Benzo diol-epoxide

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.

A-Hydroxy-4- acetylaminobiphenyl Benzo [a] pyrene diol epoxide Human TK6 lymphoblastoid Custom A-Hydroxy-4- acetylaminobiphenyl 10 xMfor27h Benzo[ajpyrene diol epoxide 10 xM for Ih Gene name, gene symbol, gene bank accession fold change in a table All data available online 116... 

Luo W, Fan W, Xie H, ling L, Ricicki E, Vouros P, et al. Phenotypic anchoring of global gene expression profiles induced by A -hydroxy-4-acetylaminobiphenyl and benzo[a]pyrene diol epoxide reveals correlations between expression profiles and mechanism of toxicity. Chem Res Toxicol 2005 18 619-29. 

Research in PAH carcinogenesis has made major advances in the past decade. Most notable has been identification of diol epoxide metabolites as the active forms of benzo[a]pyrene, 7,12-dimethylbenz[tf]anthracene, and other carcinogenic PAH. This finding has stimulated enormous research activity and opened the way to determination of the detailed molecular mechanism of action of this important class of carcinogenic molecules. 

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. 

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. 

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). 

Tetrahydroepoxides as models. Since the quantum chemical calculations apply most rigorously to the simple benzo-ring tetrahydroepoxides and since the calculations neglect influences of the hydroxyl groups in the diol epoxides, it is instructive first to examine the benzo-ring tetrahydroepoxides as simplified models for the reactive site in the diol epoxides. Most of the information about tetrahydroepoxide reactivity derives from studies of the kinetics of their hydrolysis reactions, in which cis- and trans-diols, as well as tetrahydroketones can be formed (Equation 5). 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

A Mechanism for the Stereoselectivity and Binding of Benzo[a]pyrene Diol Epoxides to DNA... 

This procarcinogen undergoes metabolic conversion to benzo[a]pyrene diol epoxides, BPDEs (5,28-31), which have been the focus of structural and conformational studies by theoretical and experimental methods. These chemically reactive BPDEs are involved in covalent binding to DNA (13-22). 

A theoretical analysis is presented for the binding of the four dia-stereoisomers of benzo[a]pyrene diol epoxides (BPDEs) to N2(g), N6(a), 06(G) and NU(c). Molecular models for binding and stereoselectivity involving intercalation, intercalative covalently and externally bound forms are presented. Molecular mechanics calculations provide the energetics which suggest possible structures for the formation of each of the principal DNA-BPDE complexes. Stereographic projections are used to illustrate the molecular structures and steric fits. The results of previous calculations on intercalation and adduct formation of BPDE l(+) in kinked DNA (37) are summarized and extended to include the four diastereoisomers l( ) and II( ). The theoretical model is consistent with the observed experimental data. 

Vl,an H( + ), benzo-ring diol-epoxide. They are ordered... 

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