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.
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.
Boyd
G W
GW
Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Coombs
M M
MM
Baird
W M
WM
D000818:Animals; D001943:Breast Neoplasms; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity*; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006067:Gonanes / Q000378:metabolism* / Q000633:toxicity*; D006801:Humans; D008745:Methylation; D051379:Mice; D018632:Mice, Inbred SENCAR; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D013997:Time Factors; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D018736:DNA Adducts; D006067:Gonanes; C005765:15,16-dihydro-11-methylcyclopenta(a)phenanthren-17-one; D004247:DNA; D013755:Tetradecanoylphorbol Acetate