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

Abstract

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 ¹H and ¹⁹⁵Pt 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 α-C atoms at pH > 9 leads to the observation of two well separated HPLC fractions for both the prevailing κ²N′_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 κ²O,S chelate is rapidly formed at pH 4.55 only slowly to convert into competitive S-bound complexes with κ²N¹,S and κ²N′_met,S 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 κ²N (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-1κ²N,N³∶2κ²N¹,S)]³⁺. In met-Hhis, κ²N (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 κ²N (amino),S complex slowly converts into a κ²N (amino),N′_his species, which subsequently affords [Pt(en-κN){met-his-κ³N (amino),N′_his,N³}]⁺ on cleavage of the Pt–N (en) bond trans to the amino N atom.