Polycyclic aromatic hydrocarbons (PAHs) are major environmental carcinogens produced in the combustionof fossil fuels, tobacco, and other organic matter. Current evidence indicates that PAHs are t
ransformedenzymatically to active metabolites that react with DNA to form adducts that result in mutations. Threeactivation pathways have been proposed: the diol epoxide path, the radical-cation path, and the quinonepath. The latter involves aldo-keto reductase mediated oxidation of PAH dihydrodiol metabolites tocatechols that enter into redox cycles with quinones. This results in generation of reactive oxygen species(ROS) that attack DNA, and the PAH quinones also react with DNA to form adducts. Several strategiesfor synthesis of the stable adducts formed by the
o-quinone metabolites of carcinogenic PAHs with 2'-deoxyribonucleosides were investigated and compared. The PAH quinones studied were benz[
a]anthracene-3,4-dione and its 7-methyl- and 7,12-dimethyl- derivatives. The parent PAHs represent a
range ofcarcinogenicity from inactive to highly potent. Two synthetic methods were devised that differ in thecatalyst employed, Pd(OAc)
2 or CuI. The Pd-mediated method involved coupling a protected amino-catechol PAH derivative with a halo-2'-deoxyribonucleoside. The copper-mediated method entailed reactionof a halo-PAH catechol derivative with a 2'-deoxyribonucleoside. Adducts of benz[
a]anthracene-3,4-dione (and its 7-methyl- and 7,12-dimethyl- derivatives) with 2'-deoxyadenosine and 2'-deoxyguanosinewere prepared by these methods. Availability of adducts of these types through synthesis makes possiblefor the first time biological studies to determine the role of these adducts in tumorigenesis. The copper-mediated method offers advantages of economy, adaptability to large-scale preparation, utility for synthesisof
13C- or
15N-labeled analogues, and nonformation of bis-adducts as secondary products.
