Novel Adducts of the Anticancer Drug Oxaliplatin with Glutathione and Redox Reactions with Glutathione Disulfide

Abstract

Reactions of [Pt(rac‐1,2‐DACH)Cl2], [Pt(1R,2R‐DACH)Cl2] and the anticancer drug oxaliplatin with the tripeptide glutathione and glutathione disulfide have been studied by HPLC, ESI‐MS and NMR methods. The same two major products are formed in each reaction: a thiolate‐bridged dimer and a novel thiolate‐bridged dinuclear macrochelate containing a nine‐membered chelate ring. Redox reactions of PtII anticancer drugs with biological disulfides are of potential importance to their mechanism of action. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Monofunctional Platinum(II) Complexes with Potent Tumor Cell Growth Inhibitory Activity: The Effect of a Hydrogen‐Bond Donor/Acceptor N‐Heterocyclic Ligand

“…[23] Pt-GSH complexes, as well as Pt complexes with other sulfurcontaining biomolecules, have been correlated to uptake, distribution, and efflux of this class of drugs. Cisplatin-resistant tumour cells contain increased levels of GSH, and this finding has been correlated to a deactivating role of GSH.…”

“…[24] Pt-GSH adducts have also been hypothesized to act as a reservoir from which the platinum drug could subsequently react with the target DNA, thus providing an alternative pathway to the direct attack on DNA. [23,25] For the above reasons, we tested the reactivity of compound 1 with GSH. The time course of the reaction between 15 N-1 and GSH (1:1 molar ratio) at 37 8C in phosphate-buffered saline (PBS) buffer was studied by NMR spectroscopy ( Figure 5) Figure 5) which are assigned to free naphthyridine.…”

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

“…The four NH 3 ligands were easily released, which most likely indicate their trans positions relative to sulfur ligands, giving rise to the hypothesis that the adduct consists in a dinuclear four-membered Pt 2 S 2 ring ( Figure 5), as similarly observed with oxaliplatin. [77] In order to determine the ability of platinum to form adducts of this kind with other model peptides, two other small peptides (Met-Arg-Phe-Ala and Ac-Met-AlaSer) were incubated with cisplatin in the same conditions. [76] Using CID fragmentation, Pt was observed to form a mono-adduct using the three donor atoms of methionine (S, NH 2 and NH) and still bearing one of its Figure 5.…”

Substitution of aqua ligands from cis‐[Pt(en)(H2O)2](ClO4)2 and cis‐[Pt(dmen)(H2O)2](ClO4)2 (en = ethylenediamine, dmen = N N′‐dimethyl ethylenediamine) by glycine in aqueous medium—a kinetic and mechanistic approach

“…amino acids, nucleosides, and nucleotides are being investigated thoroughly. Although intensive efforts of various research groups in recent past have contributed significantly toward understanding of the antitumor activity of platinum complexes, most of the studies focused on the structural identification of the binding of the DNA constituents to the metal center using HPLC, multinuclear 1 H, 15 N, and 195 Pt NMR spectroscopy [1][2][3]. Significantly less is known about the mechanistic details with regard to the various steps of adduct formation and the factors controlling such adduct formation.…”