Intramolecular competition between histidine and methionine side chains in reactions of dipeptides with [Pt(en)(H2O)(2)](2+) (en equals H2NCH2CH2NH2)

The pH-and time-dependent reactions of [Pt(en)(H2O)(2)](2+) (en = H2NCH2CH2NH2) with the histidylmethionine dipeptides cyclo(-his-met-), his-Hmet and met-Hhis at 313 K have been studied by ion-pairing reversed-phase HPLC and H-1 and Pt-195 NMR spectroscopy. Quantitative formation of the unusually large 12-membered chelate ring in the remarkably inert complex [Pt(en){cyclo(-his-met-)}](2+) is complete within a few minutes. A base-catalysed configuration inversion for one of the diketopiperazine alpha-C atoms at pH > 9 leads to the observation of two well separated HPLC fractions for both the prevailing kappa(2)N'(met),S co-ordinated species and the peptide itself. An analogous likewise kinetically stable macrochelate is present after 14 d as a major species in the [Pt(en)(H2O)(2)](2+)-his-Hmet reaction mixture over the whole range 3.2 < pH < 11.2. Time-dependent HPLC indicated that a kinetically favoured kappa(2)O,S chelate is rapidly formed at pH 4.55 only slowly to convert into competitive S-bound complexes with kappa(2)N(1),S and kappa(2)N'S-met co-ordination. After reaching a quasi-stationary state (50 h), amide N'(met) anchoring in the latter species facilitates co-ordination of the adjacent amino nitrogen to afford the thermodynamically preferred kappa(2)N (amino),N'(met) chelate. At a 2:1 molar ratio, slow reaction of the macrochelate with a second (en)Pt-II fragment led to formation of [{Pt(en)}(2)(hisH(-1)-Hmet-1 kappa(2)N,N-3:2 kappa(2)N(1),S)](3+). In met-Hhis, kappa(2)N (amino),S chelation is kinetically and thermodynamically preferred in acid solution. At pH 9;6, however, sulfur binding is thermodynamically unfavourable, and the initially formed kappa(2)N (amino),S complex slowly converts into a kappa(2)N (amino),N'(his) species, which subsequently affords [Pt(en-kappa N) {met-his-kappa(3)N(amino),N'N-his(3)}](+) on cleavage of the Pt-N (en) bond trans to the amino N atom.