Downstream reaction of cisplatin with methionine-containing peptides: pH-dependent competition between hydrolytic cleavage and macrochelation

The pH- and time-dependent reactions of the antitumor drug cisplatin, cis-[PtCl2(NH3)2], with the methionine-containing peptides Ac-Met-Gly-OH, Ac-Met-Pro-OH, Ac-Met-Pro-Gly-Gly-OH and Ac-Gly-Met-Pro-Gly-Gly-OH (Gly = glycyl, Met = d-methionyl, Pro = L-prolyl) at 313 K have been investigated by high performance liquid chromatography, mass spectrometry and nuclear magnetic resonance. As a result of the strong trans influence of the methionyl SM atom, initial Pt–SM binding at pH > 5 is followed by a rapid formation of tridentate machrochelates for the N-acetylated peptides. The site trans to SM is occupied by a carboxylate O atom in the case of the κ3SM,NM,OG/P macrochelates of the dipeptides and by the C-terminal glycylamide NG2 atom for the κ3SM,OM,NG2 macrochelate of Ac-Met-Pro-Gly-Gly-OH. Cisplatin simultaneously mediates the rapid hydrolytic cleavage of the Met-X (X = Gly, Pro) amide bond for both dipeptides over the whole range 2.8 ⩽ pH ⩽ 10.0. The released amino acids X react with the resulting κ2SM, NM chelate of N-acetylmethionine to afford mixed κSM:κ2Nx,Ox complexes of the type cis-[Pt(NH3)(Ac-Met-OH-κS)(H-X-O-κ2Nx,Ox)]+ as final products at pH < 5 for X = Gly and pH < 8 for X = Pro. In contrast to the dipeptides, hydrolytic cleavage of the Met-Pro amide bond in Ac-Met-Pro-Gly-Gly-OH at pH > 5 is significantly inhibited by the presence of high concentrations of the macrochelate [Pt(NH3)(Ac-Met-Pro-Gly-Gly)-κ3SM,OM,NG2]+. Downstream hydrolysis of the Met-Gly amide bond is competitive with upstream Ac-Gly cleavage for Ac-Gly-Met-Pro-Gly-Gly-OH at pH < 4.5.

Following initial coordination of cisplatin at the SM atom of the N-acetylated methionine-containing peptides Ac-Met-X-OH, (X = Gly,Pro) and Ac-Met-Pro-(Gly)2-OH, the strong trans influence of the thioether sulfur atom facilitates the rapid generation of tridentate macrochelates with carboxylate O atoms or amide N atoms sited opposite to SM. The rate of cisplatin-mediated cleavage of Met-X linkages at 5.0 ⩽ pH ⩽ 10.0 is influenced by the stability of the macrochelates.Figure optionsDownload as PowerPoint slide