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

Abstract

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 each case 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.

Comparison of N-acetylmethionine reactivity between oxaliplatin and an oxaliplatin derivative with chiral (S,S) amine nitrogen atoms

“…In contrast, [Pt(Me 4 en)(D 2 O) 2 ] 2+ reacted ~16 times more slowly with N-AcMet than did [Pt(en)(D 2 O) 2 ] 2+ . [11] Thus, the presence of a secondary amine N cis to the coordination site in Pt(Me 2 dach)(ox) did not significantly affect the rate of the first N-AcMet coordination.…”

“…Molecular mechanics calculations (Table 2) support the presence of more severe steric clashes between methionine residues and the Me 2 dach ligand compared with the dach ligand. Our previous studies[11–13] establish that coordination of a methionine trans to a tertiary amine nitrogen atom effectively blocks coordination of a second methionine residue cis to the methionine. Our current studies indicate that coordination trans to a secondary amine nitrogen also prevents the second methionine residue from reacting.…”

“…By contrast, [Pt(Me 4 en)(D 2 O) 2 ] 2+ reacted with N-AcMet approximately 16 times slower than did [Pt(en)(D 2 O) 2 ] 2+ . [11] Thus, whereas ligands such as Me 4 en and Me 5 dien would be expected to reduce the reactivity of methionine relative to other protein or DNA targets, the Me 2 dach ligand would not. The Me 2 dach ligand thus is unique in that the additional methyl groups affect coordination of the second coordination site but not of the first coordination site.…”

“…[10] More recently, the coordination of one N-AcMet residue to [Pt(Me 4 en)(D 2 O) 2 ] 2+ [Me 4 en = N,N,N′,N′-tetramethylethylenediamine] was determined to be approximately 16-fold slower than coordination of N-AcMet to [Pt(en)(D 2 O) 2 ] 2+ . [11] The significant slowing was attributed at least in part to steric hindrance. By contrast, the rate of reaction with N-AcHis was not affected by the additional size of the Me 4 en ligand; thus, the size of the amine ligand could impact which amino acid residues are preferentially targeted.…”

Anti-cancer characteristics and ototoxicity of platinum(II) amine complexes with only one leaving ligand

“…5'-GMP reactivity could also be affected by hydrogen bonding with the nonleaving ligands or by electronic effects. In some platinum(II) complexes, the presence of steric bulk in the form of methyl groups proximate to the leaving ligand can prevent the formation of hydrogen bonds with incoming 5’-GMP and slow reactivity considerably [ 42 ]. However, in the complexes investigated here, at least one NH 3 or NH 2 group is cis to the incoming position and, therefore, hydrogen bonding with 5'-GMP should still be possible.…”