TY - JOUR
T1 - Di-epoxides of the three isomeric dicyclopenta-fused pyrenes
T2 - Ultimate mutagenic active agents
AU - Otero-Lobato, María José
AU - Kaats-Richters, Veronica E.M.
AU - Havenith, Remco W.A.
AU - Jenneskens, Leonardus W.
AU - Seinen, Willem
N1 - Funding Information:
Financial support from the Gobierno Vasco, Beca para Formación de Investigadores (M.J. Otero-Lobato) and technical support from Dr. A.Y. Simarro and S.M. Nijmeijer (Veterinary Pharmacology, Pharmacy and Toxicology, Utrecht University, The Netherlands) are gratefully acknowledged. Dr. R.W.A. Havenith acknowledges financial support from the Netherlands Organisation for Scientific Research (NWO) grant 700.53.401.
PY - 2004/11/14
Y1 - 2004/11/14
N2 - 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 ( 1H 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.
AB - 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 ( 1H 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.
KW - Ab initio RHF/6-31G
KW - Bacterial mutagenicity
KW - Direct-acting mutagens
KW - Epoxidation
KW - IGLO/III//RHF/6-31G
KW - Salmonella typhimurium TA98
KW - Semi-empirical AM1 calculations
UR - http://www.scopus.com/inward/record.url?scp=5144230061&partnerID=8YFLogxK
U2 - 10.1016/j.mrgentox.2004.07.009
DO - 10.1016/j.mrgentox.2004.07.009
M3 - Article
C2 - 15474409
AN - SCOPUS:5144230061
SN - 1383-5718
VL - 564
SP - 39
EP - 50
JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
IS - 1
ER -