Effects of amine ligand bulk and hydrogen bonding on the rate of reaction of platinum(II) diamine complexes with key nucleotide and amino acid residues

NMR spectroscopy has been used to observe the effects of the amine ligand on the rate of reaction of platinum diamine and triamine complexes with DNA and protein residues. Whereas [Pt(dien)Cl]Cl and [Pt(dien)(D2O)]2+ have been known to react faster with thioether residues such as N-AcMet than with 5′-GMP, we found that [Pt(Me4en)(D2O)2]2+ appeared to react faster with 5′-GMP. To quantitatively assess the factors influencing the rates of reaction, rate constants at pH 4 were determined for the reactions of [Pt(en)(D2O)2]2+ [en = ethylenediamine] and [Pt(Me4en)(D2O)2]2+ with N-AcMet, N-AcHis, 5′-GMP, and Guo (guanosine). In general the less bulky complex ([Pt(en)(D2O)2]2+) reacts more quickly than does the bulkier [Pt(Me4en)(D2O)2]2+, as expected. Both complexes reacted faster with 5′-GMP; however, analysis of the rate constants suggests that the [Pt(en)(D2O)2]2+ complex favors reaction with 5′-GMP due to hydrogen bonding with the 5′-phosphate, whereas [Pt(Me4en)(D2O)2]2+ disfavors reaction with N-AcMet due to steric clashes. Bulk had relatively little effect on the rate constant with N-AcHis, suggesting that peptides or proteins that coordinate via His residues would not have their reactivity affected by bulky diamine ligands.

Graphical abstract[Pt(en)(D2O)2]2+ and [Pt(Me4en)(D2O)2]2+ were reacted with guanosine, 5′-GMP, N-acetylmethionine, and N-acetylhistidine. Both complexes reacted fastest with 5′-GMP; hydrogen bonding with 5′-GMP was important for the former and steric clashes with the methionine were important for the latter. The reaction rate of N-acetylhistidine was not affected significantly by amine bulk.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► [Pt(Me4en)(D2O)2]2+ favors 5′-GMP over N-acetylmethionine due to steric clashes. ► [Pt(en)(D2O)2]2+ favors 5′-GMP over N-acetylmethionine due to hydrogen bonding. ► Bulk of diamine ligand does not affect reaction rate with N-acetylhistidine.