AN EFFICIENT ROUTE TO N-6 DEOXYADENOSINE ADDUCTS OF DIOL EPOXIDES OF CARCINOGENIC POLYCYCLIC AROMATIC-HYDROCARBONS

Polycyclic aromatic hydrocarbons are metabolized to a wide variety of oxidized derivatives, including highly reactive diol epoxides which alkylate DNA. The reaction lacks regio- or stereospecificity but occurs primarily at the exocyclic amino groups of deoxyguanosine and deoxyadenosine. An efficient route to N-6 adducts of deoxyadenosine is described using as examples those arising from trans opening of the anti-tetrahydrodiol epoxides of naphthalene, benzo[a]pyrene, and benzo[c]phenanthrene. The adducts were synthesized in 50-92% yields by reaction of 6-fluoropurine 2'-deoxyriboside with aminotriols formed by trans opening of racemic dihydrodiol epoxides using liquid NH3. The diastereomeric adducts were separated by HPLC and their absolute configurations were assigned by circular dichroism. H-1 NMR studies revealed significant differences in conformation of the tetrahydroaromatic ring between the sterically unrestricted naphthalene derivative and the sterically congested derivatives of benzo[a]pyrene and benzo[c]phenanthrene. These differences may have a bearing on the higher carcinogenicity shown by the latter hydrocarbons. Undecadeoxyoligonucleotides bearing regio- and stereochemically defined adenine N-6-anti-trans-benzo[a]pyrene adducts have been prepared.