Benzo chrysene-11,12-diol

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

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). 

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. 

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. 

Robertson, 1. G. C, and JemstrSm, B., The enzymatic conjugation of glutathione with bay-region diol-epoxides of benzo(a)pyFene, benz(a)anthracene and chrysene. Carcinogenesis (London) 7, 1633-1636 (1986). 

Diol, epoxide, and/or diol-epoxide metabolites structurally similar to those described for B[a]P have been reported for many PAHs, for example, naphthalene, anthracene, phenan-threne, B[a]A, benzo[c]phenanthrene, pyrene, chrysene, DB[fl,/t]A, benzo[ ]triphenylene, and DMB[a]A (983). All of these and structurally similar PAHs have been reported by Snook et al. as cigarette MSS components (3756). 

Abbreviations PAH, polycyclic aromatic hydrocarbon DE, diol epoxide PAHDE, polycyclic aromatic hydrocarbon diol epoxide PAHTC, polycyclic aromatic hydrocarbon triol carbocation TC, triol carbocation BaP, benzo[a]pyrene BeP, benzo[e]pyrene BA, benz[a]anthracene DBA, dibenz[a,h]anthracene BcPh, benzo[c)phenanthrene Ch, chrysene MCh, methylchrysene MBA, 7-methyl benz[a]anthracene DMBA, 7,12-dimethyl benz[a]anthracene EBA, 7-ethyl benz[a]anthracene DB(a,l)P, dibenzo[a,l]pyrene MSCR, mechanism-based structure-carcinogenicity relationship PMO, Perturbational molecular orbital method dA, deoxyadenosine dC, deoxycytosine dG, deoxyguanosine MOS, monoxygenase enzyme system EH, epoxide hydrolase enzyme system N2(G), exocyclic nitrogen of guanine C, electrophilic centre of PAHTC K, intercalation constant CD, circular dichroism LD, linear dichroism. 

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... 

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