INHIBITORY EFFECT OF DIPYRIDAMOLE AND ITS DERIVATIVES ON LIPID-PEROXIDATION IN MITOCHONDRIA

Dipyridamole (DIP), iethanolamino)-4,8-dipiperidino-[5,4-d]pyrimidine, is a coronary vasodilator widely used in clinics. It has also been re ported to have coactivator activity for a number of antitumour drugs a nd antioxidant activity in membrane systems. In recent years we have b een studying the spectroscopic properties of this drug and several of its derivatives as well as their interaction with charged micelles and phospholipid monolayers. A strong interaction of DIP and DIP derivati ves with these model membrane systems and a dependence of the strength of the interaction upon the chemical structure of the DIP derivative was observed. Here, the antioxidant effect of DIP and the derivatives, RA14, RA47, and RA25, was compared. We observed that although it stro ngly inhibits the iron-induced lipoperoxidation on mitochondria (IC50 = 1 mu M), it shows no protection against an organic oxidant, cumene h ydroperoxide. The order of hydrophobicity of the DIP derivatives, DIP > RA14 > RA47 > RA25, correlates very well with both the values of the association constants of these derivatives to micelles, their localiz ation in the micelles, and phospholipid films and their antioxidant ef fect on mitochondria. So, a very good correlation of the structure of the drug in regarded to the nature of its substituents with the biolog ical activity is observed. Essentially the same result was observed ei ther measuring the lipid peroxidation or the membrane fluidity by ESR, suggesting that the effect of DIP and DIP derivatives is probably ass ociated to their binding to the lipid bilayer and not to interaction w ith membrane proteins. (C) 1997 Elsevier Science Inc.