1H NMR study of the reactions between carboplatin analogues [Pt(en)(Me-mal-O,O′)] and [Pt(en)(Me2-mal-O,O′)] and various methionine- and histidine-containing peptides under physiologically relevant conditions

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48 h. We found that during this time in the reaction with Ac-l-Met-Gly these monodentate bound malonate ligands have been replaced by water molecule leading to the formation of the corresponding aqua Pt(II)–peptide complex which further promotes the regioselective cleavage of the peptide.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.

Graphical abstract1H NMR spectroscopy was applied to study the reactions of carboplatin analogues [Pt(en)(Me-mal-O,O′)] and [Pt(en)(Me2-mal-O,O′)] with various methionine- and histidine-containing peptides under physiologically relevant conditions (pH 7.40 and 37 °C). In all these reactions very stable the ring-opened Me-mal and Me2-mal Pt(II) adducts as an intermediate products were observed in solution. The kinetic data and course of these reactions are discussed in terms of the peptide structure and steric hindrance of the chelating dicarboxylate-type of ligands.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Reactions of Pt(II) complexes with methionine- and histidine-containing peptides. ► 1H NMR study of the hydrolysis of peptides with Pt(II) complexes. ► Malonate ring-opened and macrochelate Pt(II)–peptide complexes. ► Reactions of carboplatin analogues with methionine-containing peptides.