Catecholamine derivative, oxidation

Peroxynitrite (ONOO ) is a cytoxic species that is considered to form nitric oxide (NO) and superoxide (Oj ) in biological systems (Beckman et al. 1990). The toxicity of this compound is attributed to its ability to oxidize, nitrate, and hydroxylate biomolecules. Tyrosine is nitrated to form 3-nitrotyrosine (Ramazanian et al. 1996). Phenylalanine is hydroxylated to yield o-, m-, and p-tyrosines. Cysteine is oxidized to give cystine (Radi et al. 1991a). Glutathione is converted to S-nitro- or S-nitroso derivatives (Balazy et al. 1998). Catecholamines are oxidatively polymerized to melanin (Daveu et al. 1997). Lipids are also oxidized (Radi 1991b) and DNA can be scissored by peroxynitrite (Szabo and Ohshima 1997). 

The characteristic transient yellow-green fluorescence exhibited by adrenaline solutions that were undergoing oxidation in the presence of alkali was first reported in 1918.182 This phenomenon was later shown to be general, and similar (but usually weaker) fluorescences were observed when other catecholamines were oxidized in alkaline solution.133 Many years were to elapse before the correct explanation of this phenomenon was forthcoming, i.e. that the fluorescent product derived from adrenaline was a rearrangement product of adrenochrome (the red oxidation product of adrenaline). 

Spectrophotometric methods for the determination of catecholamine derivatives pyrocatechol, dopamine, levodopa, and methyldopa have been developed and applied to injections and tablets. One of the methods involves the oxidation of o-dihydroxy benzene derivatives by N-bromosuccinimide followed by oxidative coupling with isoniazide, leading to the formation of a red-colored product of maximum absorbance at 480-490 nm. 

The dioximato-manganese(II) catalyst (3) increases the auto-oxidation rate of epinephrine (a catecholamine derivative) in Na2C03-NaHC03 buffer at room temperature. The proposed mechanism presumes the binding of O2 to the Mn complex, followed by the formation of a ternary intermediate active catalyst-02-substrate complex which disproportionates in the rate-determining step to the product adrenochrome. ... 

The reactions leading to the formation of highly fluorescent products following the oxidation of catecholamines and condensation with ethylenediamine are very complex, and only the product from NA is shown in Figure 1. This method is more sensitive than the trihydroxyindole method, and the fluorescent products are more stable, but it is a far less specific assay procedure. Ethylenediamine will condense with many catechol compounds to yield fluorescent derivatives. It is, therefore, essential to employ a very rigorous procedure for the isolation of the amines prior to assay. When such a procedure is used, involving, for example, the separation of acetylated catecholamine derivatives by paper chromatography, the ethylenediamine method provides one of the most sensitive assay procedures for DA. 

Identification, isolation, and removal of (polyhydroxy)benzenes from the environment have received increased attention throughout the 1980s and 1990s. The biochemical activity of the benzenepolyols is at least in part based on thek oxidation—reduction potential. Many biochemical studies of these compounds have been made, eg, of enzymic glycoside formation, enzymic hydroxylation and oxidation, biological interactions with biochemically important compounds such as the catecholamines, and humic acid formation. The range of biochemical function of these compounds and thek derivatives is not yet fully understood. 

Dopamine, norepinephrine and epinephrine are products of the metabolism of dietary phenylalanine. This is an interesting sequence of reactions in that we will be discussing not only the three neurotransmitters formed but also considering the DOPA precursor and its use in the treatment of Parkinson s Disease. These molecules are also called catecholamines. Catechol is an ortho dihydroxyphenyl derivative. Degradation of the final product in the pathway, epinephrine, can be accomplished by oxidation (monoamine oxidase - MAO)or methylation (catecholamine 0-methyl transferase - COMT). The diagram on the next page illustrates the scheme of successive oxidations which produce the various catecholamines. 

It appears that the intermediates formed from different catecholamines are of different stability. The intermediate open-chain quinones derived from catecholamines with a primary amino group in the side chain do not appear to undergo intramolecular cyclization very readily and consequently would be able to take part in competing reactions this would account for the fact that in general it is difficult to obtain efficient conversions of such catecholamines (e.g. noradrenaline) into the corresponding aminochromes. This factor is important in catecholamine assay procedures (see Section V, E) and probably explains the wide variability in the apparent efficiency of the noradrenaline oxidation procedures used (as measured by the intensity of the fluorescence of the noradrenolutin obtained by the particular method). The fact that noradrenaline-quinone is relatively more stable than adrenaline-quinone accounts for the formation of entirely different types of fluorescent products from adrenaline and noradrenaline, respectively, in the Weil-Malherbe assay procedure for catecholamines (see Sections IV, H and V, E, 5). 

