Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,/]pyrene syn and anf/'-fjord-region diol-epoxides

'To whom correspondence should be addressed Dibenzo[a,/]pyrene (DB[a,/]P) is the most potent carcinogen among polycyclic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mech-anisms of activation, (±)-flwis-DB[a,/]P-ll,12-dihydrodiol, (±)-anft-DB[a,/]PDE and (±)-syn-DB[a,l]PDE were synthe-sized. The key intermediate for these syntheses, 12-methoxy-DB[a,/]P, was successfully obtained by cyclization of 6-(3-methoxybenzyl)benzanthrone with methanesulfonic acid, which in turn was prepared by 1,4 conjugate addition of 3-methoxybenzyl magnesium bromide to benzanthrone. The presence of the DB[a,/]P nucleus in the dihydrodiol-epoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,/]P into the parent compound in several steps. The tumor-initiating activity of the two diolepoxides in mouse skin was compared to that of DB[a,/]P-ll,12-dihydrodiol and the parent DB[a,/]P. Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 133 nmol of compound in 100 (il of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol in 100 (il acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 133 nmol doses, anti-DB[a,t\PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn-DB[o,/]PDE induced 1.8,1.5 and 1.8 t/m. At the same three doses, DB[a,/]P-ll,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[o,/]P resulted in 93, 7.1 and 5.2 t/m. These results confirm that DB[a,f]P is more potent than its 11,12-dihydrodiol and show that the two diolepoxides are less tumorigenic than their precursors. At the medium and low doses, sy/i-DB[a,/]PDE is more tumorigenic than its congener anti-DB[a,/]PDE