Adrenaline quinone

Seven years previously S. Weinstein and R. J. Manning Proc. Soc. Exptl. Biol. Med. 32, 1096 (1935)] had obtained a red crystalline product from the oxidation of adrenaline by silver oxide, but they erroneously described it as the hypothetical adrenaline-quinone. 

In summary, it would appear that the oxidation of a catecholamine probably first involves the formation of a semi-quinone radical (this can be brought about by an one-electron transfer, e.g. from Cu++ ions,14 or by photoactivation 1) which rapidly undergoes further oxidation (e.g. with atmospheric oxygen) to an intermediate open-chain quinone (such as adrenaline-quinone) and then cyclizes by an oxidative nucleophilic intramolecular substitution to the amino-chrome molecule. Whilst the initial formation of a leucoaminochrome by non-oxidative cyclization of the intermediate open-chain quinone in some cases cannot be entirely excluded at the moment (cf. Raper s original scheme for aminochrome formation72), the... 

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). 

B. At pH 3.0, though, deprotonation of the conjugate acid of adrenaline-quinone (Eq. 21.10) and the subsequent cyclization of the unprotonated form of adrenalinequinone (Eq. 21.11) become important. 

Because the product of these reactions, leucoadrenochrome, is more readily oxidized than adrenaline, a homogeneous electron transfer reaction (Eq. 21.12) involving leucoadrenochrome and unreacted adrenaline-quinone ensues. In addition to the formation of adrenochrome as the final product, adrenaline is regenerated by the solution redox reaction. The reader should be satisfied that the overall transformation of adrenaline to adrenochrome requires four electrons. 

An oxidatively induced ring closure occurs during the oxidation of various catecholamines (33)72 at a carbon paste electrode. Whereas the oxidation in 1 M H2SO4 yielded the 1,2-benzoquinone (34), sufficient free amine of 34 was present at pH 3 to allow an internal Michael addition of the adrenaline quinone. As would be expected, the resulting catechol (35) is more easily oxidizable than adrenaline and is converted into the quinone adrenochrome (36) by chemical oxidation by adrenaline quinone. 

The oxidation of a number of catecholamines including adrenaline, noradrenaline, a-methylnoiadrenaline, dopamine and isoprenaline has been studied by electrochemical techniques [106, 107]. In 1 m sulphuric acid, adrenaline was reversibly oxidised to adrenaline quinone (43) and it was shown by cyclic voltammetry that under these conditions negligible cyclisation to adrenochrome occurred [106]. At pH 3, however, there was considerable cyclisation, and, as well as the adrenaline-adrenaline quinone (43) couple, the leucoadrenochrome (13)-adrenochrome and the 5,6-dihydroxy-A-methyl-indole (44)-A-methylindole-5,6-quinone (45) couples could be detected and... 

The experimental observations were interpreted by assuming that the redox cycle starts with the formation of a complex between the catalyst and the substrate. This species undergoes intramolecular two-electron transfer and produces vanadium(II) and the quinone form of adrenaline. The organic intermediate rearranges into leucoadrenochrome which is oxidized to the final product also in a two-electron redox step. The +2 oxidation state of vanadium is stabilized by complex formation with the substrate. Subsequent reactions include the autoxidation of the V(II) complex to the product as well as the formation of aVOV4+ intermediate which is reoxidized to V02+ by dioxygen. These reactions also produce H2O2. The model also takes into account the rapidly established equilibria between different vanadium-substrate complexes which react with 02 at different rates. The concentration and pH dependencies of the reaction rate provided evidence for the formation of a V(C-RH)3 complex in which the formal oxidation state of vanadium is +4. 

Studies of the oxidation products of catecholamines (i.e., seretonin, dopamine, dopa, adrenaline, and noradrenaline) have indicated that protein oxidation by quinones may lead to apoptosis. Oxidation results in formation of orrto-quinones, which contribute to cytotoxicity and have been suggested... 

