Platinum(II) catalysis and radical intervention in reductions of platinum(IV) antitumor drugs by ascorbic acid

Reductions of four platinum(IV) amine complexes, cis-diamminetetrachloroplatinum(IV), tetraammine-cis-dichloroplatinum(IV), cis,cis,trans-diamminedichlorodihydroxoplatinum(IV), and cis,trans,cis-dichloro-dihydroxo-bis(isopropylamine)platinum(IV) by ascorbic acid were catalyzed by platinum(II) at pH 7.3 and 22 degreesC. Except for the first mentioned compound, initial slow uncatalyzed reductions yielded platinum(II) products which served as catalyst as revealed by the presence of induction periods and their disappearance by the addition of the platinum(11) products. The platinum(II) catalysis generated ascorbate bound platinum(IV) intermediates. An internal electron transfer process within these intermediates led to the formation of platinum(II) complexes. Although the rate constants for the uncatalyzed reductions vary greatly depending on the nature of the ligands and their spatial arrangements, the magnitudes of the platinum(II) catalyzed rate constants fall in the narrow range, 100 to 300 M-2 s(-1). The values of the uncatalyzed reductions lie in the range 5 x 10 to 15 M-1 s(-1), the tetrachloroplatinum(IV) complex suffered the faster reduction. The reduction of iproplatin with two hydroxide ligands in trans configuration was the slowest. The internal electron transfer rate constants span two orders of magnitude, from 0.15 to 4 x 10(-3) s(-1). These reactions were accompanied by the formation of the ascorbate radical which persists throughout the entire reaction. Although the tetrachloro species exhibited simple second order reduction, first order in each of the reactants, the rate of reduction was also accelerated by the addition of cis-diamminedichoroplatinum(II) indicating the presence of catalysis in this reaction as well. (C) 2003 Elsevier Science Inc. All rights reserved.