Epoxidation of polycyclic aromatic

An example of three types of reactive substrates includes the metabolically generated epoxides of polycyclic aromatic hydrocarbons, e.g., benzo[a]pyrene-4,5-epoxide (25), the diuretic ethacrynic acid, and the hypnotic agent bromisoval as shown in Figure 7.16. 

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. 

Phillips DH, Hewer A, Seidel A, et al. 1991. Relationship between mutagenicity and DNA adduct formation in mammalian cells for fjord- and bay-region diol-epoxides of polycyclic aromatic hydrocarbons. Chem Biol Interact 1991 80(2) 177-186. 

EPHXs are important multifunctional enzymes from both the deactivation and activation of reactive species. Furthermore, they convert any potentially reactive epoxide formed by the P450s system into a diol metabolite, which is usually less reactive, more water soluble, and more easily cleared by GSTs. There are two major types of EPHX enzymes the microsomal (mEPHX), which uses epoxides of polycyclic aromatics or drugs as substrates (type 1) and which controls hepatic uptake of bile acids (type 2) [67], and the soluble EPHX (sEPHX), which forms diols from many endogenous and exogenous epoxides, including fatty acids and leukotrienes [68],... 

Yagi, H., Sayer, J.M., Jerina, D.M., and Conney, A.H., 1982, Inhibition of the mutagenicity of bay-region diol epoxides of polycyclic aromatic hydrocarbons by naturally occurring plant phenols exceptional activity of ellagic acid,... 

Flowers-Geary L, Harvey RG, Penning TM Examination of diols and diol epoxides of polycyclic aromatic hydrocarbons as substrates for rat liver dihydrodiol dehydrogenase. Chem Res Toxicol 1992, 5 576-583. 

Epoxides are often encountered in nature, both as intermediates in key biosynthetic pathways and as secondary metabolites. The selective epoxidation of squa-lene, resulting in 2,3-squalene oxide, for example, is the prelude to the remarkable olefin oligomerization cascade that creates the steroid nucleus [7]. Tetrahydrodiols, the ultimate products of metabolism of polycyclic aromatic hydrocarbons, bind to the nucleic acids of mammalian cells and are implicated in carcinogenesis [8], In organic synthesis, epoxides are invaluable building blocks for introduction of diverse functionality into the hydrocarbon backbone in a 1,2-fashion. It is therefore not surprising that chemistry of epoxides has received much attention [9]. 

Hulbert, P. B. Grover, P. L. Chemical rearrangement of phenol-epoxide metabolites of polycyclic aromatic hydrocarbons to quinone-methides. Biochem. Biophys. Res. Commun. 1983, 117, 129-134. 

Mechanisms of Interaction of Polycyclic Aromatic Diol Epoxides with DNA and Structures of the Adducts... 

Analogous results have been recently obtained with trans-1,2-dihydroxy-ant i-3, 4-epoxy- 1,2,3,4-tetrahydro-5-methy1 chrysene (13) and the epoxide 1-oxyrany1pyrene (14). Thus, the formation of non-covalent intercalative site I complexes appears to be a general phenomenon which governs the interaction of polycyclic aromatic epoxides with DNA (15-17). 

The Epoxide-Dihydrodiol Pathway of Polycyclic Aromatic Hydrocarbons... 

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

The microsomal epoxide hydrolases (microsomal EH, mEH), predominantly found in the endoplasmic reticulum, regio- and stereoselectively catalyze the hydration of both alkene and arene oxides, including oxides of polycyclic aromatic hydrocarbons. These enzymes have been purified to homogeneity from various species and tissues [22] [41 - 46], The human microsomal EH contains 455 amino acids (Mr 52.5 kDa) and is the product of the EPHX1 gene [47] (also known as HYL1 [48]). 

M. Shou, F. J. Gonzalez, H. V. Gelboin, Stereoselective Epoxidation and Hydration at the K-Region of Polycyclic Aromatic Hydrocarbons by cDNA-Expressed Cytochromes P450 1A1, 1A2, and Epoxide Hydrolase , Biochemistry 1996, 35, 15807 - 15813. 

The metabolism of polycyclic aromatic hydrocarbons by enzymes present in animal livers involves epoxidation as the initial step. As indicated in Section 5.17.1.2, evidence is available to suggest that oxepins (29)-(34) are present as minor contributors to the arene oxide-oxepin equilibrium and thus may legitimately be considered as metabolic intermediates. 

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... 

Weems, H.B., Mushtaq, M., and Yang, S.K., Resolution of epoxide enantiomers of polycyclic aromatic hydrocarbons by chiral stationary-phase high-performance liquid chromatography, Anal. Biochem., 148, 328, 1985. 

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... 

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. 

Recently, several nucleophilic reagents have been used to establish the mode of action of the metabolites of polycyclic aromatic hydrocarbons (PAH). Among them, several phosphodiesters have been examined to clarify the possibility of reaction of PAH epoxides with the phosphate groups(P-alkylation) of nucleic acids (22). In this context we have studied the reaction of 3,4-epoxyprecocene II with dibenzyl phosphate under a variety of conditions. In all cases, instead of the formation of phenol or phosphotriesters observed with PAH epoxides, we obtained predominantly dimer XI. This compound was also the main component of the mixtures obtained by reaction of the above precocene epoxide with other acid catalysts, along with dimers XII and XII. Dimer XII was formed almost exclusively by thermal treatment. The structure and configuration for compound XII has been established by spectral and X-ray diffraction analyses (23). 

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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