4-hydroxyl-2-nonenal

Ty initiates melanin synthesis by the hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (Dopa) and the oxidation of dopa to dopaquinone. In the presence of L-cysteine, dopaquinone rapidly combines with the thiol group to form cysteinyldopas, which undergo nonen-zymatic conversion and polymerization to pheomelanin via benzothiazine intermediates. In the absence of thiol groups, dopaquinone very rapidly undergoes conversion to dopachrome, which is transformed to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) by dopachrome tautomerase. Alternatively, dopachrome is converted nonenzymatically to 5,6-dihydroxyindole (DHI). Oxidation of DHICA and DHI to the corresponding quinones and subsequent polymerization leads to eumelanins. It is still questionable if Ty is involved in this step. 

Protonation of the hydroxyl and trimethylsilyloxy groups of A and D, respectively, generates carbocations B and E. In B, attack of the methyl-substituted triple bond leads to formation of the preferred linear vinyl cation. Its trapping by the formate ion furnishes the substituted bicyclo[2.2.2]octene C. On the other hand, attack of the silicon-substituted triple bond in E occurs to form the silicon-stabilized p-carbocation, which, on trapping by formate ion, yields the substituted bicyclo[3.2.2]nonene F. 

Oliw, E.H., l.D. Brodowsky, L. Hornsten, and M. Hamberg (1993). Bis-allylic hydroxylation of polyunsaturated fatty acids by hepatic monooxygenases and its relation to the enzymatic and nonen-zymatic formation of conjugated hydroxy fatty acids. Arch. Biochem. Biophys. 300, 434-439. 

Several oxysterol classes present in oxLDL appear to be cytotoxic toward fibroblasts, ECs, and vascular smooth muscle cells, especially 7-hydroperoxycholes-terol (7-OOH-chol), 7P- and 7a-hydroxycholesterol (7-OH-chol), 7-ketocholesterol (7-keto-chol), and cholesterol epoxides (epoxy-chol). 7p-OOH-chol, a precursor of hydroxyl- and keto-oxysterols, was reported to be the most toxic. During LDL oxidation 7P-OOH-chol was produced in three to five times higher quantities than 7a-OOH-chol, other oxysterols and even hydroxy-nonenal, which is one of the most abundant lipid oxidation products. Cytotoxicity of oxysterols was connected to increased cellular oxidative stress. Some studies suggest that oxysterols are even involved in oxidative stress induction. Animal models indicate that dietary oxysterols can significantly decrease glutathione levels and increase expression of glutathione peroxidase and superoxide dismutase. In apolipoprotein-deficient mice, the NADPH-oxidase activity was induced by 7-keto-chol, 7p-OH-chol, and Sp,6P-epoxy-chol. The increased activity of NADPH oxidase yields more superoxide anions that amplify oxidative stress. 

FIGURE 16.2 Structures for 4-hydroxy-2-nonenal (HNE), 4-hydroxyl-2-hexenal (HHE), acrolein, and malondialdehyde, and methyl glyoxal. 

The nature of the dienophilic part of the molecule did not have any influence on the stereochemistry of the IMDA reaction. 27 was reacted with methoxyamine, and the terminal hydroxyl of the obtained oxime was oxidized to give an aldehyde function (Figure 10.). Chain extension of the latter with allylidenetriphenylphosphorane led to the formation of a mixture of four diastereomers of 34, i.e. E-syn, E-anti, Z-syn, Z-anti, respectively. A similar mixture has been obtained from 31 with methoxyamine. When the diastereomeric mixture of 34 was heated in toluene for 8 h the azabicyclo 4.3.0 nonene 35 diastereomer was formed exclusively. The conformation of this ring system is similar to that of 33 (30,31) (Figure 11.) as evidenced by 5 (6.5 Hz). 

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