Note that the anodic peak due to the oxidation of leucoadrenochrome to adrenochrome near 0 V is not seen until the second positive-going potential sweep is made. The voltage separation between the anodic and cathodic peaks for the oxidation of adrenaline (peak B, Fig. 21.4, bottom) and the reduction of adrenalinequinone (peak C) is large when compared to most chemically reversible redox couples. However, this behavior is typical of many quinone-hydroquinone systems on a carbon paste surface at intermediate values of pH. 

The API epinephrine is an o-diphenol containing a hydroxyl group in the a-position that is easily oxidized by molecular oxygen (Fig. 87). Oxidation is proposed to occur through the transient formation of epinephrine quinone with subsequent formation of adrenochrome (126). This class of compounds (the adrenergics, including adrenaline and isoprenaline) also undergoes this reaction to the adrenochrome upon irradiation in aqueous solution (127). 

Several publications on electrochemical mechanistic studies of the oxidative transformations of catecholamines followed the contribution by R. N. Adam s group (256) and involved a-methyldopamine, a-methylnor-adrenaline, dopamine (257), a-methyldopa, 5,6-dihydroxy-2-methylin-dole (255), and dopa (259). These studies (257) (Scheme 5), which confirmed the validity of the melanization scheme by Mason and Raper (Ref. 7, p. 50), explored the pH effect on the sequence of events that characterize the electrooxidation of catecholamines. Thus, the cyclic voltammogram in I M HCIO4 (pH 0.6) shows only peaks corresponding to the catechol-quinone redox couple as the protonation of the amino group prevents the cyclization step. 

Oxidation mechanism of adrenaline and its cyclic derivatives by the system GSNO/CUSO4 in aerobic conditions. RH2, RH, and R indicate the o-diphenol, semiquinone, and o-quinone forms of adrenaline and its cyclic derivatives (leucoadrenochrome and adrenolutin), respectively, (from Rigobello eta 1.2001)... 

Adrenochrome is produced from adrenaline, noradrenochrome from noradrenaline, and products similar to quinone, which have not yet been clearly defined, derive from serotonin and bufotenin. Cytochromoxidase and ceruloplasmine are the catalysing enzymes. So far... 

Adrenochrome (1), the red oxidation product of adrenaline (2) is the best known member of the family of red to violet coloured indoline-5,6-quinones, known as the aminochromes [1], which are readily obtained on oxidation of the corresponding catecholamines. 

Harrison and Whisler have studied the mushroom tyrosinase catalysed oxidations of a number of catecholamines using fluorescence spectroscopy and tritium tracer techniques [44, 52, 53], The oxidation of adrenaline and noradrenaline to the open-chain quinone (12) was monitored by the loss of the native fluorescence of the substrate [44], The cyclisation step for this... 

On irradiation with ultraviolet light, tyrosine is readily converted to DOPA, which is then oxidised further, probably to dopachrome and then to melanin [29, 85-88]. Synephrine (41) behaves similarly, being oxidised first to adrenaline and then probably to adrenochrome which rearranges to adrenolutin [89]. These oxidations probably involved the initial formation of the semi-quinone followed by oxidation to the open-chain quinone [90]. Ultraviolet irradiation was also found to increase the rate of oxidation of tyrosine by tyrosinase in rat skin. OrrAo-quinones were produced in the reaction and it was concluded that the acceleration was due to the formation of low levels of these compounds from tyrosine [91]. 

Ukhin LY, Suponitsky KY, Shepelenko EN, Belousova LV, Borodkin GS (2012) Novel synthesis of oxonine derivatives from 3-[(2-aminophenyl)amino]-5,5-dimethyl-2-cyclohexene-l-one and o-quinones. Tetrahedron Lett 53(l) 67-70. doi 10.1016/j.tetlet.2011.10.147 Vachon J, Harthong S, Dubessy B, Dutasta JP, Vanthuyne N, Roussel C, Naubron JV (2010) The absolute configuration of an inherendy chiral phosphonatocavitand and its use toward the enantioselective recognition of L-adrenaline. Tetrahedron Asymm 21(11-12) 1534—1541. doi 10.1016/j.tetasy.2010.03.028... 

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