Synthesis and mutagenicity of the diastereomeric fjord-region 11,12-dihydrodiol 13,14-epoxides of dibenzo [a,l]pyrene

Extensive tumongenicity studies in rodents revealed that dibenzo[a,l]pyrene(DB[a,l]P) is the most potent carcinogen among all polycyclicaromatic hydrocarbons (PAHs) tested so far. The structure ofthe genotoxic metabolite(s) responsible for this exceptionalcarcinogenicity 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 ultimatemutagenic and carcinogenic metabolites of DB [a,l]P.9-Formyl-11,12-dime-thoxybenzo [g] chrysense was prepared from 9-phenanthryl- aceticacid by a photochemical route. After reaction of the aldehydewith trimethylsulfonium iodide to generate an oxiranyl side-chain,treatment with boron trifluoride produced the key intermediate11,12-dimethoxy.DB[a,l]P in 14% overall yield. From 11,12-dimethoxy-DB[a,l]Pthe syn- and anti-DB[a,l]PDE were stereoselectively preparedvia the trans-11,12-dihydrodiol. The mutagenicity of the synand anti-DB[a,l]PDE was examined in four his^– strainsof Salmonella typhimurium and in Chinese hamster V79 cells.In all five test systems, the new dihydrodiolepoxides were morepotent than any of the previously investigated dihydrodlolepoxides.The specific mutagemcity observed with anti-DB[a,l]PDE in strainTA104 exhibited the highest value ever found with any compoundin any his strains of S.typhimurium. The same appears to hetrue for the activity observed with this compound in V79 cells.In all five systems, syn-DB[a,l]PDE was only moderately lessactive than its anti-dlastereomer (