¹H NMR study of the reactions between carboplatin analogues [Pt(en)(Me-mal-O,O′)] and [Pt(en)(Me<inf>2</inf>-mal-O,O′)] and various methionine- and histidine-containing peptides under physiologically relevant conditions

Abstract

1H NMR spectroscopy was applied to the study the reactions of [Pt(en)(Me-mal-O,O′)] and [Pt(en)(Me2-mal-O,O′)] complexes (en is ethylenediamine, Me-mal and Me2-mal are bidentate coordinated anions of 2-methylmalonic and 2,2-dimethylmalonic acids, respectively) with N-acetylated Ac-l-Met-Gly and Ac-l-Met-l-His-type peptides (Ac-l-Met-l-His, Ac-l-Met-Gly-l-His-GlyNH2 and Ac-l-Met-Gly-Gly-l- His-Gly). The use of Me-mal and Me2-mal Pt(II) complexes in the above reactions allows convenient monitoring of their biscarboxylate group via methyl peaks by 1H NMR measurements. All reactions were realized at 37°C with equimolar amounts of the Pt(II) complex and the dipeptide at pH 7.40 in 50 mM phosphate buffer in D2O. In all these reactions the ring-opened Me-mal and Me2-mal Pt(II) adducts as an intermediate products were detected in solution for more than 48 h. We found that during this time in the reaction with Ac-l-Met-Gly these monodentate bound malonate ligands have been replaced by water molecule leading to the formation of the corresponding aqua Pt(II)-peptide complex which further promotes the regioselective cleavage of the peptide. However, in the reaction with Ac-l-Met-l-His-type peptides a selective intramolecular replacement of these malonate anions by the N3 imidazole nitrogen atom from histidine residue was occurred. This replacement reaction leads to the formation of the S,N3-macrochelate Pt(II)-peptide complex which was shown as very stable and hydrolytically inactive for more than two weeks. © 2012 Elsevier B.V. All rights reserved.