The presence of a trifluoromethyl rather than a methyl substituent in the bay-region greatly decreases the DNA-binding and tumour-initiating activity of the cyclopenta[alpha]phenanthren-17-ones

• Published in: Carcinogenesis (New York) Vol. 16; no. 10; p. 2543
• Main Authors: Boyd, G W, Coombs, M M, Baird, W M
• Format: Journal Article
• Language: English
• Published: England 01.10.1995
• Subjects: Animals; Breast Neoplasms; Carcinogens - metabolism; Carcinogens - toxicity; Cell Line; DNA - metabolism; DNA Adducts - metabolism; Epidermis - drug effects; Epidermis - metabolism; Epidermis - pathology; Female; Gonanes - metabolism; Gonanes - toxicity; Humans; Methylation; Mice; Mice, Inbred SENCAR; Skin Neoplasms - chemically induced; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Structure-Activity Relationship; Tetradecanoylphorbol Acetate - toxicity; Time Factors; Tumor Cells, Cultured
• ISSN: 0143-3334
• DOI: 10.1093/carcin/16.10.2543

The increase in carcinogenicity of polycyclic aromatic compounds following bay-region methyl group substitution involves a steric component: increasing the size of the alkyl substituent decreases the carcinogenic activity of the compound. To determine whether there is also an electronic component to this effect, we synthesized a bay-region 11-trifluoromethyl analogue of 15,16-dihydrocyclopenta[alpha]phenanthren-17-one which is sterically similar but electronically very different from the 11-methyl derivative. This trifluoromethyl derivative bound to DNA in cultures of the human mammary carcinoma cell line MCF-7 to a much lower extent than the methyl-substituted compound. The trifluoromethyl derivative did not form detectable levels of DNA adducts in the epidermis of Sencar mice and was inactive as an initiator after promotion with 12-O-tetradecanoylphorbol-13-acetate for 20 weeks. In contrast, the 11-methyl derivative formed > 3 pmol adducts/mg DNA and initiated eight papillomas per mouse. These data indicate that both the steric configuration and the electronic nature of a bay-region substituent are important in determining the overall effect of the substituent on the biological activity of the molecule.