Epoxides covalent activation

TNT increases UDPglucuronsyltransferase in the liver and kidneys. It increases renal epoxide hydrolase activity. Animal studies have suggested covalent binding between TNT and macromolecular proteins including serum albumin, hemoglobin (Hb), hepatic and renal proteins, and possibly lens protein. The Hb adduct was dose dependent. Macromolecular binding is likely to be correlated with toxic effects ... 

The mechanism of the a,a-L-diarylprolinol-catalysed asymmetric epoxidation of enones with TBHP has been studied by second-order Moller-Plesset perturbation theory and DFT calculations. Non-covalent activation of the reactants is shown to initiate an energetically viable pathway, thereby a two-step nucleophilic epoxidation mechanism, with the first oxa-Michael addition being the rate- and stereoselectivity-determining step. Consistent with the experimental findings, the formation of the (2/ ,35)-enantiomer of the epoxide, derived from trani -chalcone, is energetically favoured." ... 

Scheme 10.8 Biosynthesis of epothilone. Individual PKS domains are represented as circles and individual NRPS domains as hexagons. Acyl carrier proteins (ACPs) and thiola-tion domains (T) are posttranslationally modified by a phos-phopantetheinyl group to which the biosynthetic intermediates are covalently bound throughout the chain assembly. The thioesterase domain (TE) cyclizes the fully assembled carbon chain to give the 16-membered lactone. Following dehydration of Cl 2—Cl 3 to give epothilones C and D, the final step in epothilone biosynthesis is the epoxidation of the C12=C13 double bond by the cytochrome P450 enzyme P450epol<. KS ketosyn-thase KS(Y) active-site tyrosine mutant of KS AT acyltransfer-ase C condensation domain A adenylation domain ...

Very few examples have been described for the non-covalent immobilization of chiral porphyrin complexes (Fig. 26). In the first case, the porphyrin-dichlororutheninm complex was encapsulated in silica, which was prepared around the complex by a sol-gel method [78], in an attempt to prevent deactivation observed in solution in the epoxidation of different alkenes with 2,6-dichloropyridine N-oxide. In fact, the heterogeneous catalyst is much more active, with TON up to 10 800 in the case of styrene compared to a maximum of 2190 in solution. Enantioselectivities were about the same imder both sets of conditions, with values aroimd 70% ee. 

The first disclosed natural product was cerulenin (15), an irreversible inhibitor of FabB. This hydrophobic epoxide locates itself in the hydro-phobic groove of the acyl site and reacts covalently with the active site cysteine [26]. However, 15 was also found to inhibit eukaryotic fatty acid synthase. 

Recent advances in PAH carcinogenesis research over the past decade have led to identification of diol epoxide metabolites as the principal active forms of the PAH investigated to date Q,2). Benzo-(a)pyrene (BP) has been most intensively investigated, and it has been demonstrated that a diol epoxide metabolite anti-BPDE is the active intermediate which binds covalently to DNA in human and other mammalian tissues 0,4). Anti-BPDE was also demonstrated to be a powerful mutagen in both bacterial and mammalian cells (15) These findings stimulated an outpouring of research directed towards elucidation of the molecular mechanism of PAH carcinogenesis. 

The diol epoxide derivative of benzo(a)pyrene, trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene also known as (+) -73,8a-dihydroxy-9ot,10a-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene,was the first diol epoxide to be synthesized. Interest in this compound was stimulated by the report by Borgen et al. (8) that a metabolite of benzo(a)pyrene, tentatively identified as the trans-7,8-diol ( 1) became covalently bound to DNA in the presence of rat liver micro-somes. Sims et al. ( ) suggested that the active metabolite was a diol epoxide derivative of unspecified stereo chemistry. 

The existence of isomeric polycyclic aromatic diol epoxide compounds provides rich opportunities for attempting to correlate biological activities with the physico-chemical reaction mechanisms, and conformational and biochemical properties of the covalent DNA adduct8 which are formed. 

So we are still left with two models of the stereochemistry of DNA alkylated by a PAH diol epoxide the PAH either lies in a groove of DNA or else tries to intercalate between the bass of DNA. Since it is covalently bonded to a base it must cause considerable distortion if it tries to lie between the bases. However, the stacking observed in the crystalline state seems to argue for partial intercalation. We will need crystal structures of at least one appropriately alkylated polynucleotide before this problem can be resolved. And when this is done it will be just the beginning of the answer to the problem of alkylation of DNA by activated carcinogens. The subsequent question is, what is the lesion in DNA that is important in carcinogenesis, and then what does it cause to happen so that tumor formation is initiated ... 

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. 

Suicide or irreversible inhibitors of GST Pl-1 include agents that bind covalently to glutathione, thereby forming thioether adducts that are stabilized at the active site of the enzyme. These agents include activated aromatic systems (2, 3), epoxides (4, 5), esters (6), and Michael acceptors such as ethacrynic acid (7), cycloalkenones (8, 9), and haloenol lactones (10-13), among others [3,48,54-57],... 

A very successful example for the use of dendritic polymeric supports in asymmetric synthesis was recently described by Breinbauer and Jacobsen [76]. PA-MAM-dendrimers with [Co(salen)]complexes were used for the hydrolytic kinetic resolution (HKR) of terminal epoxides. For such asymmetric ring opening reactions catalyzed by [Co(salen)]complexes, the proposed mechanism involves cooperative, bimetallic catalysis. For the study of this hypothesis, PAMAM dendrimers of different generation [G1-G3] were derivatized with a covalent salen Hgand through an amide bond (Fig. 7.22). The separation was achieved by precipitation and SEC. The catalytically active [Co "(salen)]dendrimer was subsequently obtained by quantitative oxidation with elemental iodine (Fig. 7.22). 

Baleizao, C. Gigante, B. Sabater, M. J. Garcia, H. Corma, A. (2002) On the activity of chiral chromium salen complexes covalently bound to solid silicates for the enantioselective epoxide ring o emag Applied Catalysis A General 228 279-288. 

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