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Mechanisms of polycyclic aromatic hydrocarbons carcinogenesis: Synthesis and DNA binding studies of anti- and syn-3,4 -dihydrodiol-5,5a-epoxide benzo[ghi] fluoranthene

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  • Health Sciences
  • Toxicology|Chemistry
  • Biochemistry|Chemistry
  • Organic
  • Chemistry


The exceptional mutagenic and tumorigenic activities of fjord-region PAH dihydrodiol epoxides (DE) have been associated with molecular deformity, diol stereochemistry and preferred reactivities with dA rather than dG. To better understand how these structural features are related to PAH mutagenesis, the racemic anti- and syn-B[ghi]FDE were prepared through multi-step synthesis, and then reacted separately with DNA, poly(dGdC) and poly(dAdT). The structure of B[ghi]FDE differs from that of the fjord-region BcPDE, being planar with a more clearly-defined diol conformation. A total of 16 DNA adducts were isolated and their chemical structures elucidated by UV, NMR, CD and MALDI-TOF-MS analysis. The principal adducts rose both from trans and cis opening at the benzylic carbon (C5a) of the epoxides by amino groups of dG and dA. Minors adducts with the amino group of dC and with the N-7 position of guanine have also been isolated. Comparison of these data with those of the non-planar BcPDE will be discussed in terms of the relative chemical reactivities and the extent of DNA binding. ^

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