyrene (3). Esterificat ion of 3, especially to sulfate ester 4, gives compounds which are both mut agenic and carcinogenic. The major DNA adduct identified from exposure of r ats and mice to 4 is the guanine N-2 adduct [2 ' -deoxy-N-2-(benzo[alpha ]p yren-6-ylmethyl)guanosine, 5] which is also formed via activation of 2 to a radical cation species by horseradish peroxidase/H2O2 or iodine. To study the biological and structural properties of this adduct and the analogous a denine N-6 adduct (6), a nonbiomimetic synthesis of the adducted nucleoside s 5 and 6 has been developed and has been extended to preparation of oligon ucleotides containing 5 or 6 at a single site.