Synthesis and mutagenicity of the diastereomeric fjord-region 11,12-dihydrodiol 13,14-epoxides of dibenzo[a,l]pyrene.
Extensive tumorigenicity studies in rodents revealed that dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among all polycyclic aromatic hydrocarbons (PAHs) tested so far. The structure of the genotoxic metabolite(s) responsible for this exceptional carcinogenicity is unknown. The fjord-region syn- and anti-DB[a,l]P-11,12-dihydrodiol 13,14-epoxides (syn- and anti-DB[a,l]PDE) were synthesized to clarify their role as possible ultimate mutagenic and carcinogenic metabolites of DB[a,l]P.9-Formyl-11,12-dimethoxybenzo[g] chrysene was prepared from 9-phenanthrylacetic acid by a photochemical route. After reaction of the aldehyde with trimethylsulfonium iodide to generate an oxiranyl side-chain, treatment with boron trifluoride produced the key intermediate 11,12-dimethoxy-DB[a,l]P in 14% overall yield. From 11,12-dimethoxy-DB[a,l]P the syn- and anti-DB[a,l]PDE were stereoselectively prepared via the trans-11,12-dihydrodiol. The mutagenicity of the syn- and anti-DB[a,l]PDE was examined in four his- strains of Salmonella typhimurium and in Chinese hamster V79 cells. In all five test systems, the new dihydrodiolepoxides were more potent than any of the previously investigated dihydrodiolepoxides. The specific mutagenicity observed with anti-DB[a,l]PDE in strain TA104 exhibited the highest value ever found with any compound in any his- strains of S.typhimurium. The same appears to be true for the activity observed with this compound in V79 cells. In all five systems, syn-DB[a,l]PDE was only moderately less active than its anti-diastereomer (approximately 2-fold). The exceptional mutagenic activities of these dihydrodiolepoxides may be one of the reasons for the exceptional carcinogenic activity of DB[a,l]P.
Luch
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Institute of Toxicology, University of Mainz, Germany.
Glatt
H
H
Platt
K L
KL
Oesch
F
F
Seidel
A
A
D000818:Animals; D001580:Benzopyrenes / Q000138:chemical synthesis* / Q000633:toxicity; D002273:Carcinogens / Q000138:chemical synthesis* / Q000633:toxicity; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004101:Dihydroxydihydrobenzopyrenes / Q000138:chemical synthesis* / Q000633:toxicity; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000633:toxicity; D009153:Mutagens / Q000138:chemical synthesis* / Q000633:toxicity; D012486:Salmonella typhimurium / Q000187:drug effects; D013237:Stereoisomerism
D001580:Benzopyrenes; D002273:Carcinogens; D004101:Dihydroxydihydrobenzopyrenes; D004852:Epoxy Compounds; D009153:Mutagens; C087596:11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo(a,l)pyrene; C071371:dibenzo(a,l)pyrene 11,12-dihydrodiol