Interaction of cisplatin with methionine- and histidine-containing peptides: competition between backbone binding, macrochelation and peptide cleavage

The pH- and time-dependent reaction of cis[PtCl2(NH3)(2)] with the methioni ne- and histidine-containing peptides H-Gly-Met-OH, H-Gly-Gly-Met-OH, Ac-Hi s-Gly-Met-OH, and Ac-His-(Ala)(3)-Met-OH at 313 K has been investigated by ion-pairing reverse phase HPLC and NMR spectroscopy. For equimolar solution s (c=0.8 mM, pH approximate to3 or 8.8), initial formation of the kinetical ly favored S-bound complex is followed by relatively rapid metallation of t he neighboring methionine amide nitrogen NM to afford a (KNM)-N-2,S six-mem bered chelate. The strong trans effect of the methionine S then favors faci le NH3 substitution, leading to generation of tridentate complexes such as [Pt(H-Gly-MetH(-1)-OH)-(KNG)-N-3,N-M,S)(NH3)(+) or [Pt(H-Ac-His-GlyH(-1),-M etH(-1)-OH-(KNG)-N-3,N-M,S)(NH3)]. (NH3)]. In the case of H-Gly-Gly-Met-OH, this reaction is accompanied by loss of a second NH3 ligand in alkaline so lution to generate the tetradentate (KNG1)-N-4,N-G2,N-M, S species. In cont rast, cleavage of the backbone C(O)-N bond to the second metallated amide n itrogen after t>100 h is common to the tridentate complexes of the tri- and pentapeptides at pH<5. Although an imidazole-coordinated K(2)N3(H),S macro chelate is formed throughout the whole range 2.5<less than or equal to>pH l ess than or equal to 10 for Ac-His-Gly-Met-OH, it slowly decays (t=10-1000 h) to the thermodynamically more stable tridentate (KNG)-N-3,N-M,S complex. All major final products were separated and fully characterized by NMR and MS.