Bednarski, Patrick J. (1995) 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). pp. 1-19. ISSN 0162-0134
Full text not available from this repository.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) {[PtCl2(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 [PtCl2(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 [PtCl2(LL)] (8.10+/-0.03) x 10(-5) sec(-1) at 37 degrees C. The value of the hydrolysis rate constant is independent of pH over a range of 2.8-8.3 at 37 degrees C. The values of the second-order rate constants for L-cysteine, D,L-homocysteine, 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 neutral pH and 37 degrees C. The reactivity of the thiol-containing 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 [PtCl2(LL)] at rates comparable to the Pt-CI hydrolysis rate constant. The dependence of the rate constants on temperature was analyzed by Eyring plots: the Delta S-not equal values are negative for the reactions 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 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 H-1-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).
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CIS-DIAMMINEDIAQUAPLATINUM(II) CATION; PLATINUM COMPLEXES; METAL-COMPLEXES; CIS-DICHLORODIAMMINEPLATINUM(II); PHARMACOKINETICS; MECHANISMS; RESISTANCE; METHIONINE; INFUSION; BINDING |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Jan 2024 09:34 |
| Last Modified: | 04 Jan 2024 09:34 |
| URI: | https://pred.uni-regensburg.de/id/eprint/52293 |
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