Synthesis and biological activity of bay-region metabolites of a cyclopenta-fused polycyclic aromatic hydrocarbon: benz[j]aceanthrylene.
The possibility of bay-region activation of the cyclopenta PAH (polycyclic aromatic hydrocarbon with a peripherally fused cyclopenta ring) benz[j]aceanthrylene (1) was investigated by synthesis and bioassay of the bay-region metabolites trans-9,10-dihydroxy-9,10-dihydrobenz[j]aceanthrylene (4), trans-9,10-dihydroxy-anti-7,8-epoxy-7,8,9,10-tetrahydrobenz[j]a ceanthrylene (2), and 9,10-dihydrobenz[j]aceanthrylene 9,10-oxide (3). The known 1,2-dihydrobenz[j]aceanthrylene-9,10-dione (5) was obtained by published methods; however, the direct route to target dihydrodiol 4, dehydrogenation of the saturated five-membered ring of 5 followed by NaBH4 reduction, gave a poor yield of 4 contaminated with tetrahydrogenated products. Acceptable yields of 4 were obtained by reduction of 5 to the corresponding tetrahydro diol, diacetylation of the diol, and dehydrogenation of the five-membered ring followed by base-catalyzed deacetylation to 4. anti-Diol epoxide 2 was generated by m-chloroperoxybenzoic acid oxidation of 4. Oxide 3 was synthesized by treatment of the monotosylate of 4 with NaOH in monoglyme. Diol epoxide 2 was an active mutagen in Salmonella typhimurium strain TA98 in the absence of metabolic activation, 3 showed marginal activity, while 3 and 4 were mutagenic with metabolic activation. These results coupled with previous studies support activation of benz[j]aceanthrylene via both 2 and cyclopenta ring epoxidation.
Sangaiah
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University of North Carolina-Chapel Hill 27599-7400.
Gold
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A
Newcomb
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Ball
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D000818:Animals; D008748:Methylcholanthrene / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity / Q000031:analogs & derivatives; D009152:Mutagenicity Tests; D009153:Mutagens / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects
D009153:Mutagens; D008748:Methylcholanthrene; C037411:benz(j)aceanthrylene