Cisplatin-mediated selective hydrolytic cleavage of methionine-containing peptides with neighboring serine or histidine residues

The pH- and time-dependent reactions of the anticancer drug cisplatin, cis-PtCl(2)(NH(3))(2)], with the peptides Ac-Gly-Met-Gly-OH, Ac-Ser-Met-OH and Ac-Met-His-OH (Gly=glycyl, Met=methionyl, Ser=seryl, His=histidyl) at 313 K have been investigated by high-performance liquid chromatography, nuclear magnetic resonance and mass spectrometry. In the major equimolar reaction pathway for Ac-Gly-Met-Gly-OH, rapid anchoring at the methionine sulphur (kappaS) is followed by successive metalations of the methionine N(M) and glycyl N(G1) amide nitrogens in N-terminal direction to afford bidentate kappa(2)S,N(M) and tridentate kappa(3)S, N(M),N(G1) complexes. Cleavage of acetic acid at the second upstream amide bond is observed after 10 h leading to slow formation of Pt(H-Gly-MetH(-1)-Gly-OH-kappa(3)S,N(M),N(G1))(NH(3))](+) at pH<6. Pt(H-Ser-MetH(-1)-OH-kappa(3)S,N(M),N(S))(NH(3))](+) results from an analogous cisplatin-mediated regioselective hydrolytic cleavage reaction for Ac-Ser-Met-OH in moderately acid solution (pH<4). After passing through a minimum at pH 4.4, the concentration of the cleavage product in the reaction mixture after 500 h increases steadily on raising the pH and release of acetic acid is effectively quantitative for 7pH9.5. A competing mechanism involving nucleophilic attack of the serine side chain on the acetyl function can be inferred for pH>6 by the HPLC detection of a second intermediate kappa(3)S,N(M),N(S) species. In striking contrast, the reaction of cisplatin with Ac-Met-His-OH leads to release of acetylmethionine and formation of a final histidine product cis-PtCl(H-His-OH-kappa(2)N3,N(H)) (NH(3))](+) at pH<6 by a kappaS-->kappa(2)S, N3-->kappa(3)S, N(H),N3-->kappa(2)N3,N(H)(H-His-OH) pathway.