SYNTHESIS AND STRUCTURE DETERMINATION OF THE ADDUCTS FORMED BY ELECTROCHEMICAL OXIDATION OF 1,2,3,4-TETRAHYDRO-7,12-DIMETHYLBENZ[A]ANTHRACENE IN THE PRESENCE OF DEOXYRIBONUCLEOSIDES OR ADENINE

Study of DNA adducts formed with aromatic hydrocarbons is part of the strategy to elucidate the mechanisms of tumor initiation by these comp ounds. 1,2,3,4-Tetrahydro-7,12-dimethylbenz[a]anthracene (THDMBA) is o f special interest because it allows discrimination between the pathwa ys of bioactivation by one-electron oxidation and monooxygenation. To study and identify adduces formed biologically, synthetic adducts are needed as reference standards. THDMBA was electrochemically oxidized i n the presence of deoxyadenosine (dA), adenine (Ade), deoxyguanosine ( dG), or deoxycytidine (dC). In the presence of dA, four adducts were i solated: l-1,2,3,4-tetrahydrobenz[a]anthracene-12-CH2-N7Ade (7-MTHBA-1 2-CH2-N7Ade, 3.6%), 12-MTHBA-7-CH2-N7Ade (4.2%), 7-MTHBA-12-CH2-N(6)dA (5.8%), and 12-exo-methylene- 7-MTHBA-7-N(6)dA (22.8%); a dehydrogena ted product, 7,12-di-exo-methylene-THBA (44.2%), was also obtained. In the presence of Ade, nine adducts were synthesized: 7-MTHBA-12-CH2-N7 Ade (1.1%), 12-MTHBA-7-CH2-N7Ade (2.4%), 7-MTHBA-12-CH2-N1Ade (10.2%), 12-MTHBA-7-CH2-N1Ade (13.2%), 7-MTHBA-12-CH2-N3Ade (1.7%), 12-MTHBA-7 -CH2-N3Ade (1.7%), 7-exo-methylene-12-MTHBA-12-N3Ade (11.2%), 12-exo-m ethylene-7-MTHBA-7-N3Ade (27.9%), and 12-exo-methylene-7-MTHBA-7-N(6)A de (12.1%), as well as the behydrogenated product 7,12-di-exo-methylen e-THBA (16.7%). In the presence of dG, three adducts were produced: 7- MTHBA-12-CH2-N7Gua (24.2%), 12-MTHBA-7-CH2-N7Gua (12.2%), and 7-MTHBA- 12-CH2-N(2)dG (3.7%), as well as the dehydrogenated product 7,12-di-ex o-methylene-THBA (38.9%). Anodic oxidation in the presence of dC yield ed a large amount of 7,12-exo-methylene-THBA (80.4%), but no adducts. The structure of the adducts was elucidated by using UV, NMR, and MS. The N-7 positions in dG, dA, and Ade, the 2-NH2 in dG, and the N-1 pos ition in Ade form exclusively methyl-linked adducts. In contrast, the 6-NH2 group of dA and Ade and the N-3 of Ade prefer to attack the meso -anthracenic positions rather than the methyl groups. The order of rea ctivity of dG and dA in the formation of methyl-linked THDMBA adducts agrees well with that previously found for 7,12-dimethylbenz[a]anthrac ene [RamaKrishna et al. (1992) J. Am. Chem. Sec. 114, 1863-1874].