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SYNTHESIS OF OPTICALLY ACTIVE TETRAMERIC MELANIN INTERMEDIATES BY OXIDATION OF THE MELANOGENIC PRECURSOR 5,6-DIHYDROXYINDOLE-2-CARBOXYLIC ACID UNDER BIOMIMETIC CONDITIONS
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New reaction pathways of dopamine under oxidative stress conditions: nonenzymatic iron-assisted conversion to norepinephrine and the neurotoxins 6-hydroxydopamine and 6,7-dihydroxyisoquinoline.
No full textAerial oxidation of dopamine at concentrations as low as 50 mu M in the presence of ferrous ions in phosphate buffer (pH 7.4) led in the early stages (6-8 h) to the formation of the quinone of the neurotoxin B-hydroxydopamine, 2, followed (24 h) by a complex product pattern comprising main components norepinephrine (5), 3,4-dihydroxybenzaldehyde (4), and the neurotoxic alkaloid 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (3). Product formation required the assistance of metal ions such as Mn(II), Zn(II), and iron, in either the ferrous or ferric form. Product yields were shown to vary linearly with iron and dopamine concentration in the early phases of the reaction (2 h). Biologically relevant antioxidants, like glutathione and ascorbate, and metal chelators, e.g., 2,2'-bipyridyl, inhibited dopamine conversion to products 2-5, but not substrate consumption, while hydroxyl radical scavengers such as DMSO and mannitol did not alter the course of the reaction. On the contrary, mannitol increased product yields, an effect seen for other monosaccharides. Catalase exhibited a significant inhibitory effect particularly on the formation of 3 and 4. By using O-18(2), evidence was obtained for incorporation of the label into the carbonyl oxygen of 4, but not into the hydroxyl group of 5. On the basis of these and other results, a complete mechanistic picture of the oxidation is drawn involving conversion of dopamine to the corresponding o-quinone and its quinonemethide tautomer with concomitant reduction of Oa to H2O2 Nucleophilic attack by H2O to the quinonemethide gives rise to 5, while H2O2 addition leads to benzaldehyde 4 via a beta-amino-hydroperoxide intermediate. This latter reaction path also gives formaldehyde which yields the isoquinoline 3 by Pictet-Spengler condensation with dopamine. The quinone 2 results from H2O2 attack at the 6-position of dopamine o-quinone in agreement with previous studies. These results provide an insight into new routes of nonenzymatic conversion of dopamine to its metabolite norepinephrine and neurotoxic species which may become operative under conditions relevant to neurodegeneration
Eumelanin: An Old Natural Pigment and a New Material for Organic Electronics–Chemical, Physical, and Structural Properties in Relation to Potential Applications
No full text6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinoline formation by iron mediated dopamine oxidation: a novel route to endogenous neurotoxins under oxidative stress conditions.
No full textAerobic oxidation of dopamine mediated by iron ions gives 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (2) and 3,4-dihydroxybenzaldehyde (4) in yields up to 10% and 15%, respectively. Based on C-13 labelling experiments, a reaction mechanism is proposed involving oxidative fission of the dopamine side chain to give 4 and formaldehyde, the latter giving 2 by Pictet-Spengler condensation with dopamine. This provides a novel route to endogenous generation of neurotoxic isoquinoline alkaloids under oxidative stress condition
Generation of the neurotoxin 6-hydroxydopamine by peroxidase/H2O2 oxidation of dopamine.
