Epoxides K region

Figure 3. The K-region epoxides of 7-methylbenz[a]anthracene and benzo[a]pyrene.

Figure 3. Mechanism of microsomal EH-catalyzed hydration of the K-region epoxide enantiomers of BA, BaP, and DMBA. The percentages of the trans-addition product by water for each enantiomeric epoxide are indicated. The enantiomeric composition of the dihydrodiol enantiomers formed from the hydration of DMBA 5S,6R-epoxide was determined using 1 mg protein equivalent of liver microsomes from pheno-barbital-treated rats per ml of incubation mixture and this hydration reaction is highly dependent on the concentration of the microsomal EH (49). The epoxide enantiomer formed predominantly from the respective parent hydrocarbon by liver microsomes from 3-methylcho-lanthrene-treated rats is shown in the box.

Detailed kinetic studies comparing the chemical reactivity ofK-region vs. non-K-region arene oxides have yielded important information. In aqueous solution, the non-K-region epoxides of phenanthrene (the 1,2-oxide and 3,4-oxides) yielded exclusively phenols (the 1-phenol and 4-phenol, respectively, as major products) in an acid-catalyzed reaction, as do epoxides of lower arenes (Fig. 10.1). In contrast, the K-region epoxide (i.e., phenanthrene 9,10-oxide 10.29) gave at pH < 7 the 9-phenol and the 9,10-dihydro-9,10-diol (predominantly trans) in a ratio of ca. 3 1. Under these conditions, the formation of this dihydrodiol was found to result from trapping of the carbonium ion by H20 (Fig. 10.11, Pathway a). At pH > 9, the product formed was nearly ex-... 

In other words, the non-K-region epoxides of phenanthrene react like epoxides of lower arenes (Fig. 10.1). In contrast, the K-region epoxide of phenanthrene, under alkaline conditions, hydrolyzes as does an olefin epoxide (i.e., as in Fig. 10.4), but seemingly faster. Under acidic conditions, however, it exhibits dual behavior, isomerizing mainly like an arene oxide (i.e.,... 

The EH-catalyzed hydration of the enantiomers of the K-region epoxides of BaA, CR, and BcPh allows informative comparisons to be made [92 - 94], With four among the six substrates, nucleophilic attack is selective for the oxirane C-atom with (5)-configuration (Fig. 10.12). This is, for example, true for the two enantiomers of chrysene 5,6-oxide. Looking at the data in another way, it is also apparent that, irrespective of the enantiomer, nucleophilic attack occurs preferentially at C(5) for benz[a]anthracene 5,6-oxide, but at C(6) for benzo[c]phenanthrene 5,6-oxide. In other words, the regio- and... 

Fig. 10.12. Upper part The K, M, bay, and fjord regions of three isomeric tetracyclic aromatic hydrocarbons (benz[a]anthracene (BaA, 10.31), chrysene (CR, 10.32), and benzo[c]phenanthrene (BcPh, 10.33)). Lower part. The three pairs of enantiomeric (S,R)- and (R,S)-K-region epoxides and...

Here, K-region epoxides are discussed first since they are often the predominant metabolites in the oxidation of PAHs catalyzed by cytochromes P450 [93a]. Furthermore, from a toxicology point of view, the epoxide-dihy-drodiol pathway of K-region epoxides is considered a route of detoxification [95] [96],... 

The formation of BaP 9,10-epoxide is considered a reaction of detoxification of BaP, as is the formation of its K-region epoxide. However, this last statement must now be qualified by the recent finding that the K-region dihydrodiol of benzo[a]pyrene, i.e., /ra .v-4,5-dihydro-4,5-dihydroxy-BaP (10.35, Fig. 10.13), can ultimately form DNA adducts. This is due to its further metabolism to bis [dihydrodiols] such as 1,2,4,5-, 4,5,7,8-, and 4,5,9,10-bis[dihydrodiol]. The tran,y-/ra ,y-BaP-4,5,7,8-bis[dihydrodiol] has been shown to be a metabolic intermediate in the formation of DNA-adducts [103],... 

Polynuclear aromatics that cannot form K-region epoxides such as anthracene may be oxidized to the corresponding quinones806 by these reagents. Others, such as naphthalene and triphenylene, may be converted to polyepoxides under carefully controlled reaction conditions and workup procedures.808,809... 

Naphthalene 1,2-oxide (45) can be prepared by treatment of bromohydrin 46 with sodium methoxide in THF. Cyclization and dehydrobromination are achieved in a single pot.28 By this method, the non-K-region epoxide phenanthrene 1,2-oxide (47) and the bay-region oxide phenanthrene 3,4-oxide (48) have also been prepared.28 The syntheses of homobenzene analog 49 and... 

