Kinetics and mechanism for reduction of oral anticancer platinum(IV) dicarboxylate compounds by L-ascorbate ions

Ascorbate (Asc) reductions of the oral anticancer platinum(IV) prodrugs cis ,trans,cis-[PtCl2(OAc)(2)(cha)(NH3)] (JM216) and cis,trans,cis-[PtCl2(OCOC3 H7)(2)(cha)(NH3)] (JM221) and of the isomers of JM216, viz. trans,cis,cis-[ PtCl2(OAc)(2)(cha)(NH3)] (JM394) and trans,trans,trans-[PtCl2(OAc)(2)(cha)( NH3)] (JM576) (OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to cis-[PtCl2(cha)(NH3)] (JM118) and JM394 and 576 to cis- and trans-[Pt(OAc)(2)(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: -d[Pt(IV)]/dt = k [Pt(IV)] [Asc](tot) where k is a pH dependent second-order overall rate constant and [Asc](tot) = [Asc(2-)] + [HAsc(-)] + [H(2)Asc]. Reduction of JM216 and JM221 is slow (overall rate constants k(298) = 5.08 +/- 10(-2) and 3.25 x 10(-2) mol(-1) dm(3) s(-1) a t pH 7.12, respectively) and is suggested to take place via an outer-sphere mechanism. Reductions of JM394 and JM576 are more than three orders of mag nitude faster (k(298) = 230 +/- 6 mol(-1) dm(3) s(-1) at pH 7.0 for JM394). They are suggested to take place by a mechanism involving a reductive atta ck on one of the mutually trans chloride ligands by Asc(2-) and less effici ently by HAsc(-) leading to the formation of a chloride-bridged activated c omplex. The second-order rate constants for reduction of JM394 by HAsc(-) a nd Asc(2-) at 25 degrees C are 0.548 +/- 0.004 and (4.46 +/- 0.01) x 10(6) mol(-1) dm(3) s(-1), respectively. The rate constants for reduction of JM21 6 and JM221 by Asc(2-) at 25 degrees C are calculated to be 672 +/- 15 and 428 +/- 10 mol(-1) dm(3) s(-1), respectively and reduction by HAsc(-) was n ot observed under these conditions. Thus, Asc(2-) is up to 7 orders of magn itude more efficient as a reductant than HAsc(-). H(2)Asc is virtually inac tive. The activation parameters Delta H double dagger and Delta S double da gger, for reduction of JM216, JM221, JM394, and JM576 by Asc(2-) are 52 +/- 1, 46 +/- 1, 56.2 +/- 0.5, and 63 +/- 2 kJ mol(-1) and -97 +/- 4, -120 +/- 4, -24 +/- 2, and -8 +/- 5 J K-1 mol(-1), respectively. An isokinetic rela tionship gives further support to the mechanistic assignments.