Tetrahydrobiisoquinoline derivatives by reaction of dopamine with glyoxal: a novel potential degenerative pathway of catecholamines under oxidative stress conditions.
In 0.1 M phosphate buffer, pH 7.4, dopamine reacts with glyoxal, a cytotoxic and genotoxic alpha-oxoaldehyde produced by oxidative degradation of carbohydrates, to give three main products, two of which could be isolated and identified as the isomeric tetrahydrobiisoquinolines 1 and 2 by extensive two-dimensional NMR and mass spectrometric analysis. Time course studies indicated that 1 is the first intermediate in the process and changes slowly to 2 via an unstable species that escaped all efforts at isolation and structural identification. Products 1 and 2 were detected also among the species formed by the interaction of dopamine with oxidized carbohydrates, such as glucose, ribose, and fructose. Mechanistic evidence suggests that the formation of 1 proceeds by an unusual reaction pathway involving intramolecular cyclization of a double Schiff base intermediate followed by glyoxal-induced oxidation of the resulting octahydrobiisoquinoline intermediate (4). Subsequent conversion of 1 to 2 would involve a complex redox mechanism depending on an initial oxidation step. Product 2 was only poorly toxic to PC12 cells, whereas its methylated derivative 3 was as toxic as salsolinol, an established neurotoxin. Overall, these results throw light on a novel pathway of dopamine modification of potential relevance to the mechanisms underlying neurodegenerative changes in Parkinson's disease and other disorders characterized by a prooxidant state.
Manini
Paola
P
Department of Organic Chemistry and Biochemistry, University of Naples Federico II, Complesso Universitario Monte S. Angelo, Via Cinthia 4, I-80126 Naples, Italy.
Panzella
Lucia
L
Tedesco
Idolo
I
Petitto
Fabio
F
Russo
Gian Luigi
GL
Napolitano
Alessandra
A
Palumbo
Anna
A
d'Ischia
Marco
M
D000818:Animals; D004298:Dopamine / Q000737:chemistry* / Q000378:metabolism; D006037:Glyoxal / Q000737:chemistry* / Q000378:metabolism; D007536:Isomerism; D007700:Kinetics; D018384:Oxidative Stress; D016716:PC12 Cells; D051381:Rats; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D018675:Toxicity Tests
D044005:Tetrahydroisoquinolines; D006037:Glyoxal; D004298:Dopamine