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 degreesC, L-DOPA. a widely us ed 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 st ereoselective cyclisation of a transient Schiff base in accord with the Fel kin-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 b etween L-DOPA and the metal ions. Both metal ions markedly decreased the st ereoselectivity of the reaction. Product 1 exhibited chelating properties t oward 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-Spen gler reaction and suggest a possible role of tetrahydroisoquinoline product s from L-DOPA and carbohydrate metabolites in the severe side effects of th e drug. (C) 2001 Elsevier Science Ltd. All rights reserved.