Tumor-Initiating Activity Of Fluorinated 5-Methylchrysenes

The environmental carcinogen, 5-methylchrysene, is more carcinogenic than are any of the other monomethylchrysene isomers or chrysene. For investigation of the site of metabolic activation of 5-methylchrysene, a series of fluorinated 5-methylchrysene derivatives was prepared and tested for tumor-initiating activity on mouse skin. The compounds tested were 1-fluoro-5-methylchrysene, 3-fluoro-5-methylchrysene, 6-fluoro-5-methylchrysene, 7-fluoro-5-methylchrysene, 9-fluoro-5-methylchrysene, 11-fluoro-5-methylchrysene, and 12-fluoro-5-methylchrysene, as well as 5,12-dimethylchrysene and 12-methoxy-5-methylchrysene. Each compound was assayed at total initiating doses of 30 or 100 μg with promotion by three-times weekly application of 2.5 μg of tetradecanoylphorbol acetate. Of the fluoro compounds, 12-fluoro-5-methylchrysene, 1-fluoro-5-methylchrysene, and 3-fluoro-5-methylchrysene were less active than was 5-methylchrysene, whereas 6-fluoro-5-methylchrysene, 7-fluoro-5-methylchrysene, 9-fluoro-5-methylchrysene, and 11-fluoro-5-methylchrysene were as potent as was 5-methylchrysene. Both 5,12-dimethylchrysene and 12-methoxy-5-methylchrysene were also less active than was 5-methylchrysene. These results indicate that positions 12,1, and 3 of 5-methylchrysene are involved in metabolic activation to the ultimate carcinogen. The requirements favoring carcinogenicity in this series are a bay-region methyl group and an unhindered peri position adjacent to an unsubstituted angular ring.