The influence of methionine-containing peptides on the reaction of carboplatin with 5′-guanosine monophosphate: a comparison with cisplatin

Abstract

The pH- and time-dependent reaction of the anticancer drug carboplatin, [Pt(cbdca-κ 2 O, O′)(NH 3) 2] (cbdca=cyclobutane-1,1-dicarboxylate), with the tripeptides H-glyglymet-OH (glycylglycyl- l-methionine) and Ac-glyglymet-OH at 313 K was investigated by high-performance liquid chromatography, NMR and mass spectrometry. The relative stability of the initial ring-opened κ S complex [Pt(cbdca-κ O)(Ac-glyglymet-OH-κ S)(NH 3) 2] leads to increased formation of the kinetically favoured κ S:κ S′ bis-adduct [Pt(Ac-glyglymet-OH-κ S) 2(NH 3) 2] 2+ in comparison with cisplatin. As a result a second 1:2 reaction pathway κ S→κ S:κ S′→κ 2 N M, S:κ S′→κ 3 N G2, N M, S:κ S′, where N M and N G2 represent, respectively, metallated methionine and glycine nitrogen atoms, competes with the 1:1 route κ S→κ 2 N M, S→κ 3 N G2, N M, S also observed for cisplatin. Cleavage of N-acetylglycine at the backbone C(O)–N bond to the second gly residue (G2) is observed after 100 h for the respective tridentate complexes [Pt(Ac-glyglyH −1metH −1-OH-κ 3 N G2, N M, S) (Ac-glyglymet-OH-κ S)] and [Pt(Ac-glyglyH −1metH −1-OH-κ 3 N G2, N M, S)(NH 3)] at pH <5.2. The longevity of the initial κ S complex leads to about an eight-fold increase in the rate of formation of the κ N7:κ N7′ bis-adduct [Pt(5′-GMP-κ N7) 2(NH 3) 2] 2− for the reaction of carboplatin with 5′-GMP 2− at pH 7 in the presence of Ac-glyglymet-OH. A mixed-ligand κ S:κ N7 species [Pt(5′-GMP-κ N7)(Ac-glyglymet-OH-κ S)(NH 3) 2] provides the major precursor for this 1:2 nucleotide complex and κ N7 coordination of 5′-GMP 2− is also observed in the κ 2 N M, S:κ N7 complex [Pt(5′-GMP-κ N7)(Ac-glyglymetH −1-OH-κ 2 N M, S)(NH 3) 2] − formed by substitution of the ammine ligand trans to the methionine sulphur. As the intermediate κ S:κ N7 species is formed rapidly within the first 10 h of reaction, these results suggest that the transfer reaction pathway κ S→κ S:κ N7→κ N7:κ N7′ involving κ S platinated peptides could play an important role in accelerating the rate of DNA binding for carboplatin.