Reduction of the Nitro Group to Amine by Hydroiodic Acid to Synthesize o-Aminophenol Derivatives as Putative Degradative Markers of Neuromelanin

Abstract

Neuromelanin (NM) is produced in dopaminergic neurons of the substantia nigra (SN) and in noradrenergic neurons of the locus coeruleus (LC). The synthesis of NM in those neurons is a component of brain aging and there is the evidence that this pigment can be involved in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. NM is believed to derive from the oxidative polymerization of dopamine (DA) or norepinephrine (NE) with the participation of cysteine, dolichols and proteins. However, there are still unknown aspects in the chemical structure of NM from SN (SN-NM) and LC (LC-NM). In this study, we designed a new method to synthesize o-aminophenol compounds as putative degradation products of catecholamines and their metabolites which may be incorporated into NM. Those compounds are aminohydroxyphenylethylamine (AHPEA) isomers, aminohydroxyphenylacetic acid (AHPAA) isomers and aminohydroxyethylbenzene (AHEB) isomers, which are expected to arise from DA or NE, 3,4-dihydroxyphenylacetic acid (DOPAC) or 3,4-dihydroxyphenylmandelic acid (DOMA) and 3,4-dihydroxyphenylethanol (DOPE) or 3,4-dihydroxyphenylethyleneglycol (DOPEG), respectively. These o-aminophenol OPEN ACCESSMolecules 2014, 19 8040 compounds were synthesized by the nitration of phenol derivatives followed by reduction with hydroiodic acid (HI), and they could be identified by HPLC in HI hydrolysates of SN-NM and LC-NM. This degradative approach by HI hydrolysis allows the identification of catecholic precursors unique to SN-NM and LC-NM, which are present in catecholaminergic neurons.

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

“…Other enzymes than tyrosinase might be involved in NM biosynthesis (as discussed in chapter 3), but to date a specific enzymatic synthesis pathway for NM has not been unequivocally proven; additionally, the existence of an auto-oxidation process of catecholamines must be also taken into account for NM biosynthesis (Zucca et al, 2014). The substrate principally involved in the oxidative polymerization is either DA, in the SN and most other brain areas, or norepinephrine in the LC, although different catecholamines seem to be involved in the synthesis of human NM pigment (Wakamatsu et al, 2014; Zecca et al, 2008b). In this NM pigment, the melanic groups are covalently bound to aliphatic chains and peptides moieties (Engelen et al, 2012); dolichols and dolichoic acid were identified as the major components of NM lipids (Fedorow et al, 2005; Ward et al, 2007; Zecca et al, 2000, 2008b).…”

“…A variety of phenolic precursors can be used for the preparation of pheomelanins and eumelanins: L-tyrosine, L-DOPA, DA or norepinephrine (d’Ischia et al, 2013; Manini et al, 2007). To resemble NM from human SN, the precursor of choice is DA, since chemical degradative analyses demonstrated that NM from human SN mainly consists of DA-derived and cysteinyl-DA-derived units (Wakamatsu et al, 2003), although other catecholamines may participate in its synthesis (Wakamatsu et al, 2014). Notably, in vitro experiments confirmed that DA (derived from L-DOPA) is likely the most important precursor in NM biosynthesis (Sulzer et al, 2000).…”

Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen

“…Bestätigt wird dies durch die CID/MS-Analyse eines Melanin-Myoglobin-Präzipitats,indem das Peptid 80-96 durch 5D A-Einheiten im His 81/His 82-Cluster und durch 4D A-Einheiten bei His 93 (dem proximalen Hämliganden;d ie Zahlen beziehen sich auf die Pferdeherz-Sequenz) modifiziert war. [163] Eisen spielt eine Rolle dabei, die cytosolische DA-Oxidation in Gang zu bringen, und bleibt in der Melaninfraktion durch Chelatbildung mit dem Netzwerk der Catecholgruppen im Melaninpolymer gefangen. In Schema 7i st der konkurrierende Reaktionspfad zu DA-Melanin (Eumelanin) ebenfalls dargestellt.…”

“…[24,27,159] Chemische Abbaustudien von NM-Pigment der SN mit H 2 O 2 ,H I und HCl lieferten Produkte,d ie typisch fürd en Cys-DA-Melanin-, den DA-Melanin-und den proteingebundenen DA-Melanin-Abbau sind. [27,163,166,167] [27,162] Sollte sich dies bestätigen, nehmen wir an, dass ein noch unbekannter,u nstrukturierter Eumelanintyp im humanen NM vorkommt.…”

Effect of Buffer Capacity and Ascorbic Acid on the Cyclization Reaction of Electrochemically Oxidized Dopamine, Levodopa, and Adrenaline on the Glassy Carbon Electrode

“…17 Moreover, NM is derived not only from DA but also from several catecholamines, such as levodopa (L-D) and adrenaline (AD). 19 The results indicated that the aforementioned catecholamines are transformed into NM after the cyclization reaction.Evidently, the intramolecular cyclization step would be vital for the formation of NM. The cyclization reaction of oxidized catecholamines is strongly dependent on the pH of the solution because the positive charge degree of the amine group depends on the pH of the solution.…”