K region

Instrumentation. The k region was developed usiag dispersive techniques adapted as appropriate from uv—vis spectroscopy. Unfortunately, k sources and detectors tend to be kiefficient compared to those for other spectral regions. 

Although details vary for particular cases, a common synthetic route to diol epoxides such as (30) frequently begins with the ketone (33) (78MI50700). The final epoxidation is often highly stereoselective. A general route to non-K-region arene oxides has been described (75JA3185). 

McMillan DC, PP Fu, CE Cerniglia (1987) Stereoselective fungal metabolism of 7,12-dimethylbenz[a]anthra cene identification and enantiomeric resolution of a K-region dihydrodiol. Appl Environ Microbiol 53 2560-2566. 

Sutherland JB, JP Freeman, AL Selby, PP Fu, DW Miller CE Cerniglia (1990) Stereoselective formation of a K-region dihydrodiol from phenanthrene by Streptomyces flavovirens. Arch Microbiol 154 260-266. 

Marien, M., Brien, J., and Jhamandas, K., Regional release of [3H]dopamine from rat brain in vitro effects of opioids on release induced by potassium nicotine, and L-glutamic acid, Can. J. Physiol. Pharmacol., 61, 43, 1983. 

Figure 1. Benz[a]anthracene with regions of low bond localization energy (K-region) and low para localization energy (L-region) indicated.

The structure-activity considerations at that time naturally enough focussed interest on epoxides formed at the K-regions of the carcinogenic hydrocarbons (Figure 3), but it was not until 1964 that the synthesis of such putative metabolites was achieved (46). 

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

The configuration of the 4R,5R-dihydrodiol was established by application of the exciton chirality method (6). To minimize undesired interactions between the electric transition dipoles of the two j>-N,N-dimethylaminobenzoate chromophores and the dihydrodiol chromo-phore, a 4,5-dihydrodiol enantiomer was first reduced to 1,2,3,3a,4,5,7,8,9,10-decahydro and 4,5,7,8,9,10,11,12-octahydro derivatives (6). We found that it is not necessary to reduce the chrysene chromophore of a BaP 4,5-dihydrodiol enantiomer (Figure 2). Similarly, the absolute configurations of the K-region dihydrodiol enantiomers of BA (7), 7-bromo-BA (8), 7-fluoro-BA (9), 7-methyl-BA (10). and 7,12-dime thy 1-BA (DMBA) (7 ) can also be determined by the exciton chirality method without further reduction. 

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.

Stereochemically this is opposite to the 5S,6R-epoxide formed predominantly from the metabolism at the K-region of BA (47). 

Bonds in the "K-region" are usually short (1.34-1.35 A), near in values to that for a pure double bond, while most other C-C bonds in PAHs are in the range 1.36-1.44 A. The second area of interest is the "bay region" (27) which corresponds to the hindered region between the 4- and 5- positions of phenanthrene (the area between CIO and Cll of BP (I) or Cl and C12 of DMBA (II), for example). 

At first three K-region oxides were studied, those of DMBA (XI), BP (XII) and phenanthrene, the non-carcinogenic parent (XIII) the structures are shown in Figure 8. These epoxides, which were considered very reactive, were found to remain stable both in air and in the X-ray beam when in the crystalline state (82, 83). 

Figure 8. The structures of the K-region oxides of DMBA (XI) (a, b and c), BP (XII) (d) and phenanthrene (XIII) (e). Views (c), (d) and (e) are directly onto the plane of the epoxide group.

Figure 11. (a) View of K-region oxide of DMBA. (b) View of... 

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. 

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