Diol epoxides reactivity

The scope and direction of these biological investigations have been largely determined by the development of methods for the synthesis of the PAH metabolites. The diol epoxides are not isolable as products of metabolism due to their exceptional chemical reactivity. 

Both diastereomers are relatively reactive, complicating their isolation and purification. The half-lives of anti-and syn-BPDE in water at pH 7 are 2 hr and 30 min., respectively. Although they tend to decompose on chromatographic absorbants, these diol epoxides can be purified by rapid chromatography on low activity alumina columns or by HPLC in the presence of triethylamine as a stabilizer. 

Epoxidation of the 1,2- and 7,8-dihydrodiols of 5-MC with m-chloroperbenzoic acid furnished the corresponding anti diol epoxides 26 and J27. Compound 26 was the first diol epoxide bearing a methyl group in the same bay region as the epoxide function to be synthesized. While the diol epoxide 26 is relatively reactive (104), it is more stable than the structurally analogous DMBA 1,2-diol-3,4-epoxide (21) it was obtained as a white crystalline solid. 

Tetrahydroepoxides as models. Since the quantum chemical calculations apply most rigorously to the simple benzo-ring tetrahydroepoxides and since the calculations neglect influences of the hydroxyl groups in the diol epoxides, it is instructive first to examine the benzo-ring tetrahydroepoxides as simplified models for the reactive site in the diol epoxides. Most of the information about tetrahydroepoxide reactivity derives from studies of the kinetics of their hydrolysis reactions, in which cis- and trans-diols, as well as tetrahydroketones can be formed (Equation 5). 

For the alternant PAH that have been studied extensively, bay-region diol epoxides are important metabolically activated forms. Studies of the chemical and biological activity of a variety of diol epoxides have provided insight into the factors related to reactivity and biological activity. Chemical reactivity, as measured by spontaneous hydrolysis, correlated well with calculated quantum chemical parameters that estimate ir-electron stabilization upon conversion of the epoxide to a benzylic carbocation, provided... 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

These results can now be used to consider what happens when a diol epoxide attacks DNA. The epoxide group will open and trans addition will occur. The product (XXVI) will have the DNA substituted adjacent to the bay region (particularly if it is hindered so that the epoxide group is made more reactive) and will lie axial to the PAH ring system. This means that the plane of the PAH and the alkylated base of DNA must have a perpendicular relationship to each other as indicated in Figure 19. In this Figure those sites in... 

Methylated derivatives of 7-methylB[a]A are particularly carcinogenic when substitutes in the 7-, 12-, or 6- and 8-positions (152,153). The increased carcinogenicity of these compounds may result from the inhibition of metabolism at the 8-11 positions which increases the amounts of bay region diol epoxides formed, the greater reactivity of such epoxides with DNA, or an intrinsic difficulty for cells to repair such adducts (154). 

This procarcinogen undergoes metabolic conversion to benzo[a]pyrene diol epoxides, BPDEs (5,28-31), which have been the focus of structural and conformational studies by theoretical and experimental methods. These chemically reactive BPDEs are involved in covalent binding to DNA (13-22). 

Model computational studies aimed at understanding structure-reactivity relationships and substituent effects on carbocation stability for aza-PAHs derivatives were performed by density functional theory (DFT). Comparisons were made with the biological activity data when available. Protonation of the epoxides and diol epoxides, and subsequent epoxide ring opening reactions were analyzed for several families of compounds. Bay-region carbocations were formed via the O-protonated epoxides in barrierless processes. Relative carbocation stabilities were determined in the gas phase and in water as solvent (by the PCM method). 

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

This chapter begins, thus, with a short introduction to the chemical reactivity of epoxides. We continue with a description of the epoxides hydrolases and their biochemistry, and devote most of its length to a systematic discussion of the substrates hydrated by these enzymes. Arene oxides and diol epoxides will be presented first, followed by a large variety of alkene and cy-cloalkene oxides. 

Fig. 10.14. Reactivity ofdiol epoxides (Nu = H20, HCT, or another nucleophile), a) Hydrolytic reaction of diol epoxides to tetrols. b) Internal H-bonding in diol epoxides with syw-config-uration and rendering the distal C-atom more electrophilic (modified from [104]). c) General representation of proton-catalyzed (A-H = H+), general acid catalyzed (A-H = acid), or intra-molecularly catalyzed (A-H = syn-OW group) activation of the distal C-atom toward... 

The high reactivity of bay-region (and fjord-region) diol epoxides has intrigued chemists for years. Numerous experimental and computational studies have been carried out, affording a wealth of information on the mechanisms by which bay-region diol epoxides form adducts with nucleic acids and are deactivated by reaction with protective nucleophiles or by hydrolysis. Indeed, the hydration of diol epoxides forms unreactive tetrahydroxy metabolites known as tetrols (10.39, Fig. 10.14,a). 

Hulbert published a landmark paper [104], in which he reasoned that diol epoxides should react with nucleophiles as carbonium ions. Although bay-region diol epoxides were not specifically considered in this hypothesis paper, the essence of the argument was that diol epoxides with yyn-con figuration (see Fig. 10.13) should be more reactive than their anti-stereoisomers since... 

Further studies that demonstrate that hydration of bay-region diol epoxides under acidic conditions can occur by general acid catalysis in addition to proton catalysis have expanded our understanding of their reactivity. General acid catalyzed hydration involves H-bonding of the epoxide O-atom by the acid catalyst, followed by nucleophilic attack of the distal C-atom by H20/H0 [108][109],... 

In conclusion, it is clear that a variety of stereoelectronic (internal) factors and external conditions favor a substantial positive charge in the transition state of diol epoxides as they undergo hydration or react with nucleophiles [115-118], Interpreting the reactivity of diol epoxides (or of numerous other electrophilic metabolites) in terms of toxification vs. detoxification is particularly difficult since toxicity depends as much on the nature of the endogenous nucleophile as on the intrinsic reactivity of the metabolites. 

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. 

L. Lewis-Bevan, S. B. Little, J. R. Rabinowitz, Quantum Mechanical Studies of the Structure and Reactivities of the Diol Epoxides of Benzo[c]phenanthrene , Chem. Res. Toxicol. 1995, 8, 499 - 505. 

Although dihydrodiols are readily excreted, in general, it is now clear that diol-epoxides are formed and that these highly reactive intermediates may be important in mutagenicity, tumorigenesis, toxicity, and birth defects. Diols can therefore imdergo further Goxygenations (Thble 5.3). 

The diol-epoxide contains a reactive carbon center, namely the C-10 position, which can open to form a carbonium ion that is susceptible to nucleophilic attack (Scheme 3.4). The predominant nucleophile among DNA bases is guanine, which preferentially interacts with the carbonium ion at the N2-amine position of guanine to form the BaP-N 2-guanine adduct. The epoxide bond of the diol-epoxide metabolite is particularly resistant to hydrolysis because it is located in the Bay region of the BaP molecule, where steric hindrance prevents the attack of hydrolytic enzymes, such as epoxide hydrolase. 

Figure 7.2 The metabolic activation of benzo[a]pyrene by cytochrome P-450 1A1 to a diol epoxide metabolite, a mutagen. This is believed to be the ultimate carcinogenic metabolite. Other routes of metabolism also catalyzed by cytochrome P-450 give rise to the 9,10, and 4,5 oxides and subsequent metabolites namely phenols, diols, and glutathione conjugates. The reactive site (carbon atom) on the metabolite is indicated.

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