No full textAt physiological pH values, oxidation of the neurotransmitter dopamine (DA) by the peroxidase/H2O2 system leads to, besides dopaminochrome and 5,6-dihydroxyindole resulting from oxidative cyclization of dopaminequinone (DQ), significant amounts of the neurotoxin 6-hydroxydopamine (6-OHDA) in the oxidized quinonoid form (topaminequinone, TQ). Formation of TQ was shown to depend critically on the presence of hydrogen peroxide in the reaction medium and was not observed when DA oxidation was carried out using the tyrosinase/O2 system or chemical agents such as periodate or ferricyanide. These and other data suggest that, under the conditions adopted, nucleophilic attack of the hydrogen peroxide anion on DQ leading to TQ significantly competes with the intramolecular cyclization path. In line with this mechanism, the reaction course was not affected by the presence of hydroxyl radical scavengers. Peroxidase/H2O2 oxidation of the model N-acetyldopamine (1) gave, as expected, the 2-hydroxy-1,4-benzoquinone 3 in yields up to 55%, depending on the catecholamine/H2O2 mole ratio. Likewise, reaction of 4-methyl-1,2-benzoquinone (4) with hydrogen peroxide afforded 2-hydroxy-5-methyl-1,4-benzoquinone (5) in good yields. Collectively, these results would point to the possibility that intraneuronal formation of 6-OHDA is associated with an increased production of hydrogen peroxide under oxidative stress condition
Mass spectrometric behavior of 5-S-cysteinyldopa and structurally related phenolic compounds. Fragmentation susceptibility of the alkylthioether bond under electron impact and fast atom bombardment conditions
No full textThe marked proclivity of 5-S-cysteinyldopa (I) and related phenolic alkylthioethers to undergo UV-induced desulfurization via primary photohomolytic cleavage of the CH2-S bond prompted an investigation of the mass spectrometric behavior of these compds. with a view to obtaining information on the intrinsic susceptibility to dissocn. of the alkylthioether bond under nonirradiative conditions. Dealkylative fission of the CH2-S bond was an important dissociative channel in the fragmentation patterns of 1 and related compds., including cysteinylhydroquinone (II), 4-S-cysteaminylphenol (III) and 4-S-cysteaminylcatechol (IV) under electron impact conditions. The mode of fission and relative susceptibility of the CH2-S bond were, however, profoundly different in cysteaminyl vs. cysteinyl compds. In particular, the former showed a marked tendency to undergo simple homolytic fission, whereas in the latter dealkylative C-S bond cleavage occurred largely via an intramol. rearrangement mechanism, and proved highly sensitive to protonation-induced effects, as evidenced in fast atom bombardment expts. Desulfurization processes with neat loss of the alkylthio residue, like those occurring upon UV irradn., were virtually absent in the fragmentation patterns of III and IV, and provided only a minor contribution to those of I and II. These and other data reported open fresh prospects for future studies on the chem. and mass spectrometric behavior of I and structurally related phenolic compds. of biol. relevance
The First 5,6-Dihydroxyindole Tetramer by Oxidation of 5,5',6,6'-Tetrahydroxy- 2,4'-biindolyl and an Unexpected Issue of Positional Reactivity en Route to Eumelanin-Related Polymers.
No full textThe first tetramer of the eumelanin precursor 5,6-dihydroxyindole has been obtained, as the acetyl derivative, by peroxidase/H2O2-induced oxidative coupling of 5,5',6,6'-tetrahydroxy-2,4'-biindolyl (2) in the presence of Zn2+ ions. The tetramer, 5,5',5' ',5' '',6,6',6' ',6' ''-octaacetoxy-2,4':2',3' ':2' ',4' ''-tetraindolyl (acetylated 7), incorporates an unprecedented 2,3'-biindolyl substructure suggestive of a different positional reactivity of the 5,6-dihydroxyindole system when framed into a dimeric scaffol
Preparation and oxidation chemistry of the catechol estrogens:relevance to estrogen-related carcinogenesis and potential for drug design.
No full textIn this review we will briefly survey the oxidn. chem. of the catechol estrogens (2-hydroxy- and 4-hydroxyestradiol, 2-OH-E and 4-OH-E) as a result of the research carried out in the authors' lab. and other centers during the past decade. The central focus of the paper will be on the main pathways of oxidative modification and their possible relevance to the mechanisms of estrogen-related carcinogenesis. The chem. bases underlying the different reactivity and toxicity of 2-hydroxy and 4-hydroxyestradiol will be addressed. The value of catechol estrogen oxidn. in the discovery of novel functionalized or modified steroidal scaffolds of potential pharmaceutical interest will be also briefly highlighted
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