Bay-region diol epoxides

Anthracene is noncarcinogenic and is structurally incapable of forming a bay region diol epoxide. Anthracene 1,2-dihydrodiol is most conveniently synthesized from 2-anthranol by oxidation with phenylseleninic anhydride to anthracene 1,2-dione (55) followed by reduction with NaBH in ethanol (22) or LiAlH (55). Anthracene 1,2-dihydrodiol has also been synthesized via the Prdvost reaction route... 

Several observations can be made about the mutagenicity values. First, the highly-hindred BcPh bay-region diol epoxides exhibit mutagenicities far in excess of what might have been anticipated based upon their calculated AEd values, and the basis... 

The mutagenicities of the bay region diol epoxides derived from BA, BaAcr and BcAcr toward S. typhimurium strain TA 100 (similar results are obtained in strain TA 98) and Chinese hamster V79 cells... 

For the alternant PAH that have been studied extensively, bay-region diol epoxides are important metabolically activated forms. Studies of the chemical and biological activity of a variety of diol epoxides have provided insight into the factors related to reactivity and biological activity. Chemical reactivity, as measured by spontaneous hydrolysis, correlated well with calculated quantum chemical parameters that estimate ir-electron stabilization upon conversion of the epoxide to a benzylic carbocation, provided... 

Figure 7. Mutagenicities of BA, BaAcr, and BcAcr bay region diol epoxides in S. typhimurium TA 100 and Chinese hamster V79 cells. (Adapted from Ref. 29).

Methylated derivatives of 7-methylB[a]A are particularly carcinogenic when substitutes in the 7-, 12-, or 6- and 8-positions (152,153). The increased carcinogenicity of these compounds may result from the inhibition of metabolism at the 8-11 positions which increases the amounts of bay region diol epoxides formed, the greater reactivity of such epoxides with DNA, or an intrinsic difficulty for cells to repair such adducts (154). 

In the case of 7-methyl-B[a]A (155) and 7,12-dimethyl-B(a]A (DMBA) (50,55,57,156-158) most of the evidence supports bay region diol epoxide adducts. Thus, fluorescence studies (50,55,56,159), light sensitivity of the adducts (160), and analysis of adducts formed by further oxidations of the 3,4-dihydrodiol all suggest a bay region diol epoxide intermediate (161,162). More recent evidence... 

Methvlcholanthrene. This PAH gives rise to many metabolites and a complex pattern of DNA adducts (159,171-173). All of the evidence suggests again that the bay region diol epoxides are involved with additional oxidation possibly having occurred at the methyl, or Cl or C2 positions. 

The carcinogenicity of PAH with relativelyTigh IP, such as benzo[c]phenanthrene, benz[a]anthracene, chrysene, 5-methyl chrysene and dibenz[a,h]anthracene (Table I), can be related to the formation of bay-region diol epoxides catalyzed by monooxygenase enzymes (j>). However, the most potent carcinogenic PAH have IP < ca. 7.35 eV. 

These findings indicate that PGH synthase in the presence of arachidonate can catalyze the terminal activation step in BP carcinogenesis and that the reaction may be general for dihydrodiol metabolites of polycyclic hydrocarbons. Guthrie et. al. have shown that PGH synthase catalyzes the activation of chrysene and benzanthracene dihydrodiols to potent mutagens (33). As in the case with BP, only the dihydrodiol that is a precursor to bay region diol epoxides is activated. We have recently shown that 3,4-dihydroxy-3,4-dihydro-benzo(a)anthracene is oxidized by PGH synthase to tetrahydrotetraols derived from the anti-diol epoxide (Equation 4) (34). 

DNA binds and reacts with carcinogenic and similar compounds which alkylate it through cationic intermediates, in some cases extraordinarily fast 1371 and can in the process catalyse the hydrolysis of some substrates, like the bay-region diol epoxides derived from benzpyrene.1381 In the context of enzyme mimics these reactions are primarily of curiosity value DNA lacks the conformational flexibility and the chemical functionality to offer the prospect of efficient catalysis for ordinary reactions. 

Figure 8. Epoxide ring opening reactions of bay-region diol epoxides and epoxides from dibenzo[a,h] acridine, and epoxides from benzo[a]acridine and benzo[c]acridine. Figure adaptedfrom reference 27. 

Fig. 10.13. Metabolism of benzo[ ]pyrene (10.34). Shown are stereoselective formation of three isomeric epoxides, EH-catalyzed, stereoselective hydration to the dihydrodiols 10.35, 10.36, and 10.37, and, finally, 9,10-epoxidation of 10.36 to the bay-region diol epoxide 10.38. The latter exists as...

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). 

Hulbert published a landmark paper [104], in which he reasoned that diol epoxides should react with nucleophiles as carbonium ions. Although bay-region diol epoxides were not specifically considered in this hypothesis paper, the essence of the argument was that diol epoxides with yyn-con figuration (see Fig. 10.13) should be more reactive than their anti-stereoisomers since... 

Further studies that demonstrate that hydration of bay-region diol epoxides under acidic conditions can occur by general acid catalysis in addition to proton catalysis have expanded our understanding of their reactivity. General acid catalyzed hydration involves H-bonding of the epoxide O-atom by the acid catalyst, followed by nucleophilic attack of the distal C-atom by H20/H0 [108][109],... 

Sayer JM, Whalen DL, Jerina DM. Chemical strategies for the inactivation of bay-region diol-epoxides, ultimate carcinogens derived from polycyclic aromatic hydrocarbons. Drug Metab Rev 1989 20 155. 

Comparison of Predicted Chemical Reactivity of Bay-Region Diol Epoxides with Approximate Tumorigenicity of the Parent Hydrocarbon0... 

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