Anti-Benzo pyrene diol epoxide

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. 

J. W. Keller, C. Heidelberger, F. A. Beland, R. G. Harvey, Hydrolysis of syn- and anti-Benzo[a]pyrene Diol Epoxides Stereochemistry, Kinetics, and the Effect of an Intramolecular Hydrogen Bond on the Rate of. vyn-Diol Epoxide Solvolysis ,./. Am. Chem. Soc. 1976, 98, 8276 - 8277. 

Even the 1,2-dihydrodiol derivatives of polycyclic aromatic hydrocarbons are converted to the corresponding epoxydiols with MCPBA. The reaction is stereoselective only in some cases. The trans-dihydrodiols (6) give the antiepoxide (7), whereas the cfs-dihydrodiols (8) give a mixture of anti- (9) and syn-epoxy compounds (10). The anti- and syn-diol epoxides of benz[a]anthracene and benzo[a]pyrene have been prepared by this method.10... 

Benzo[a]pyrene diol epoxides react with adenine residues in DNA to give 105(-l-)- and 10R(-)-tra s-anti-benzo[a]pyrene-N -dA adducts (103), lOR(-) shown, which give rise to mutational hot spots. The solution structure of an 11-mer duplex in which there is a modified adenine has been studied, and it was... 

Shen, Y., Troxel, A.B., Vedantam, S., Penning, T.M., and Field, J.M. (2006) Comparison of p53 mutations induced by PAH o-quinones with those caused by anti-benzo[a]pyrene-diol-epoxide in vitro role of reactive oxygen and biological selection. Chem. Res. Toxicol., 19, 1441-1450. 

Xie, X.M., Geadntov, N.E., and Broyde, S. (1999) Stereochemical origin of opposite orientations in DNA addurts derived from enantiomeric anti-benzo[a] pyrene diol epoxides with different tumorigenic potentials. Biochemistry, 38, 2956-2968. 

N.E., Broyde, S., et al. (1992) Solution conformation of the major adduct between the carcinogen (+)-anti-benzo[a]pyrene diol epoxide and DNA. Proc. Natl. Acad. Sci. USA, 89, 1914-1918. 

S. (1999) Origins of conformational differences between cis and trans DNA adduds derived from enantiomeric anti-benzo[a]pyrene diol epoxides. 

Conformations of adducts and kinetics of binding to DNA of the optically pure enantiomers of anti-benzo(a)pyrene diol epoxide. Biochem. Biophys. Res. Commun., 122, 33-39. 

Tan, J., Geacintov, N.E., and Broyde, S. (2000) Conformational determinants of structures in stereoisomeric cis-opened anti-benzo[a]pyrene diol epoxide adducts to adenine in DNA. Chem. Res. Toxicol, 13, 811-822. 

NF-kB and COX-2 is a common feature in many cancers, and blocking these proteins usually provides significant chemopreventive potential. Anthocyanins have exhibited anti-inflammatory effects in multiple cell t) es in vitro, through their ability to inhibit the mRNA and/or protein expression levels of COX-2, NF-kB, and various interleukins. Treatment of JB-6 C141 mouse epidermal cells with an anthocyanin-rich extract from black raspberries resulted in the downregulation of benzo(a) pyrene diol-epoxide (BaPDE)-induced NF-kB expression [41]. 

Recent advances in PAH carcinogenesis research over the past decade have led to identification of diol epoxide metabolites as the principal active forms of the PAH investigated to date Q,2). Benzo-(a)pyrene (BP) has been most intensively investigated, and it has been demonstrated that a diol epoxide metabolite anti-BPDE is the active intermediate which binds covalently to DNA in human and other mammalian tissues 0,4). Anti-BPDE was also demonstrated to be a powerful mutagen in both bacterial and mammalian cells (15) These findings stimulated an outpouring of research directed towards elucidation of the molecular mechanism of PAH carcinogenesis. 

The diol epoxide derivative of benzo(a)pyrene, trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene also known as (+) -73,8a-dihydroxy-9ot,10a-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene,was the first diol epoxide to be synthesized. Interest in this compound was stimulated by the report by Borgen et al. (8) that a metabolite of benzo(a)pyrene, tentatively identified as the trans-7,8-diol ( 1) became covalently bound to DNA in the presence of rat liver micro-somes. Sims et al. ( ) suggested that the active metabolite was a diol epoxide derivative of unspecified stereo chemistry. 

Figure U. Anti and syn diastereoisomers of the benzo diol-epoxide (BDE). For the 7,8-diol-9,10-epoxide of benzo[a]pyrene (BPDE), these would be the (+)-anti or l(+) and (+)-syn or Il(+) isomers as indicated. Atom numbers for BDE are those for the diol epoxide of benzo[a]pyrene.

Rodriguez, H., and Loechler, E. L. (1995). Are base substitution and frameshift mutagenesis pafliways interrelated An analysis based upon studies of flie frequencies and specificities of mutations induced by the (+)-anti diol epoxide of benzo[a]pyrene. Mutat Res 326, 29-37. 

Weston, A., Rowe, M. L., Manchester, D. K., Farmer, P. B., Mann, D. L., and Harris, C. C. (1989). Fluorescence and mass spectral evidence for the formation of benzo[a]pyrene anti-diol-epoxide-DNA and -hemoglobin adducts in humans. Carcinogenesis 10, 251-257. 

Fig. 5. Detoxification of epoxide-containing carcinogens by GST. The following carcinogens are GST substrates (a) aflatoxin Bj-8,9-epoxide, (b) anti-benzo[a]pyrene-7,8-diol-9,10-oxide, and (c) benz[fl]anthracene-5,6-epoxide.

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