Peroxidation-Derived Adducts

Table 5.1 Mutations induced by peroxidation-derived adducts in site-specific mutagenesis experiments. 

Reactive aldehydes derived from lipid peroxidation, which are able to bind to several amino acid residues, are also capable of generating novel amino acid oxidation products. By means of specific polyclonal or monoclonal antibodies, the occurrence of malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) bound to cellular protein has been shown. Lysine modification by lipid peroxidation products (linoleic hydroperoxide) can yield neo-antigenic determinants such as N-c-hexanoyl lysine. Both histidine and lysine are nucleophilic amino acids and therefore vulnerable to modification by lipid peroxidation-derived electrophiles, such as 2-alkenals, 4-hydroxy-2-alkenals, and ketoaldehydes, derived from lipid peroxidation. Histidine shows specific reactivity toward 2-alkenals and 4-hydroxy-2-alkenals, whereas lysine is an ubiquitous target of aldehydes, generating various types of adducts. Covalent binding of reactive aldehydes to histidine and lysine is associated with the appearance of carbonyl reactivity and antigenicity of proteins [125]. 

Figure 2.8 Lipid peroxidation-derived etheno adducts.

Nair, J., De Flora, S., Izzotti, A., and Bartsch, H. (2007) lipid peroxidation-derived etheno-DNA adducts in human atherosclerotic lesions. Mutat. Res., 621, 95-105. 

Bartsch, H. and Nair, J., Potential role of lipid peroxidation derived DNA damage in human colon carcinogenesis studies on exocyclic base adducts as stable oxidative stress markers. Cancer Detection Prev., 26, 308-312, 2002. 

This chapter summarizes the state of knowledge abont protein lipoxidation, focusing on the chemistry of lipid peroxidation-derived aldehydes and their adducts with amino acid residnes. In addition, the recent findings on ligand function of lipoxidation products are also reviewed. 

At low temperature a 1 1 adduct of thioacetic acid and an enamine could be prepared (709). The previously described reaction of aminomethylene ketones with hydrogen peroxide was extended to bisaminomethylene compounds. However, acylated cyclohexenamines led to cyclopentane-carboxamides (770), Trichloromethyl adducts of enamines and the rearranged amine derivatives were described in a further study (777). 

With the above procedure, dienoic fatty acid peroxidation products yield a conjugated triene chromophore with second-derivative absorption minima iocated at 258, 269.5 and 281 nm, whilst trienoic fatty-acid peroxidation products give rise to a conjugated tetraene chromophore with minima at 278, 289, 303 and 318 nm. The arrows in (c) denote second-derivative absorption minima corresponding to the conjugated triene adduct arising from linoleate-derived peroxidation products (conjugated hydroperoxydienes, hydroxydienes and oxodienes). 

In case of scavenging of lipid-derived peroxyl radicals (LOO"), the radical adduct formed [LOO-CaiT is less reactive than the LOO, so carotenoids act as chain-breaking antioxidants in lipid peroxidation (Equation 15.6) ... 

The fused heterocycles 58 have been synthesized via cycloaddition of 1-phenylisobenzofuran 467 (prepared in situ from 466) and methyl a-phenylselenoacrylate. The cycloaddition was carried out in toluene at 80 °C for 2 h to give adduct 468. Hydrogen peroxide on reaction with 468 at —40 °C provided product 469. The [3+2] cycloaddition between 469 and an amine-derived dipole has been accomplished under acidic conditions <1985CPB2762> to provide the heterocycle 58 as a single diastereomer (Scheme 105) <20000L923>. 

Two types of addition to pyrimidine bases appear to exist. The first, the formation of pyrimidine photohydrates, has been the subject of a detailed review.251 Results suggest that two reactive species may be involved in the photohydration of 1,3-dimethyluracil.252 A recent example of this type of addition is to be found in 6-azacytosine (308) which forms a photohydration product (309) analogous to that found in cytosine.253 The second type of addition proceeds via radical intermediates and is illustrated by the addition of propan-2-ol to the trimethylcytosine 310 to give the alcohol 311 and the dihydro derivative 312.254 The same adduct is formed by a di-tert-butyl peroxide-initiated free radical reaction. Numerous other photoreactions involving the formation by hydrogen abstraction of hydroxyalkyl radicals and their subsequent addition to heterocycles have been reported. Systems studied include 3-aminopyrido[4,3-c]us-triazine,255 02,2 -anhydrouri-dine,256 and sym-triazolo[4,3-fe]pyridazine.257 The photoaddition of alcohols to purines is also a well-documented transformation. The stereospecific addition of methanol to the purine 313, for example, is an important step in the synthesis of coformycin.258 These reactions are frequently more... 

See also Acetoacetyl-CoA in citric acid cycle, 6 633 Acetyl cyclohexanesulfonyl peroxide (ACSP), 74 282 78 478 Acetylene(s), 7 177-227, 227-228 25 633 addition of hydrogen chloride to, 73 821 from calcium carbide, 4 532, 548 carbometalation of, 25 117 as catalyst poison, 5 257t chemicals derived from, 7 227-265 decomposition of, 70 614 Diels-Alder adduct from cyclopentadiene, 8 222t direct polymerization, 7 514 economic aspects of, 7 216-217 explosive behavior of, 7 181-187 as fuel, 7 221-222 health and safety factors related to, 7 219... 

Anderson, L. R. et al., J. Fluorine Chem., 1976, 7, 481-500 Five derivatives, including the 0-0 lithium or sodium salts of the hydrogen peroxide adduct of hexafluoroacetone (2-hydroxyhexafluoro-2-propyl hydroperoxide), and their reaction products with acyl halides, are less flammable or explosive than their hydrocarbon analogues, though less stable than the parent hydroperoxides. Relevant entries are ... 

The addition of allylic boron reagents to carbonyl compounds first leads to homoallylic alcohol derivatives 36 or 37 that contain a covalent B-O bond (Eqs. 46 and 47). These adducts must be cleaved at the end of the reaction to isolate the free alcohol product from the reaction mixture. To cleave the covalent B-0 bond in these intermediates, a hydrolytic or oxidative work-up is required. For additions of allylic boranes, an oxidative work-up of the borinic ester intermediate 36 (R = alkyl) with basic hydrogen peroxide is preferred. For additions of allylic boronate derivatives, a simpler hydrolysis (acidic or basic) or triethanolamine exchange is generally performed as a means to cleave the borate intermediate 37 (Y = O-alkyl). The facility with which the borate ester is hydrolyzed depends primarily on the size of the substituents, but this operation is usually straightforward. For sensitive carbonyl substrates, the choice of allylic derivative, borane or boronate, may thus be dictated by the particular work-up conditions required. 

A recently proposed explanation of PD involves the formation of adducts between dopamine and the products of the peroxidation of arachidonic acid and docosahexanoic acid (Liu et ah, 2008b). At least two compounds, hexanoyl-dopamine and propanoyl-dopamine, derived... 

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