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.
Kim
H Y
HY
Chemistry Department and Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235, USA.
Cooper
M
M
Nechev
L V
LV
Harris
C M
CM
Harris
T M
TM
D000225:Adenine / Q000737:chemistry; D001564:Benzo(a)pyrene / Q000737:chemistry*; D001580:Benzopyrenes / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry; D009153:Mutagens / Q000737:chemistry*; D009705:Nucleosides / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry; D009841:Oligonucleotides / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
D001580:Benzopyrenes; D018736:DNA Adducts; D009153:Mutagens; D009705:Nucleosides; D009841:Oligonucleotides; C017503:6-methylbenzo(a)pyrene; D001564:Benzo(a)pyrene; D006147:Guanine; D000225:Adenine