Pictet-Spengler condensation of the antiparkinsonian drug L-DOPA with D-glyceraldehyde. Opposite kinetic effects of Fe3+ and Cu2+ ions and possible implications for the origin of therapeutic side effects.
In 0.05 M phosphate buffer, pH 7.4, and at 37 degrees C. L-DOPA, a widely used antiparkinsonian drug, reacted smoothly with D-glyceraldehyde to afford diastereoisomeric (1R, 1'S,3S)-3-carboxy-1-(1',2'-dihydroxyethyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline (1) and (1S,1'5S,3S)-3-carboxy-1-(1',2'-dihydroxyethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (2) in an approx. 3:2 ratio. The prevalent formation of 1 over 2 reflects stereoselective cyclisation of a transient Schiff base in accord with the Felkin-Anh model. Fe3+ ions, present at relatively high levels in parkinsonian brains, markedly accelerated formation of 1 and 2, whereas Cu2+ decreased the reaction rate, due apparently to different sites of chelate formation between L-DOPA and the metal ions. Both metal ions markedly decreased the stereoselectivity of the reaction. Product 1 exhibited chelating properties toward metal ions comparable or stronger than those of L-DOPA. These results throw new light on the effects of transition metal ions on the Pictet-Spengler reaction and suggest a possible role of tetrahydroisoquinoline products from L-DOPA and carbohydrate metabolites in the severe side effects of the drug.
Manini
P
P
Department of Organic and Biological Chemistry, University of Naples Federico II, Italy.
Dischia
M
M
Prota
G
G
D000447:Aldehydes / Q000737:chemistry; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000737:chemistry*; D017666:Deuterium Oxide / Q000737:chemistry; D005985:Glyceraldehyde / Q000737:chemistry*; D007501:Iron / Q000737:chemistry*; D007700:Kinetics; D007980:Levodopa / Q000009:adverse effects / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D013056:Spectrophotometry, Ultraviolet
D000447:Aldehydes; D000978:Antiparkinson Agents; D002614:Chelating Agents; D005985:Glyceraldehyde; D007980:Levodopa; D003300:Copper; D007501:Iron; D017666:Deuterium Oxide