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 ring enhances the carcinogenicity of many PAH compounds in contrast to structural analogues lacking this feature. For example, on mouse skin 5-methylchrysene is more carcinogenic than all other monomethylchrysenes or chrysene itself; 11-methylbenzo[a]pyrene is more tumorigenic than other monomethylbenzo[a]pyrenes or benzo[a]pyrene itself, anti-7,8,9,10-Tetrahydro-11-methylbenzo[a]pyrene-7,8-diol-9,10-epoxide (11-MeBPDE) is the ultimate carcinogenic form 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 100, 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 times 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 deoxyguanosine-modified adducts, similar to those observed with BPDE.