scholarly journals Oxidative Transformations of 3,4-Dihydroxyphenylacetaldehyde Generate Potential Reactive Intermediates as Causative Agents for Its Neurotoxicity

2021 ◽  
Vol 22 (21) ◽  
pp. 11751
Author(s):  
Shosuke Ito ◽  
Hitomi Tanaka ◽  
Makoto Ojika ◽  
Kazumasa Wakamatsu ◽  
Manickam Sugumaran
Keyword(s):  
Oxidation Product ◽  
Oxidation Reaction ◽  
Reactive Intermediates ◽  
Quinone Methide ◽  
Toxic Metabolite ◽  
Mushroom Tyrosinase ◽  
Toxic Compounds ◽  
Causative Agents ◽  
Oxidative Transformations ◽  
Aldehyde Groups

Neurogenerative diseases, such as Parkinson’s disease, are associated, not only with the selective loss of dopamine (DA), but also with the accumulation of reactive catechol-aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is formed as the immediate oxidation product of cytoplasmic DA by monoamine oxidase. DOPAL is well known to exhibit toxic effects on neuronal cells. Both catecholic and aldehyde groups seem to be associated with the neurotoxicity of DOPAL. However, the exact cause of toxicity caused by this compound remains unknown. Since the reactivity of DOPAL could be attributed to its immediate oxidation product, DOPAL-quinone, we examined the potential reactions of this toxic metabolite. The oxidation of DOPAL by mushroom tyrosinase at pH 5.3 produced conventional DOPAL-quinone, but oxidation at pH 7.4 produced the tautomeric quinone-methide, which gave rise to 3,4-dihydroxyphenylglycolaldehyde and 3,4-dihydroxybenzaldehyde as products through a series of reactions. When the oxidation reaction was performed in the presence of ascorbic acid, two additional products were detected, which were tentatively identified as the cyclized products, 5,6-dihydroxybenzofuran and 3,5,6-trihydroxybenzofuran. Physiological concentrations of Cu(II) ions could also cause the oxidation of DOPAL to DOPAL-quinone. DOPAL-quinone exhibited reactivity towards the cysteine residues of serum albumin. DOPAL-oligomer, the oxidation product of DOPAL, exhibited pro-oxidant activity oxidizing GSH to GSSG and producing hydrogen peroxide. These results indicate that DOPAL-quinone generates several toxic compounds that could augment the neurotoxicity of DOPAL.

[4+n] Annulation Reactions Using ortho-Halomethyl Anilines as Aza-ortho-Quinone Methide Precursors

Synthesis ◽  
2021 ◽  
Author(s):  
Xiao-Yu He ◽  
Yu-Hong Ma ◽  
Qing-Qing Yang ◽  
Wen-Jing Xiao
Keyword(s):  
Convenient Method ◽  
Reactive Intermediates ◽  
Quinone Methide ◽  
Synthetic Chemistry ◽  
Important Class ◽  
Quinone Methides ◽  
Aniline Derivatives

Aza-ortho-quinone methides are an important class of reactive intermediates, which have found broad applications in synthetic chemistry. Recently, 1,4-elimination of ortho-halomethyl aniline derivatives has emerged as a new powerful and convenient method for aza-ortho-quinone methide generation. This review will highlight their recent applications as aza-ortho-quinone methide precursors in annulation reactions to access various biologically important nitrogen-containing heterocycles. The general mechanisms are briefly discussed as well.

scholarly journals The mechanism of tyrosinase-catalysed oxidative decarboxylation of α-(3,4-dihydroxyphenyl)-lactic acid

1991 ◽  
Vol 277 (3) ◽  
pp. 849-853 ◽  
Author(s):  
M Sugumaran ◽  
H Dali ◽  
V Semensi
Keyword(s):  
Lactic Acid ◽  
Enzyme Reaction ◽  
Quinone Methide ◽  
Oxidative Decarboxylation ◽  
Mushroom Tyrosinase ◽  
Mechanistic Studies ◽  
Methyl Group ◽  
Enzymic Oxidation ◽  
Steady State Kinetic ◽  
State Kinetic

Mushroom tyrosinase, which is known to catalyse the conversion of o-diphenols into o-benzoquinones, has been shown to catalyse the oxidative decarboxylation of 3,4-dihydroxymandelic acid [Sugumaran (1986) Biochemistry 25, 4489-4492]. To account for this unusual reaction, a quinone methide intermediate has been proposed. Since all attempts to trap this intermediate ended in vain, mechanistic studies were designed to support the formation of this transient product. Replacement of the alpha-proton in 3,4-dihydroxymandelic acid with a methyl group generates alpha-(3,4-dihydroxyphenyl)-lactic acid, the enzymic oxidation of which should produce 3,4-dihydroxyacetophenone as the end product if the oxidative decarboxylation proceeds through the quinone methide intermediate. Accordingly, chemically synthesized alpha-(3,4-dihydroxyphenyl)-lactic acid on enzymic oxidation produced 3,4-dihydroxyacetophenone as the major isolatable product. Non-steady-state kinetic analysis of the enzyme reaction attested to the transient formation of the conventional quinone product. Thus the enzymic oxidation of alpha-(3,4-dihydroxyphenyl)-lactic acid seems to generate the conventional quinone, which, owing to its instability, is rapidly decarboxylated to yield the transient quinone methide. The coupled dieneonephenol re-arrangement and ketol-enol tautomerism transforms the quinone methide into 3,4-dihydroxyacetophenone.

Biocatalyst-Initiated Ortho-Quinone Methide Formation and Derivatization

2019 ◽  
Author(s):  
Tyler Doyon ◽  
Jonathan Perkins ◽  
Summer A. Baker Dockrey ◽  
Kevin Skinner ◽  
Paul M. Zimmerman ◽  
...  
Keyword(s):  
Reactive Intermediates ◽  
Heme Iron ◽  
Quinone Methide ◽  
Reaction Conditions ◽  
One Pot ◽  
Mild Conditions ◽  
Non Heme Iron ◽  
Common Strategy ◽  
Aqueous Conditions ◽  
Ortho Cresol

Generation of reactive intermediates and interception of these fleeting species in a cascade is a common strategy employed by Nature. However, formation of these species under mild conditions using traditional synthetic techniques can present a challenge. Here, we demonstrate the utility of biocatalysis in generating ortho-quinone methide intermediates under aqueous conditions and at reduced temperatures. Specifically, we applied an α-ketoglutarate-dependent non-heme iron enzyme, CitB, in the selective modification of benzylic C–H bonds of ortho-cresol substrates to afford a benzylic alcohol product which, under the reaction conditions, is in equilibrium with the corresponding ortho-quinone methide. Interception of the ortho-quinone methide by a nucleophile or a dienophile allows for one-pot conversion of benzylic C–H bonds into C–C, C–N, C–O, and C–S bonds in a chemoenzymatic cascade.

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