Reduction of the nitro group to amine by hydroiodic acid to synthesize o-aminophenol derivatives as putative degradative markers of neuromelanin.

Kazumasa Wakamatsu,Makoto Ojika,Luigi Zecca,Fabio Zucca,Hitomi Tanaka,Keisuke Tabuchi,Shosuke Ito

doi:10.3390/molecules19068039

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 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.

Highlights

There are two chemically distinct types of peripheral melanins, black to brown pigments called eumelanin, and yellow to reddish-brown pigments called pheomelanin [1,2,3]
We developed a convenient reduction of the nitro group to amine with hydroiodic acid (HI) to synthesize o-aminophenol derivatives as putative degradative markers of human NM
The biosynthesis of NM, oxidative polymerization of catecholamines, suggests the possibility that various catecholic metabolites would participate in NM genesis (Scheme 1)

Summary

Introduction

There are two chemically distinct types of peripheral melanins, black to brown pigments called eumelanin, and yellow to reddish-brown pigments called pheomelanin [1,2,3]. The synthesis of NMs in the various regions of the human brain is an important protective process because the melanic components are generated through the removal of reactive or toxic o-quinones that would otherwise cause neurotoxicity. Another important aspect of the protective role of NM is the ability to bind toxic metals forming stable complexes thereby blocking their toxicity [10]. In cell culture and in vivo studies it was shown that human NM induces microglia activation and neuronal death [11,12,13,14]. In SN and LC, catecholamine neurons containing NM highly express major histocompatibility complex-I which triggers neuronal death mediated by cytotoxic T cells [15]

Methods

Results

Conclusion