Di-epoxides of the three isomeric dicyclopenta-fused pyrenes: ultimate mutagenic active agents

Abstract To rationalize the high bacterial mutagenic response recently found for the (di-) cyclopenta-fused pyrene congeners, viz. cyclopenta[ cd ]-( 1 ), dicyclopenta[ cd,mn ]-( 2 ), dicyclopenta[ cd,fg ]-( 3 ) and dicyclopenta[ cd,jk ]pyrene ( 4 ), in the presence of a metabolic activation mixture (S9-mix), their (di-)epoxides at the externally fused unsaturated five-membered rings were previously proposed as the ultimate mutagenic active forms. In this study, cyclopenta[ cd ]pyrene-3,4-epoxide ( 5 ) and the novel dicyclopenta[ cd,mn ]pyrene-1,2,4,5-di-epoxide ( 6 ), dicyclopenta[ cd,fg ]pyrene-5,6,7,8-di-epoxide ( 7 ) and dicyclopenta[ cd,jk ]pyrene-1,2,6,7-di-epoxide ( 8 ) were synthesised from 1 to 4 , respectively, and subsequently assayed for bacterial mutagenicity in the standard microsomal/histidine reverse mutation assay (Ames-assay with Salmonella typhimurium strain TA98). The di-epoxides 6 – 8 are present as a mixture of their cis - and trans -stereo-isomers in a close to 1:1 ratio ( 1 H NMR spectroscopy and ab initio IGLO/III//RHF/6-31G** calculations). The direct-acting mutagenic activity and the strong cytotoxicity exerted by 5 – 8 both in the absence or presence of an exogenous metabolic activation system (±S9-mix) demonstrate that the ultimate mutagenic active forms are the proposed (di-)epoxides of 1 – 4 .