Arenes, polycyclic, oxidation

Dihydro-9,10-epoxyphenanthrene and related arene oxides are of considerable interest as carcinogens formed by polycyclic aromatic hydrocarbons in vivo.45 Phenanthrene oxide does not isomerize to the corresponding dibenzoxepin under thermal conditions. Photolysis of... 

In nonaqueous solutions, two other types of reactions have been observed with polycyclic arenes condensation via free-radical reactions and oxidative ring fission. 

Two other polycyclic hydrocarbons, 3-methylcholanthrene and 7,12-dimethylbenzanthracene are oxidized during arachidonate metabolism (21,26). Hydroxymethyl compounds that do not arise from arene oxides appear to be the products formed from 7,12-dimethylbenzanthracene. ... 

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that can be toxic or even carcinogenic, e.g., epoxides of some polycyclic aromatic hydrocarbons. The question of whether their formation is obligatory is significant for drug design and development and has implications for toxicity as discussed in Chapter 8. 

In contrast, the primary role of microsomal EH appears to be in detoxifying the metabolically produced epoxides of drugs, e.g., carbamazepine epoxide, the arene oxide of diphenylhydantoin, and the epoxides of environmental contaminants like the polycyclic aromatic hydrocarbons, e.g., benzo[a]pyrene. 

Foureman GL, Hernandez O, Bhatia A, et al. The stereoselectivity of four hepatic glutathione S-transferases purified from a marine elasmobranch (Raja erinacea) with several K-region polycyclic arene oxide substrates. Biochim Biophys Acta 1987 914(2) 127-135. 

Polycyclic arenes having a high degree of bond fixation undergo epoxidation when exposed to tetra-alkylammonium hypochlorites over a pH range of ca. 8-9 [13] phenathridine is oxidized to phenanthridine. 

Another isomerization reaction of arene oxides is equilibrium with oxe-pins [5], Here, the fused six-membered carbocycle and three-membered oxirane merge to form a seven-membered heterocycle, as shown in Fig. 10.2. An extensive computational and experimental study involving 75 epoxides of monocyclic, bicyclic, and polycyclic aromatic hydrocarbons has revealed much information on the structural factors that influence the reaction rate and position of equilibrium [11], Thus, some compounds were stable as oxepins (e.g., naphthalene 2,3-oxide), while others exhibited a balanced equilibrium... 

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]). 

Together with glutathione conjugation, hydration is a major pathway in the inactivation and detoxification of arene oxides. Exceptions to this rule will be treated when discussing polycyclic aromatic hydrocarbons. Arene oxides are good substrates for microsomal EH, as evidenced in Table 10.1, where hydration of selected arene oxides, alkene oxides, and cy-cloalkene oxides by purified rat liver epoxide hydrolase is compared. The hy- ... 

The delocalised radical formed by protonation of the radical-anion is more easily reduced than the starting arene. For some polycyclic aromatic hydrocarbons, the redox potential for this radical species can be determined using a cyclic voltammetry technique [10]. Reduction in dimethylformamide is carried out to the potential for formation of the dianion. The dianion undergoes rapid monoprotonation and on the reverse sweep at a fast scan rate, oxidation of the monoanion to the radical can be observed. The radical intermediate from pyrene has E° = -1.15 V vs. see in dimethylformamide compared to E° = -2.13 V vs. see for pyrene,... 

Earlier progress in these studies has been summarized in reviews published in the last decade, emphasizing carbocations and oxidation dications, RCs, as well as reactive intermediates from the nitro- and nitroso-derivatives. The review article published in 1996 emphasized groundwork studies on protonation as well as oxidation (both RCs and stable dications) of polycyclic arenes and explored possible relationships between charge distribution and carcinogenicity, in concert with its... 

In the aromatic-ring-annelated oxepin series the resonance effect is clearly the major influence dominating other factors (e.g. temperature, solvent, etc.) which affect the oxepin-arene oxide equilibrium. It is however very difficult to exclude the presence of a minor (spectroscopically undetectable) contribution from either tautomer at equilibrium. This problem has been investigated by the synthesis of chiral arene oxides from polycyclic aromatic hydrocarbons (PAHs). The presence of oxepin (26) in equilibrium with naphthalene 1,2-oxide has been excluded by the synthesis of the optically active arene oxide which showed no evidence of racemization in solution at ambient temperature via the achiral oxepin (26) <79JCS(Pl)2437>. 

As stated in Section 5.17.1.4, simple thiepins (e.g. 44) are generally too reactive to be isolable under ambient conditions. Thiepins (49), (50) and (51) are among the relatively few stable monocyclic thiepins to have been reported and the majority of reactivity studies on thiepins have been carried out on polycyclic thiepins. The chemical reactivity of thiepins can be considered separately from the reactivity of the valence tautomeric thianorcaradienes more readily than was the case for oxepins-arene oxides. A spontaneous thermal extrusion of sulfur appears to occur from the episulfide tautomer of thiepins and the stable thiepins (49)-(51) would thus appear to exist exclusively in this valence isomeric form. 

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. 

Polycyclic aromatic hydrocarbons were epoxidized by DMD to arene oxides by... 

Oxidation to Arene Oxides and Arene Diols. Arene oxides and arene diols have been widely studied particularly concerning the metabolism of polycyclic aromatic compounds and their implication as intermediates responsible for the carcinogenicity and mutagenicity of polycyclic aromatic hydrocarbons.803,804... 

The bulk of the polycyclic arene oxides do not show a dynamic equilibrium with the oxepin valence tautomer. This is particularly true for the K-region arene oxides, which exist exclusively in the arene oxide forms. A number of oxepins exist only as such and do not show physical, spectroscopic, or chemical reactivities corresponding to the arene oxide form, e.g., 70,170,171, etc. Tautomeric behavior of some representative arene oxide-oxepin pairs is summarized in Table I.8... 

Comparison of the reactivities of benzene oxides, naphthalene oxides, phenanthrene oxides, and arene oxides derived from benzo [a] pyrene and 7,12-dimethylbenz[a] anthracene with hepatic glutathione S-epoxide transferase showed that benzene oxides without electron-withdrawing groups are poor substrates as also are polycyclic arene oxides. Only naphthalene oxide was a good substrate. 

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