METAL ION-PROMOTED HYDROLYSIS OF THE ANTIOXIDANT CARDIOPROTECTIVE AGENT DEXRAZOXANE (ICRF-187) AND ITS ONE-RING OPEN HYDROLYSIS PRODUCTS TO ITS METAL-CHELATING ACTIVE FORM

摘要

The metal ion-promoted hydrolysis of the doxorubicin cardioprotective agent dexrazoxane (ICRF-187) has been studied by HPLC and spectrophotometrically. Dexrazoxane is thought to be cardioprotective through the ability of its rings-opened hydrolysis product (D) to chelate loosely bound iron, thus preventing iron-based oxygen free radical damage. While neither Mg(II) nor Ca(ll) promoted the hydrolysis of the opening of the first dexrazoxane ring, Zn(ll) strongly promoted (60-fold) hydrolysis. However, physiological concentrations of Mg(II) and Ca(ll) promoted hydrolysis of the one-ring open dexrazoxane hydrolysis intermediates (B and C) by up to 18-fold. Thus, Mg(ll) and Ca(ll) may be, in part, responsible for mediating the formation of the active metal ion-chelating form of the drag in vivo. A variety of other metal ions (Mn(ll), Co(ll), Ni(II), Cu(ll) and Zn(II)) strongly promoted hydrolysis of B and C by factors ranging from 25 for Mn(ll), to greater than 50,000 for Zn(ll) and Cu(ll). The Zn(ll)-promoted hydrolysis of B and C showed a strong pH dependence, which may be due either to a hydroxide bound to Zn(ll) or free hydroxide in solution acting as a nucleophile. Titration of the Fe(III)-B and Fe(lll)-D complex with azide resulted in spectral changes consistent with formation of ternary complexes, indicating that these complexes have open or loosely bound coordination sites. (C) 1997 Elsevier Science Inc. [References: 32]