Synthesis of the tumorigenic 3,4-dihydrodiol metabolites of dibenz[a,j]anthracene and 7,14-dimethyldibenz[a,j]anthracene.
Syntheses are described of the trans-3,4-dihydrodiol derivatives (2a and 2b) of dibenz[a,j]anthracene and 7,14-dimethyldibenz[a,j]anthracene (1a and 1b), implicated as their proximate carcinogenic metabolites. Conversion of 2a to the bay region anti-diol epoxide derivative 3a, its putative ultimate carcinogenic metabolite, is also reported. The related diol epoxide derivative of 2b could not be prepared due to its chemical instability. Tumorigenicity assays confirm that 1b and 2b are potent carcinogens on mouse skin, while 1a and 2a are only relatively weakly active. The diol epoxide 3a exhibited significantly higher tumorigenicity than its dihydrodiol precursor 2a. These findings are consistent with the hypothesis that the bay region diol epoxide metabolites are the active carcinogenic forms of these hydrocarbons. They also support the generalization that methyl substitution in bay regions enhances the carcinogenic activity of polycyclic aromatic hydrocarbons.
Harvey
R G
RG
Ben May Institute, University of Chicago, Illinois 60637.
Cortez
C
C
Sawyer
T W
TW
DiGiovanni
J
J
D000818:Animals; D001551:Benz(a)Anthracenes / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis*; D010212:Papilloma / Q000139:chemically induced; D012878:Skin Neoplasms / Q000139:chemically induced*; D013329:Structure-Activity Relationship
D001551:Benz(a)Anthracenes; D007555:Isoxazoles; D010080:Oxazoles; C056428:3,4-dihydrodioldibenz(a,j)anthracene; C056430:3,4-dihydrodiol-7,14-dimethylbenz(a,j)anthracene