Reactions of a cisplatin analog bearing an estrogenic 1,2-diarylethylenediamine ligand with sulfur-containing amino acids and glutathione

Abstract

The kinetics and the products of the reactions of the cisplatin analog [ meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] dichloroplatinum(II) {[PtCl 2(LL)]} with l-cysteine, d,l-homocysteine, l-methionine, and glutathione (GSH) were investigated by means of reversed-phase HPLC with diode-array UV-spectroscopic detection. The loss of [PtCl 2(LL)] in the presence of nucleophile obeys the usual two-term rate law for substitution reactions with Pt(II); the values of the pseudo-first-order rate constants correspond to the hydrolysis rate constant for [PtCl 2(LL)] (8.10 ± 0.03) × 10 −5 sec −1 at 37°C. The value of the hydrolysis rate constant is independent of pH over a range of 2.8–8.3 at 37°C. The values of the second-order rate constants of l-cysteine, d,l-homocysteine, l-methionine, and GSH are (2.34 ± 0.37), (0.85 ± 0.25), (3.74 ± 0.60), and (1.13 ± 0.17) × 10 −2 M −1·sec −1, respectively, at neutral pH and 37°C. The reactivity of the thiolcontaining nucleophiles 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 with [PtCl 2(LL)] at rates comparable to the Pt-Cl hydrolysis rate constant. The dependence of the rate constants on temperature was analyzed by Eyring plots: the ΔS ≠ values are negative for the reactions with H 2O, GSH, and l-methionine, consistent with associative-type substitution reactions. All nucleophiles initially react with the Pt-complex to form mono-adducts that have the diamine (LL) still chelated to platinum. In the case of the thiol-containing nucleophiles, however, the final product of these reactions is free LL. l-Methionine was found considerably less effective in causing the release of LL; the final products were identified by 1-H-NMR to be diastereomeric monomethionine adducts, i.e., [Pt(LL)(Met- N, S)] +. The apparent rate of LL release is greatest with the sulfur-containing nucleophiles when the pH is 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).