© 1994 Oxford University Press
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Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides
Marion Merrell Dow Inc. 2110 East Galbraith Road, Chemical Development Bldg. 51, Cincinnati, OH 45215
1Chemsyn Science Laboraiories 13605 W. 96th Terracc, Lenexa, KS 66215–1297
2Eppley Institute, University of Nebraska Medical Center 600 South 42nd Street, Omaha, NE 68198–6805, USA
3To whom correspondence should be addressed
Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycycic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mech anisms of activation, (±)-trans-DB [a,l]P-11,12-dihydrodiol,(±)-anti-DB[a,l]PDE and (±)-syn-DB[a,l]PDE were synthesized. The key intermediate for these syntheses, 12-methoxy-DB[a,l]P, was successfully obtained by cyclizatlon 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,l]P nucleus in the dihydrodiol epoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,l]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,l]P-11,12-dihydrodiol and the parent DB[a,l]P Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 133 nmol of compound In 100 µl of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol In 100 µl acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 1.33 nmol doses, anti-DB[a,l]PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn DB[a,l]PDE induced 1.8, 1.5 and 1.8 t/m. At the same three doses, DB[a,l]P-11,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[a,l]P resulted in 9.3,7.1 and 5.2 t/m. These results confirm that DB[a,l]P is more potent than its 11,12-dihydrodlol and show that the two diolepoxides are less tumorlgenic than their precursors. At the medium and low doses, syn-DB[a,l]PDE is more tumorigenic than its congener anti-DB[a,l]PDE.
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