Fjord-region diol epoxides

The high reactivity of bay-region (and fjord-region) diol epoxides has intrigued chemists for years. Numerous experimental and computational studies have been carried out, affording a wealth of information on the mechanisms by which bay-region diol epoxides form adducts with nucleic acids and are deactivated by reaction with protective nucleophiles or by hydrolysis. Indeed, the hydration of diol epoxides forms unreactive tetrahydroxy metabolites known as tetrols (10.39, Fig. 10.14,a). 

S. Vepachedu, N. Ya, H. Yagi, J. M. Sayer, D. M. Jerina, Marked Differences in Base Selectivity between DNA and the Free Nucleotides upon Adduct Formation from Bay- and Fjord-Region Diol Epoxides , Chem. Res. Toxicol. 2000, 13, 883 -890. 

Substitution at bay/fjord region benzo ring J, if ring substitution at each and every bay/fjord region benzo ring Prevent formation of bay/ fjord region diol epoxide... 

PAH diol epoxide-DNA adducts have not only been detected in rodent tissues in experimental systems after PAH exposure, but have also been identified in (a) populations exposed to complex mixtures containing PAHs, (b) foundry workers (Perera et al. 1988 Hemminki et al. 1988), (c) coke oven workers (Rojas et al. 1995 Pavanello et al. 1999), (d) cigarette smokers (Lodovici et al. 1998 Rojas et al. 1995), (e) chimney sweeps (Pavanello et al. 1999), and (f) populations exposed to smoky coal combustion mixtures (Mumford et al. 1993). Some bay- or fjord-region diol epoxides form DNA adducts in the human p53 tumor suppressor gene at sites that are hotspots for lung cancer (Smith et al. 2000). 

Amin, S., Krzeminski, J., Rivenson, A., Kurtzke, C., Hecht, S.S., and El-Bay-oumy, K. (1995) Mammary cardno-genidty in female CD rats of fjord region diol epoxides of benzo[c] phenanthrene, benzo[g]chrysene and dibenzo[a,l]pyrene. Carcinogenesis, 16, 1971-1974. 

The diol epoxides (83) and (84) of the carcinogen fluoroanthene have been prepared". MO theory has been used to predict that (83) should be substantially more reactive than (84) and this has been verified by mutagenicity tests. Force field molecular structures for the fjord region diol epoxides of benzol phenanthrene (85) have revealed steric crowding which influences the relative confoimer stabilities in this system99. 

In addition to syn- and a t/-bcPhDE s four more fjord region diol epoxides have been synthesised and investigated, viz., syn and anti-benzo[c]chrysene DE s (BcChDE) as well as syn- and anti-benzo[g]chrysene DE s (BgChDE) [87]. All six fjord-region diol... 

Phillips DH, Hewer A, Seidel A, et al. 1991. Relationship between mutagenicity and DNA adduct formation in mammalian cells for fjord- and bay-region diol-epoxides of polycyclic aromatic hydrocarbons. Chem Biol Interact 1991 80(2) 177-186. 

In contrast, the pathway best known to yield adduct-forming metabolites (the ultimate carcinogens) is the formation of dihydrodiol epoxides, usually referred to as diol epoxides . This pathway involves three steps a) formation of an M-region epoxide, b) its hydration to the M-region dihydrodiol, and c) epoxidation of the latter at the vicinal C=C bond bordering the bay or fjord region. 

The diol epoxide pathway does, however, account for the structure-activity relationships in the bay region, methylated bay region, and fjord region PAH, since diol epoxides would not form without this structural feature. 

Figure 12.2 Chemical structures of the PAH compounds considered in this chapter, definitions of the bay and fjord region topologies, the stereochemical characteristics of the biologically relevant PAH diol epoxide metabolites, and stereochemical characteristics of PAH diol epoxide-DNA adducts. The aromatic rings metabolized by mammalian CYP 450 enzymes are the 7,8,9,10 ring of B[o]P, the 1,2,3,4 ring of B[c]Ph, and the 11,12,13,14 rings of B[g]C and DB[o,/]P. The absolute configurations of the PAH diol epoxides and DNA adducts are illustrated in the case of the (+)- and (-)-arrt/-B[a]PDE diol...

NER Efficiencies Bay and Fjord Region PAH Diol Epoxide-N6-dA Adducts... 

In summary, our hypothesis is that the increased polycyclic aromatic ring-base stacking interactions in the fjord region PAH diol epoxide-N -dA adducts stabilize the duplexes and inhibit the extent of strand opening in XPC/HR23B complexes that is critically important for successful NER [38], possibly by preventing the flipping out of nucleotides from the complementary strand. 

Amin, S., Desai, D., Dai, W., Harvey, R.G., and Hecht, S.S. (1995) Tumori-genicity in newborn mice of fjord region and other sterically hindered diol epoxides of benzo[g]chrysene, dibenzo[a,l]pyrene (dibenzo[de/p] chrysene), 4H -cyclopenta[de/]chrysene and fluoranthene. Carcinogenesis, 16, 2813-2817. 

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