The first arene oxides to be synthesized (1964) were obtained by the cyclization of appropriate seco derivatives. 0,0-Diformylbiphenyl derivatives, when treated with Mark s reagent [tris(dimethylamino)phosphine], gave arene oxides [Eq. (3)]. Thus K-region epoxides from phenanthrene and its analogs, benz[a]anthracene and its 7,12-dimethyl analog, have been prepared.34... 

Naphthalene 1,2-oxide (136), a non-K-region epoxide, shows low thermal stability. Anthracene 1,2-oxide, on the other hand, is stable at ambient temperatures for several weeks. Preparation of (+ )-(lR,2S)-anthracene 1,2-oxide (137), using the above method, constitutes the first example of preparation of an optically pure arene oxide. However, the non-K-region oxides of phenanthrene, namely, its 1,2- and 3,4-oxides (47 and 48), obtained from chiral precursors, racemize fast.66 Perturbational molecular orbital calculations indicate that epoxide-oxepin valence tautomerism is possible. However, the oxepin could not be detected by NMR. 

For oxirane rings an IR absorption around 890 cm-1 is characteristic. This is also observed in the case of K-region epoxides and can be used for diagnostic purposes, but it is not sensitive enough to provide detailed structural information. The oxepins ordinarily do not show this band. Ultraviolet spectroscopy has been invaluable in studying the dynamic equilibrium between the arene oxides and oxepins. The solvent variation of UV spectra has also been exploited very effectively.8... 

Keller and Heidelberger131 reported the kinetics of solvolysis of 1, 30, 38, and benz[a,/i]anthracene 5,6-oxide (228). These studies were carried out mostly in the pH < 7 region where nucleophilic addition ordinarily does not take place with either K-region or non-K-region epoxides. These authors found evidence for the formation of a carbonium ion and consequently were led to believe that the cell macromolecules react with arene oxides through a carbonium ion-trapping mechanism and not by a direct nucleophilic displacement on the oxides. 

In non-K-region epoxides like 86, second-order nucleophilic addition and water-catalyzed aromatization compete. Nitrogen and oxygen nucleophiles are not able to compete, whereas polarizable nucleophiles do. The factor most important is apparently the polarizability of the nucleophile rather than its basicity. The basicity of the thiolate species has little influence on the rate of reaction of 86 (Bronsted / -value = 0.2).138,139... 

A detailed study of the reaction of (-butyl mercaptide anion with K-region epoxides, derived from carcinogenic and related polycyclic hydrocarbons, was carried out in aqueous dioxane and in THF.147 In the former solvent system, 1,2-trans stereospecific addition took place, whereas addition-dehydration was observed in THF. 

Figure 3. Comparison of Sephadex LH-20 column chromatography of DMBA K-region epoxide deoxyribonucleoside products (0-0) formed by enzymatic digestion of calf thymus DNA which had been reacted with DMBA K-region epoxide jji vitro with enzymatically digested DMBA-DNA products from (a) female NIH Swiss mouse skin treated 24 h with [3h]-DMBA (10 yg/mouse) and (b) calf thymus DNA treated with [ H]-DMBA (320 nmol/mg microsomal protein) for 2 h in the presence of Aroclor-induced rat liver microsomes. The arrow is as defined in Figure 2.

K-region epoxide adducts at higher doses Dihydrodiol epoxide adducts at lower doses in most cases, but always accompanied by other adducts... 

Figure 3 A, steric model of the active site of cytochrome P450-IA1 based on the metabolism of benzo[a]pyrene the binding site is asymmetrically positioned toward the activated iron-bound oxygen species. (From Jerina et al 1985.) expanded model of A in order to accommodate also non-bay-region or K-region epoxides. (From Kadlubar and Hammons, 1987 Yang, 1988.) C, proposed model in which some flexibility in the angle of oxygen addition to the substrate is allowed. (From Kadlubar and Hammons, 1987.)...

Yang, S. K. and Bao, Z.-P. (1987). Stereoselective Formations of K-Region and Non-K-Region Epoxides in the Metabolism of Chrysene by Rat Liver Microsomal Cytochrome P-450 Isozymes, Mol. Pharmacol, 32 73-80. 

Grover, P. L., Sims, P. K-region epoxides of polycyclic hydrocarbons Reactions with nucleic acids and polyribonucleotides. Biochem. Pharmacol. 22, 661 (1973). 

Oesch F, Golan M. 1980. Specificity of mouse liver cytosolic epoxide hydrolase for K-region epoxides derived from polycyclic aromatic hydrocarbons. Cancer Lett 9 169-175. 

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