Hydrolysis of the amide bond in N-acetylated l-methionylglycine catalyzed by various platinum(II) complexes under physiologically relevant conditions

The hydrolytic reactions between various Pt(II) complexes of the type [Pt(L)Cl2] and [Pt(L)(CBDCA-O,O′] (L is ethylenediamine, en; (±)-trans-1,2-diaminocyclohexane, dach; (±)-1,2-propylenediamine, 1,2-pn and CBDCA is the 1,1-cyclobutanedicarboxylic anion) and the N-acetylated l-methionylglycine dipeptide (MeCOMet–Gly) were studied by 1H NMR spectroscopy. 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. Under these experimental conditions, a very slow cleavage of the Met–Gly amide bond was observed and this hydrolytic reaction proceeds through the intermediate [Pt(L)(H2O)(MeCOMet–Gly–S)]+ complex. In general, it can be concluded that faster hydrolytic cleavage of the MeCOMet–Gly dipeptide was observed in the reaction with the chloride complex than with corresponding CBDCA Pt(II) complexes. The steric effects of the Pt(II) complex on the hydrolytic cleavage of the amide bond in the MeCOMet–Gly dipeptide were also investigated by 1H NMR spectroscopy. It was found that the rate of hydrolysis decreases as the steric bulk of the CBDCA and chlorido Pt(II) complexes increase (en > 1,2-pn > dach). These results contribute to a better understanding of the toxic side effects of Pt(II) antitumor drugs and should be taken into consideration when designing new potential Pt(II) antitumor drugs with preferably low toxic side effects.

1H NMR spectroscopy was applied to study the hydrolytic cleavage of the MeCOMet–Gly dipeptide in reactions with [Pt(L)Cl2]- and [Pt(L)(CBDCA-O,O′]-type complexes under physiologically relevant conditions (pH 7.40 and 37 °C). The observed rates of these hydrolytic reactions are discussed in terms of the leaving ligand (chlorido or CBDCA) and steric hindrance of the chelating diamine ligand (L) on the Pt(II) complex (L is en, 1,2-pn or dach).Figure optionsDownload as PowerPoint slideResearch highlights
► Hydrolytic cleavage of a methionine-containing peptides with Pt(II) complexes.
► Dependence of the peptide hydrolysis on the structure of the Pt(II) complexes.
► Peptide cleavage in relation to the toxic side effects of Pt(II) antitumor drugs.