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.

Mutagenicity of cyclopenta-fused isomers of benz(a)anthracene in bacterial and rodent cells and identification of the major rat liver microsomal metabolites.

The microsomal metabolites and mutagenic activity of four cyclopenta-fused benz(a)anthracenes, benz(j)aceanthrylene [B(j)A], benz(e)aceanthrylene [B(e)A], benz(l)aceanthrylene [B(l)A], and benz(k)acephenanthrylene [B(k)A], have been studied. Aroclor 1254-induced rat liver microsomes metabolized B(j)A to B(j)A-1,2-dihydrodiol, B(j)A-9,10-dihydrodiol, B(j)A-11,12-dihydrodiol, and 10-hydroxy-B(j)A; B(e)A-1,2-dihydrodiol, B(e)A-3,4-dihydrodiol, and B(e)A-5,6-dihydrodiol; B(l)A to B(l)A-1,2-dihydrodiol, B(l)A-4,5-dihydrodiol, and B(l)A-7,8-dihydrodiol; and B(k)A to B(k)A-4,5-dihydrodiol and B(k)A-8,9-dihydrodiol. With each polycyclic aromatic hydrocarbon, metabolism occurred on the cyclopenta ring. All four isomers were active as gene mutagens in Salmonella typhimurium and in Chinese hamster V79 cells. In the S. typhimurium mutation studies, using Aroclor 1254-induced rat liver S9, B(j)A, B(e)A, and B(l)A required significantly less microsomal protein for maximal mutation response than B(k)A and B(a)P, suggesting a one-step activation mechanism, presumably on the cyclopenta-fused ring. B(j)A, B(e)A, and B(l)A were significantly more mutagenic than B(k)A and B(a)P in S. typhimurium. In the Aroclor 1254-induced rat liver S9-mediated V79 mutagenesis system, all four isomers were active, with B(l)A the most active. When Syrian hamster embryo cells were used as the metabolic activation component for V79 cells, only B(l)A produced a significant response and was equivalent in activity to B(a)P. A helical configuration for B(l)A is inferred from the identification of two trans-B(l)A-1,2-dihydrodiols, syn and anti, which have been synthesized, separated, and characterized. The metabolically formed dihydrodiol is anti-trans-B(l)A-1,2-dihydrodiol, and experimental evidence suggests that the metabolically formed B(l)A-1,2-oxide is the anti-isomer. Synthetic B(l)A-1,2-oxide was found to be a direct-acting mutagen in S. typhimurium and Chinese hamster V79 cells and is estimated to account for up to 40% of the mutagenic activity of the parent hydrocarbon. Therefore, certain cyclopenta-ring fusions on benz(a)anthracene appear to markedly increase its genotoxic and carcinogenic activities.