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

Gary Boyd, Maurice M Coombs, William M Baird

Research output: Contribution to journalArticle

Abstract

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[a]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.
Original languageEnglish
Pages (from-to)2543-2547
JournalCarcinogenesis
Volume16
Issue number10
DOIs
Publication statusPublished - Oct 1995
Externally publishedYes

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DNA Adducts
DNA
Polycyclic Compounds
Neoplasms
Papilloma
Tetradecanoylphorbol Acetate
Epidermis
Breast Neoplasms
Cell Line
15,16-dihydrocyclopenta(a)phenanthren-17-one

Cite this

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title = "The presence of a trifluoromethyl rather than a methyl substituent in the bay-region greatly decreases the DNA-binding and tumour initiating activity of cyclopenta[a]phenanthren-17-ones",
abstract = "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[a]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.",
author = "Gary Boyd and Coombs, {Maurice M} and Baird, {William M}",
year = "1995",
month = "10",
doi = "10.1093/carcin/16.10.2543",
language = "English",
volume = "16",
pages = "2543--2547",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
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TY - JOUR

T1 - The presence of a trifluoromethyl rather than a methyl substituent in the bay-region greatly decreases the DNA-binding and tumour initiating activity of cyclopenta[a]phenanthren-17-ones

AU - Boyd, Gary

AU - Coombs, Maurice M

AU - Baird, William M

PY - 1995/10

Y1 - 1995/10

N2 - 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[a]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.

AB - 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[a]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.

U2 - 10.1093/carcin/16.10.2543

DO - 10.1093/carcin/16.10.2543

M3 - Article

VL - 16

SP - 2543

EP - 2547

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 10

ER -