In 0.05 M phosphate buffer, pH 7.4. and at 37 degreesC, 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- 1,1,3,4-tetrahydroisoquinoline (1) and (1S,1 'S,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.
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
D'ISCHIA, MARCO;
2001
Abstract
In 0.05 M phosphate buffer, pH 7.4. and at 37 degreesC, 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- 1,1,3,4-tetrahydroisoquinoline (1) and (1S,1 'S,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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
