Syntheses of anti-7,8,9,10-tetrahydro-11-, and 12-methylbenzo[a]pyrene-7,8-diol-9,10-epoxides: Identification and comparison of DNA adduct formation with calf-thymus DNA in vitro

The presence of a methyl group in the bay region adjacent to an angular rin g enhances the carcinogenicity of many PAH compounds in contrast to structu ral analogues lacking this feature. For example, on mouse skin 5-methylchry sene is more carcinogenic than all other monomethylchrysenes or chrysene it self 11-methylbenzo[a]pyrene is more tumorigenic than other monomethylbenzo [a]pyrenes or benzo[a]pyrene itself. anti-7,8,9,10-Tetrahydro-11-methylbenz o[a]pyrene-7,8-diol-9,10-epoxide (11-MeBPDE) is the ultimate carcinogenic f orm of 11-MeBP. We have now synthesized it and its structural analogue, 12- MeBPDE, by photochemical cyclization of appropriate olefin derivatives, to enable further studies on the mechanisms of mutagenesis and carcinogenesis. In assays of 11-MeBPDE, 12-MeBPDE and BPDE in Salmonella typhimurium TA 10 0, 11-MeBPDE was most mutagenic, followed by BPDE and 12-MeBPDE. In studies on adduct formation with calf thymus DNA, 11-MeBPDE formed 1.7 limes more adducts than BPDE, while BPDE formed 3.3 times more adducts than 12-MeBPDE. The predominant adducts formed from both 11-MeBPDE and 12-MeBPDE are the d eoxyguanosine-modified adducts, similar to those observed with BPDE.