Synthesis and tumor-initiating activities of dimethylchrysenes.
Previous studies have shown that 5-methylchrysene (5-MeC) is more carcinogenic on mouse skin than the other methylchrysenes and that the structural requirements favoring tumorigenicity of methylated polynuclear aromatic hydrocarbons are the presence of a bay region methyl group and free peri position, both adjacent to an unsubstituted angular ring. The purpose of this study was to extend these structure-activity relationships to dimethylchrysenes. The following dimethylchrysenes were synthesized: 1,5-dimethylchrysene (1,5-diMeC), 5,6-diMeC, 5,7-diMeC, 5,12-diMeC, 1,6-diMeC, 6,7-diMeC, and 6,12-diMeC. Bioassays of these compounds for tumor-initiating activity on mouse skin demonstrated that all were significantly less tumorigenic than 5-MeC; only 5,6-diMeC had significant tumorigenic activity. Since the relatively low activities of 5,7-diMeC and 5,6-diMeC were unexpected on the basis of the structural requirements stated above, anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5,7-dimethylchrysene+ ++ (anti-5,7-diMeC-1,2-diol-3,4-epoxide) was synthesized. Its mutagenicity in Salmonella typhimurium and reactivity with calf thymus DNA were compared to those of the major ultimate carcinogen of 5-MeC, anti-5-MeC-1,2-diol-3,4-epoxide. It was strongly mutagenic (2500 revertants/nmol), although less active than anti-5-MeC-1,2-diol-3,4-epoxide (7200 revertants/nmol). Its reactivity with calf thymus DNA was similar to that of anti-5-MeC-1,2-diol-3,4-epoxide. The results of this study demonstrate that the structural requirements which favor tumorigenicity of monomethylchrysenes are not sufficient for high tumorigenicity of dimethylchrysenes.
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Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Balanikas
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Huie
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Hecht
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D000818:Animals; D002273:Carcinogens / Q000138:chemical synthesis*; D002911:Chrysenes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D008745:Methylation; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009153:Mutagens / Q000138:chemical synthesis*; D010212:Papilloma / Q000139:chemically induced*; D012486:Salmonella typhimurium / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced*; D013329:Structure-Activity Relationship
D002273:Carcinogens; D002911:Chrysenes; D009153:Mutagens