Mutagenicity of 1,2 ring-fused acenaphthenes against S. typhimurium TA1537 and TA1538: structure-activity relationship.

A number of 1,2-ring fused acenaphthenes, together with the parent compounds acenaphthene and acenaphthylene, were evaluated for mutagenicity, using the Pour-Plate Technique with S. tpyhimurium strains TA1538 and TA1537. Although acenaphthene and acenaphthylene were non-mutagenic, all the 1,2-ring fused acenaphthene were found to be indirect frameshift mutagens in strain TA1537. The chemical nature of the 1,2-fused ring did not appear to be important for mutagenic activity against TA1537, however, its nature did affect the mutagenesis of strain TA1538. Only acenaphthenes fused with a pyrimidine or pyrazine ring were capable of mutating the hiD 3052 locus of TA1538. Substitution at the 8-position of the ring system with an amino group rendered the molecule inactive against TA1538, whilst substitution at the 10-position only reduced, but did not eliminate the mutagenic effect against TA1538. Methyl substitution at various sites on the molecule modified the mutagenic activity against TA1537, and indicated the formation of an electrophilic species (epoxide) at the 2,3-position of the acenaphthene nucleus. The incorporation of a competitive substrate for ring hydroxylation (naphthalene) reduced the mutagenic effect of acenaphthopyrimidine against TA1537 and confirmed this assumption. However, naphthalene did not reduce the mutagenic effect of the compound against TA1538, indicating the possible formation of a second metabolite by an alternative enzymic pathway. The fusion of a pyridine ring to the system to give a pentacyclic compound resulted in a molecule sufficiently planar to allow for a weak direct mutagenic effect against TA1537.