A combination of decarboxylation and hydroxyla-tion of the ring of tyrosine produces derivatives of o-dihydroxybenzene (catechol), which play important roles as neurotransmitters and are also precursors to melanin, the black pigment of skin and hair. Catecholamines may be formed by decarboxylation of tyrosine into tyramine (step e, Fig. 25-5) and subsequent oxidation. However, the quantitatively more important route is hydroxylation by the reduced pterin-dependent tyrosine hydroxylase (Chapter 18) to 3,4-dihydroxyphenylalanine, better known as dopa. The latter is decarboxylated to dopamine.1313 Hydroxylation of dopamine by an ascorbic acid and... 

Electrochemical oxidation of some catecholamines such as dopamine, L-dopa, and methyldopa has been studied using cyclic voltammetry. The catecholamines undergo intramolecular cyclization to form the corresponding o-quinone derivatives. The significant differences in the electrochemical behaviour of the catecholamines have been attributed to the effects of the side-chain carboxyl group.253 Electron-transfer reactions of 2,-deoxyguanosine-5,-monophosphate (dGMP) in phosphate buffers by cyclic... 

Dopaminergic neurons contain neuromelanin, a pigment composed of lipofus-cin along with a complex mixture of polymers of the various catecholamines, metal ions, cysteine, and possibly other substances (A4). This waste pigment is presumed to be derived from the oxidation of dopamine and other catecholamines to produce quinones, semiquinones, and quinhydrones, some of which undergo... 

Electrochemical detectors are based upon the volta-metric oxidation or reduction of separated analytes at a micro- or thin-film electrode. A number of pharmacologically active compounds that are aldehydes, ketones, or quinones (such as doxorubicin), or nitro compounds (such as nitrofurantoin) are amenable to reduction at a mercury or platinum electrode electron-rich indole derivatives and catecholamines can be oxidized at these electrodes. An important condition that must be fulfilled for electrochemical detection to be practicable is that the mobile phase must be capable of conducting an electrical current. This makes electrochemical detection particularly useful in reversed-phase liquid chromatography, where buffered water mixed with one or more organic cosolvents is usually the mobile phase. 

The initial attack in the anodic oxidation of papaverine [75] probably involves a similar attack further oxidation and dimerization leads to the isolated product, 12,12 -bis-(2,3,9,10-tetramethoxyindolo[2,l-fl]isoquinolyl). An analogous reaction is the electrooxidation of a tetramethoxy-substituted 2-methyl-l-phenethyl-l,2,3,4-tetrahydroisoquinoline to a dibenzoquinolizinium derivative [76] and the oxidation of A,A -triphenyl-( -phenyle-nediamine to 9,10-diphenylphenazine [77]. Intramolecular Michel addition of nitrogen in a tetrahydroquinoline derivative to an o-quinone moity have resulted in the formation of a 5,6-dihydrodibenz[6,d]indolizine derivative [78]. A similar ring closure occurs during the oxidation of various catecholamines [79] and similar compounds [79] to indoles. Cyclic a-carbonylazo compounds, generated by anodic oxidation of the hydrazines, may be trapped by reaction with dienes to the expected heterocycles [80]. 

Absorption spectra of phenoxyl radicals derived from biologically important molecules were recorded in numerous cases. The tyrosyl radical was studied by many investigators and its spectrum was used to detect tyrosine oxidation in a protein and to follow intramolecular electron transfer from tyrosine to the tryptophan radical in dipeptides and polypeptides . A number of catecholamines, such as adrenaline and dopa, were also studied by kinetic spectrophotometric pulse radiolysis " ". The absorption spectra of most of these substituted o-semiquinone anion were similar to those of the unsubstituted... 

A more recent application of oxime derivatives as prodrugs is the design of cascade prodmgs of dopamine agonists for the treatment of Parkinson s disease. As shown in Scheme 16, enones such as S-(-)-6-(Af,Af-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2//-naphthalen-l-one (103) can be oxidized in vivo to catecholamines... 

Fig. 48.6. Inactivation of catecholamines. Methylation and oxidation may occur in any order. Methylated and oxidized derivatives of norepinephrine and epinephrine are produced, and 3-methoxy-4-hydroxymandelic acid is the final product. These compounds are excreted in the urine. MAO = monoamine oxidase COMT = catechol 0-methyltransferase SAM = S-adenosyhnethionine SAH = S-adenosylhomocysteine.

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