Pj. Bednarski, REACTIONS OF A CISPLATIN ANALOG BEARING AN ESTROGENIC 1,2-DIARYLETHYLENEDIAMINE LIGAND WITH SULFUR-CONTAINING AMINO-ACIDS AND GLUTATHIONE, Journal of inorganic biochemistry, 60(1), 1995, pp. 1-19
The kinetics and the products of the reactions of the cisplatin analog
hydroxyphenyl)ethylenediamine]dichloroplatinum(II) {[PtCl2(LL)]} with
L-cysteine, D,L-homocysteine, L-methionine, and glutathione (GSH) wer
e investigated by means of reversed-phase HPLC with diode-array UV-spe
ctroscopic detection. The loss of [PtCl2(LL)] in the presence of nucle
ophile obeys the usual two-term rate law for substitution reactions wi
th Pt(II); the values of the pseudo-first-order rate constants corresp
ond to the hydrolysis rate constant for [PtCl2(LL)] (8.10+/-0.03) x 10
(-5) sec(-1) at 37 degrees C. The value of the hydrolysis rate constan
t is independent of pH over a range of 2.8-8.3 at 37 degrees C. The va
lues of the second-order rate constants for L-cysteine, D,L-homocystei
ne, L-methionine, and GSH are (2.34+/-0.37), (0.85+/-0.26), (3.74+/-0.
60), and (1.13+/-0.17) x 10(-2)M(-1). sec(-1), respectively, at neutra
l pH and 37 degrees C. The reactivity of the thiol-containing nucleoph
iles increases with increasing pH; this effect is most pronounced with
L-cysteine. At lower pH (i.e., 2.8) both L-cysteine and GSH react wit
h [PtCl2(LL)] at rates comparable to the Pt-CI hydrolysis rate constan
t. The dependence of the rate constants on temperature was analyzed by
Eyring plots: the Delta S-not equal values are negative for the react
ions with H2O, GSH, and L-methionine, consistent with associative-type
substitution reactions. Ail nucleophiles initially react with the Pt.
-complex to form mono-adducts that have the diamine (LL) still chelate
d to platinum. In the case of the thiol-containing nucleophiles, howev
er, the final product of these reactions is free LL. L-Methionine was
found considerably less effective in causing the release of LL; the fi
nal products were identified by H-1-NMR to be diastereomeric monomethi
onine adducts, i.e., [Pt(LL)(Met-N,S)](+). The apparent rate of LL rel
ease is greatest with the sulfur-containing nucleophiles when the pH i
s maintained between 5.5 and 6.1. Diamine release slows moderately at
higher pH (i.e., 7.9) and slows considerably at lower pH (i.e., 2.8).