Di-epoxides of the three isomeric dicyclopenta-fused pyrenes: ultimate mutagenic active agents.
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.
Department of Physical Organic Chemistry, Debye Institute, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
María José
MJ
Otero-Lobato
Veronica E M
VE
Kaats-Richters
Remco W A
RW
Havenith
Leonardus W
LW
Jenneskens
Willem
W
Seinen
D000818:Animals; D004269:DNA, Bacterial / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011721:Pyrenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D004269:DNA, Bacterial; D004852:Epoxy Compounds; D009153:Mutagens; D011721:Pyrenes