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© 1994 Oxford University Press
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Synthesis and mutagenicity of the diastereomeric fjord-region 11,12-dihydrodiol 13,14-epoxides of dibenzo [a,l]pyrene
Institute of Toxicology, University of Mainz Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany
1To whom corresponde should be addressed
Extensive tumongenicity studies in rodents revealed that dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among all polycyclic aromatic hydrocarbons (PAHs) tested so far. The structure of the genotoxic metabolite(s) responsible for this exceptional carcinogenicity is. unknown. The fjord-region syn- and anti-DB [a,l]P-11,12-dihydrodiol 13,14-epoxides (syn- and anti-DB[a,l]PDE) were synthesized to clarify their role as possible ultimate mutagenic and carcinogenic metabolites of DB [a,l]P.9-Formyl-11,12-dime- thoxybenzo [g] chrysense was prepared from 9-phenanthryl- acetic acid by a photochemical route. After reaction of the aldehyde with trimethylsulfonium iodide to generate an oxiranyl side-chain, treatment with boron trifluoride produced the key intermediate 11,12-dimethoxy.DB[a,l]P in 14% overall yield. From 11,12-dimethoxy-DB[a,l]P the syn- and anti-DB[a,l]PDE were stereoselectively prepared via the trans-11,12-dihydrodiol. The mutagenicity of the syn and anti-DB[a,l]PDE was examined in four his– strains of Salmonella typhimurium and in Chinese hamster V79 cells. In all five test systems, the new dihydrodiolepoxides were more potent than any of the previously investigated dihydrodlolepoxides. The specific mutagemcity observed with anti-DB[a,l]PDE in strain TA104 exhibited the highest value ever found with any compound in any his strains of S.typhimurium. The same appears to he true for the activity observed with this compound in V79 cells. In all five systems, syn-DB[a,l]PDE was only moderately less active than its anti-dlastereomer (
2-fold). The exceptional mutagenic activities of these dihydrodiolepoxides may be one of the reasons for the exceptional carcinogenic activity of DB[a,l]P.
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