Diol epoxides aromatic hydrocarbons

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. 

As with several other functional groups considered earlier, epoxides are most commonly found in alkaloid metabolites rather than the original compound. These epoxides may arise via oxidation of alkenes or aromatic hydrocarbons. Epoxide hydrolase catalyzes hydrolysis of epoxides to the more hydrophilic diol. As seen in Scheme 6, this is usually a stereospecific reaction that always yields a... 

Diol epoxides, a very special and highly reactive subclass of alkene oxides encountered in the metabolism of polycyclic aromatic hydrocarbons. 

In the pH range of 5 - 10, H20-catalyzed hydrolysis is the predominant mechanism (see Fig. 10.11, Pathway b), resulting in the formation of the (8R,9R)-dihydrodiol (10.133, Fig. 10.30). Thus, aflatoxin B1 exo-8,9-epoxide is possibly the most reactive oxirane of biological relevance. Such an extreme reactivity is mostly due to the electronic influence of 0(7), as also influenced by stereolectronic factors, i.e., the difference between the exo- and endo-epoxides. The structural and mechanistic analogies with the dihydro-diol epoxides of polycyclic aromatic hydrocarbons (Sect. 10.4.4) are worth noting. 

J. M. Sayer, R. E. Lehr, D. L. Whalen, H. Yagi, D. M. Jerina, Structure-Activity Indices for the Hydrolysis of Diol Epoxides of Polycyclic Aromatic Hydrocarbons , Tetrahedron Lett. 1982, 23, 4431 - 4434. 

Sayer JM, Whalen DL, Jerina DM. Chemical strategies for the inactivation of bay-region diol-epoxides, ultimate carcinogens derived from polycyclic aromatic hydrocarbons. Drug Metab Rev 1989 20 155. 

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... 

Polycyclic aromatic hydrocarbons (PAH), which are ubiquitous in the environment, including surface waters, undergo facile chlorination by hypochlorite when dissolved in humus-poor water to give a suite of chlorinated PAH (1660). It is therefore conceivable that this chlorination can occur under natural conditions, but this is yet to be determined. Another new possible source of natural chlorinated PAH is the reported in vitro reaction of benzo [a pyrene diol epoxide, the ultimate carcinogen of benzo aIpyrene with chloride ion to give chlorohydrin DDD, which has been isolated and identified as an intermediate en route to a benzol a pyrene-DN A adduct (1661). However, DDD is not considered to be a natural compound at this time. 

Analytical Properties Resolution of several enantiomers of polycyclic aromatic hydrocarbons, for example, chrysene 5,6-epoxide, dibenz[a,h]anthracene 5,6-epoxide, 7-methyl benz[a]anthracene 5,6-epoxide resolution of barbiturates, mephenytoin, benzodiazepinones, and succinimides direct separation of some mono-ol and diol enantiomers of phenanthrene, benz[a]anthrene, and chrysene ionically bonded to silica gel, this phase provides resolution of enantiomers of c/s-dihydroidiols of unsubstituted and methyl- and bromo-substituted benz[a]anthracene derivatives having hydroxyl groups that adopt quasiequatorial-quasiaxial and quasiaxial-quasiequatorial conformation Reference 31-35... 

Formation of a dihydrodiol by hydration of epoxide groups can be an important detoxication process in that the product is often much less reactive to potential receptors than is the epoxide. However, this is not invariably the case because some dihydrodiols may undergo further epoxidation to form even more reactive metabolites. As shown in Figure 7.3, this can happen with benzo(a)pyrene 7,8-epoxide, which becomes oxidized to carcinogenic benzo(a)pyrene 7,8-diol-9,10-epoxide. The parent polycyclic aromatic hydrocarbon benzo(a)pyrene is classified as a procarcinogen, or precarcinogen, in that metabolic action is required to convert it to a species, in this case benzo(a)pyrene 7,8-diol-9,10-epoxide, which is carcinogenic as such. 

Some toxicants are known to affect the female reproductive system and processes. Exposure to the alkylating agents cyclophosphamide and vincristine can lead to loss of female sexual function. Cyclophosphamide may attack and damage the oocytes, cells that lead to egg formation. Pharmaceutical busulfan damages ovaries. The 7,8-diol-9,10-epoxide of benzo(a)pyrene, as well as some other metabolites of polycyclic aromatic hydrocarbons, can be toxic to oocytes. 

Many chemicals are metabolized to carcinogens by processes that do not seem to involve free radicals a well-understood example is the oxidation of benzo(a)pyrene [B(a)P] to the diol epoxide by the cytochrome P450 system. However, the oxidation of B(a)P and other polynuclear aromatic hydrocarbons (PAH) to carcinogenic compounds can involve radicals. This statement, while once controversial, now has ample evidence (12.,22,25.). Although it is clear that some products arise from radical-mediated metabolism of PAH, the involvement of these products in tumorigenesis is less clear nevertheless, I believe that such evidence does now exist (12,12). 

The Suzuki cross-coupling reaction is recognized as a novel, abbreviated method for the synthesis of 2-hydroxychrysene, 2-hydroxy-5-methylchrysene, and 8-hydroxy-5-methyl-chrysene from easily accessible reactants (Eq. (8)) [23]. These phenolic compounds constitute precursors for the synthesis of dihydrodiol and bay-region diol epoxide derivatives of chrysene and 5-methylchrysene, which are implicated as the active forms of carcinogenic polynuclear aromatic hydrocarbons. 

Figure 24.13. Examples of bay region diol epoxide ultimate carcinogenic species of various polycyclic aromatic hydrocarbons (PAHs). Polycyclic aromatic hydrocarbons are metabolized to highly electrophihc bay region diol epoxides that are considered to be the ultimate carcinogenic species. (Adapted from Conney, A. H. Cancer Res. 42, 4875, 1982.)...

S. M. Adams and L. S. Kaminsky, Mol. Pharmacol., 22, 459 (1982). Molecular Orbital Studies of Epoxide Stability of Carcinogenic Polycyclic Aromatic Hydrocarbon Diol Epoxides. 

Lodovici, M., Akpan, V., Giovannini, L., MigUani, F. Dolara, P. (1998). Benzo[n]pyrene diol-epoxide DNA adducts and levels of polycyclic aromatic hydrocarbons in autoptic samples from human lungs. Chemico-Biological Interactions, 116, 199-212. 

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