Trans-dihydrodiol

In early studies of the metabolism of hydrocarbons, it was noted that vicinal trans dihydrodiols were frequently found as hydrocarbon metabolites and, because of their trans configuration, Boyland... 

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. 

Five vicinal trans-dihydrodiols of BA are known. One of these,... 

Diol epoxides. Structural considerations. Because enzymatic hydration of arene oxides produces trans dihydrodiols in mammalian cells, there are two diastereomeric series of diol epoxides. In... 

Unhindered angular ring trans-dihydrodiols such as trans-7,8-dihydro-... 

Reactive Metabolites of PAHs. A wide variety of products have been identified as metabolites of PAHs. These include phenols, quinones, trans-dihydrodiols, epoxides and a variety of conjugates of these compounds. Simple epoxides, especially those of the K-region, were initially favored as being the active metabolites responsible for the covalent binding of PAH to DNA. Little direct experimental support exists for this idea (62.63,64) except in microsomal incubations using preparation in which oxidations at the K-region are favored (65,66). Evidence has been presented that a 9-hydroxyB[a]P 4,5-oxide may account for some of the adducts observed in vivo (67.68) although these products have never been fully characterized. 

Although a number of the epoxides and diol epoxides are mutagenic, the 7,8-dihydrodiol 9,10-oxide, shown in Figure 7.2, is believed to be the ultimate carcinogen. It should be noted that there are several possible diastereoisomers of this metabolite, but as the action of epoxide hydrolase yields a trans dihydrodiol and the epoxide ring produced by the cytochrome P-450 may be cis or trans, there are two diastereoisomers produced metabolically. Thus, benzo(a)pyrene... 

As has been stated before, oxirane derivatives are formed as intermediates during metabolic oxidations at carbon-carbon double bonds. These epoxides (arene oxides) undergo spontaneous isomerization to phenols, or enzymic hydration via epoxide hydrase to trans- dihydrodiols, or reaction with reduced glutathione (GSH) via specific GSH-transferases to the corresponding conjugates (Scheme 11), which eventually appear in urine... 

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... 

The first example of syn stereoselective expoxidation of arene dihydrodiols was reported in 1981.11 The trans-dihydrodiols 11 and 12, when treated with a 10-fold excess of MCPBA in tetrahydrofuran (THF) at room temperature, gave stereoselectively the syn-diol epoxides 13 and 14, respectively. This stereoselectivity has been ascribed to the operation of steric control by the axial benzylic hydroxy group the equatorial hydroxy group does not exert such control. The isomeric 9,10-epoxides of 7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene can be prepared by the same method.12... 

Relatively stable arene oxides are the expected intermediates in the metabolism of halobenzenes to a variety of products.214 Oxide 107 isomerizes exclusively to 2-chlorophenol, whereas 109 rearranges exclusively to 4-chlorophenol. Both 107 and 109 react with glutathione and are converted to trans-dihydrodiols. 

Boyd DR, Sharma ND, Llamas NM, O Dowd CR, Allen CCR (2006) Chemoenzymatic Synthesis of the trans-Dihydrodiol Isomers of Monosubstituted Benzenes via anti-Benzene Dioxides. Org Biomol Chem 4 2208... 

The addition of H20 to epoxide rings, a process called epoxide hydration, is important in the metabolism of some xenobiotic materials. This reaction can occur, for example, with benzo(a)pyrene 7,8-epoxide, formed by the metabolic oxidation of benzo(a)pyrene, as shown in Figure 7.3. Hydration of an epoxide group on a ring leads to the trans dihydrodiols in which the -OH groups are on opposite sides of the ring. 

Smithgall, T. E., Harvey, R. G., and Penning, T. M. (1986). Regio- and stereospecificity of homogeneous 3-alpha-hydroxysteroid-dihydrodiol dehydrogenase for trans-dihydrodiol metabolites of polycyclic aromatic hydrocarbons. J Biol Chem 261, 6184-6191. 

Hydrolases catalyze the addition of a molecule of water to a variety of functional moieties. Thus, epoxide hydrolase hydrates epoxides to yield trans-dihydrodiols (reaction 1-B in Fig. 13.5). This reaction is documented for many arene oxides, particularly metabolites of aromatic compounds, and epoxides of olefins. Here, a molecule of water has been added to the substrate without loss of a molecular fragment, therefore the use of the term "hydration" sometimes found in the literature. 

Human recombinant AKRs have been shown to catalyze identical reactions for bay region trans-dihydrodiols (phenanthrene, chrysene, B[a]P, benz[a]anthracene), methylated bay region trarcs-dihydrodiols (5-methylchrysene and 7,12-DMBA), and fjord region trans-dihydrodiols (B[g]C) [18-20], Thus far, no human AKR has been show to be an efficient catalyst of the oxidation of the potent proximate carcinogen HR,12R-dihydroxy-dihydro-DB[a,l]P. Interestingly, this metabolic pathway of... 

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