K. Lemma et al., Kinetics and mechanism for reduction of the anticancer prodrug trans,trans,trans-[PtCl2(OH)(2)(c-C6H11NH2)(NH3)] (JM335) by thiols, INORG CHEM, 39(8), 2000, pp. 1728-1734
The reduction of the platinum(IV) prodrug trans,trans,trans-[PtCl2(OH)(2)(c
-C6H11NH2)(NH3)] (JM335) by L-cysteine, DL-penicillamine, DL-homocysteine,
N-acetyl-L-cysteine, 2-mercaptopropanoic acid, 2-mercaptosuccinic acid, and
glutathione has been investigated at 25 degrees C in a 1.0 M aqueous perch
lorate medium with 6.8 less than or equal to pH less than or equal to 11.2
using stopped-flow spectrophotometry. The stoichiometry of Pt(IV):thiol is
1:2, and the redox reactions follow the second-order rate law -d[Pt(IV)]/dt
= k[Pt(IV)][RSW](tot), where k denotes the pH-dependent second-order rate
constant and [RSH](tot) the total concentration of thiol. The pH dependence
of k is ascribed to parallel reductions of JM335 by the various protolytic
species of the thiols, the relative contributions of which change with pH.
Electron transfer from thiol (RSH) or thiolate (RS-) to JM1335 is suggeste
d to take place as a reductive elimination process through an attack by sul
fur at one of the mutually trans chloride ligands, yielding trans-[Pt(ON)(2
)-(c-C6H11NH2)(NH3)] and RSSR as the reaction products, as confirmed by H-1
NMR. Second-order rate constants for the reduction of JM335 by the various
protolytic species of the thiols span more than 3 orders of magnitude. Red
uction with RS- is similar to 30-2000 times faster than with RSH. The linea
r correlation log(k(RS-)) = (0.52 +/- 0.06)-pK(RSH) - (2.8 +/- 0.5) is obse
rved, where k(RS-) denotes the second-order rate constant for reduction of
JM335 by a particular thiolate RS- and K-RSH is the acid dissociation const
ant for the corresponding thiol RSH. The slope of the linear correlation in
dicates that the reactivity of the various thiolate species is governed by
their proton basicity, and no significant steric effects are observed. The
half-life for reduction of JM335 by 6 mM glutathione (40-fold excess) at ph
ysiologically relevant conditions of 37 degrees C and pH 7.30 is 23 s. This
implies that JM335, in clinical use, is likely to undergo in vivo reductio
n by intracellular reducing agents such as glutathione prior to binding to
DNA. Reduction results in the immediate formation of a highly reactive plat
inum(II) species, i.e., the bishydroxo complex in rapid protolytic equilibr
ium with its aqua form.