Abstract
The cyclopenta[aJphenanthren-17-ones, in common with many other PAH series, exhibit the phenomenon of bay-region methyl group activation. Substitution of a methyl group into the bay-region (C-11) of 15,16-dihydrocyclopenta[a]phenanthren-17-one confers carcinogenic activity on the molecule. Investigations were carried out in order to elucidate any metabolic differences between cpp-17-one and its carcinogenic 11-methyl analogue. 15,16-dihydro-11-methylcyclopenta[ajphenanthren-17-one was shown to be metabolised more readily to the proximate genotoxic form of the cyclopenta[a]phenanthren-17-ones, the 3,4-dihydrodiol. Moreover the 11-CH3 analogue was demonstrated to more efficiently induce cytochrome P-4501A1 and microsomal epoxide hydrolase, the enzymes responsible for its activation to genotoxins. Investigations into the precise nature of the effect of the methyl group revealed that steric considerations were rather more important than electronic effects, since an 11-trifluoromethyl derivative was activated to mutagens in an entirely analogous manner to the 11-methyl compound. Preliminary studies into the metabolism of 15-16-dihydro-11-methyl-cyclopenta[a]phenanthren-17-one by species other than the rat suggested that primates such as the cynomolgous monkey might be efficient A-ring metabolisers. Further studies established that the pseudo-diequatorial conformation of the proximate genotoxin, the 3,4-dihydrodiol, was vital in determining biological activity, since it was observed that the pseudo-diaxial 3,4-dihydrodiol of 15,16-dihydro-6-methylcyclopenta[a]phenanthren-17-one could not be activated to genotoxic intermediates.