Arene oxides of polycyclic aromatic hydrocarbons

Two comprehensive reviews of arene oxides-oxepins have been produced to date. The first review in 1967 dealt mainly with the concept of valence tautomerism in the monocyclic arene oxide-oxepin series, while the second article in 1973 also included the arene oxides of polycyclic aromatic hydrocarbons (PAH) and placed more emphasis upon their chemistry and biochemistry. In addition, a number of more speciahzed reviews dealing with aspects of arene oxide-oxepin chemistry including oxepins and hydrooxepins, solution chemistry, and roles in metabolism have appeared. The profusion of papers associated with the title arene oxides-oxepins that have appeared since 1973 (> 300 papers) allied to the significance of advances contained therein has prompted the present chapter. Particular stress is placed upon the material appearing during the period 1973-1982, with appropriate cross-references to the earlier literature. ... 

Figure 9. Structures of synthesized non-K-region arene oxides of polycyclic aromatic hydrocarbons. References to each synthesis are superscripted. See also Figure 2.

The primary goal of initial studies of the microsomal and purified epoxide-hydrolase catalyzed hydration of arene oxides of polycyclic aromatic hydrocarbons was an attempt to identify structure-activity relationships. To this end, some selected values for the hydration of a series of arene oxides are given in Table 2. One of the more obvious aspects of this study was that there is no apparent relation-... 

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]). 

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>. 

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,... 

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. 

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... 

C. Arene Oxides and Oxepins of Polycyclic Aromatic Hydrocarbons. 213... 

Synthesis and Reactivities of Aromatic Oxides. Certain optically active arene oxides, which are of biological significance as metabolites of polycyclic aromatic hydrocarbons (PAH), undergo spontaneous racemisation. The most plausible mechanism for this involves ring opening to the corresponding oxepins... 

For many years applications of the Bradsher reaction were restricted due to its limited substrate scope and requirement for harsh reaction conditions. However, after the advancement of the arene oxide concept concerning the metabolism of polycyclic aromatic hydrocarbons, synthesis of all the nuclear monohydroxylated derivatives of 7,12-dimethylbenz[a]-anthracene (DMBA), diol epoxide metabolites of DMBA, and fluoro derivatives of DMBA was undertaken for carcinogenicity and mutagenicity determination studies. " Interest in the Bradsher reaction has increased greatly as a consequence of the need to construct these polycyclic aromatic hydrocarbons. Development of fluoroanthracenylmethyl cinchonidine as an efficient phase-transfer catalyst for asymmetric glycine alkylation also expanded the scope of the Bradsher reaction. ... 

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... 

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. 

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... 

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- ... 

Arene oxides-1 The acetone-oxone system (11, 442) converts several polycyclic aromatic hydrocarbons into the K-region oxide, often in synthetically useful yield. Thus the 9,10-oxide of phenanthrene is formed with this system in 60% yield. 

In addition to the temperature, solvent, and substituent effects, a preference for either the arene oxide or oxepin form may be achieved by localization of one double bond as part of an aromatic ring system. Thus the reluctance to form a cyclobutadiene ring causes 10 to exist preponderantly as its oxide form. Naphthalene 1,2-oxide 11 is the simplest arene-oxide member in the polycyclic aromatic hydrocarbon (PAH) series and exists exclusively in that tautomeric form. In contrast, naphthalene 2,3-oxide exists exclusively as the oxepin form 12 since the C4-CS bond in the oxepin ring forms part of an aromatic ring. ... 

The simplest member of the polycyclic aromatic hydrocarbon (PAH) series, naphthalene, may in principle form four possible arene oxide-oxepin tautomeric pairs (A-D). In practice, the valence tautomers that have an intact aromatic-ring structure 11, 12, 100, 101 predominate. This discussion of arene oxide synthesis... 

Another carcinogenic polycyclic aromatic hydrocarbon, 7,l2-dimethylben/.lajanthracene. also forms covalent adducts with nucleic acids (RNA)."" The ultimate carcinogenic reactive species apparently is the S.6-oxidc that results from epoxidation of the 5,6-double bond in this aromatic hydrocarbon. The arene oxide intermediate binds covalently to guanosinc residues of RNA to yield the two adducts. 

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