Benzo phenanthrene-3,4-diol

A. Harsch, J. M. Sayer, D. M. Jerina, P. Vouros, HPLC-MS/MS Identification of the Positionally Isomeric Benzo[c]phenanthrene Diol Epoxide Adducts in Duplex DNA , Chem. Res. Toxicol. 2000, 13, 1342 - 1348. 

Dipple, A., Pigott, M. A., Agarwal, S. K., Yagi, H., Sayer, J. M and Jerina, D. M. (1987). Optically Active Benzo[c]phenanthrene Diol Epoxides Bind Extensively to Adenine in DNA, Nature, 327 535-536. 

PAHs are ubiquitous environmental pollutants known to be mutagenic and carcinogenic in mammalian cells [131, 132]. PAHs require metabolic activation that results in diol epoxide formation via reactions that are catalyzed by epoxide hydrolase and the CYP450 family of enzymes [133], Diol epoxides are highly reactive, particularly toward purines in DNA, forming guanine and adenine adducts that exist as as and trans stereoisomers [134]. Transcription past adducts derived from diol epoxides of benzo[o]pyrene (benzo[a]pyrene diol expoxide (B[a]PDE)), benzo[c]phenanthrene (benzo[c]phenanthrene diol epoxide (B[c]PhDE)), and dibenzo[a,l]pyrene (dibenzo[o,l]pyrene diol epoxide (B[a,l]PDE)) has been studied. 

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. 

Benzo(c)phenanthrene (BcP) is exceptionally weak or inactive as a carcinogen in experimental animals (51). On the other hand, the bay region anti diol epoxide of BcP (14) exhibits high tumor initiating activity on mouse skin (65). 

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. 

L. Lewis-Bevan, S. B. Little, J. R. Rabinowitz, Quantum Mechanical Studies of the Structure and Reactivities of the Diol Epoxides of Benzo[c]phenanthrene , Chem. Res. Toxicol. 1995, 8, 499 - 505. 

Lewis-Bevan, L., Little, S. B., and Rabinowitz, J. R. (1995). Quanmm mechanical studies of the structure and reactivities of the diol epoxides of benzo[c]phenanthrene. Chem Res Toxicol 8, 499—505. Lodovici, M., Akpan, V., Giovannini, L., Migliani, E., and Dolara, P. (1998). Benzo[a]pyrene diol-epoxide DNA adducts and levels of polycyclic aromatic hydrocarbons in autoptic samples from human... 

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. 

Ronai, Z.A., Gradia, S., el-Bayoumy, K., Amin,S.,andHecht,S.S.(1994)Con-trasting incidence of ras mutations in rat mammary and mouse skin tumors induced by onti-benzo[c]phenanthrene-3,4-diol-l, 2-epoxide. Carcinogenesis,... 

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. 

Scheme 16 Synthesis of l,12-bis(2-pyridyl)benzo[c]phenanthrene-2,ll-diol 81 [75]...

A number of instances can be cited from the literature wherein the isosteres had similar transformations. Bacterial dioxygenase-catalyzed ci5-dihydroxylation of the tetracyclic arene benzo[c]phenanthrene was found to occur exclusively at fjord region (cavity region) bonds. The isosteric compounds benzo[b]naphthol [l,2-d]furan and benzo[b]naphthol[l,2-d]thiophene were also similarly ci5-dihydroxylated at the fjord region bonds by bacterial dioxygenases (Boyd et al., 2001) (see Fig. 4.3). The isosteres 1,2-dihydronaphthalene, 2,3-dihydrobenzothiophene, and 2,3-dihydro-benzofuran gave similar corresponding diol products on incubation with Pseudomonas putida UV4. Microbes that possess the metabolic pathways to metabolize benzene, when substituted by... 

---