κ²N(imidazole), S(thioether) Macrochelation of [Pt(en)]²⁺ (en = H₂NCH₂CH₂NH₂) by terminal histidine and methionine side-chains in tri-, tetra- and penta-peptides

Abstract

The pH and time dependent reactions of [Pt(en)(H₂O)₂]²⁺ (en = H₂NCH₂CH₂NH₂) with the histidylmethionine peptides Hhis-gly-metH, Ac-his-gly-gly-metH [Ac = CH₃C(O)] and Ac-his-ala-ala-ala-metH (Hgly = glycine, Hala = L-alanine) at 313 K have been studied by ion-pairing reversed-phase HPLC and ¹H and ¹⁹⁵Pt NMR spectroscopy. Following initial anchoring of the [Pt(en)]²⁺ fragment on the thioether S in a κ²O,S complex, metallation of the neighbouring amide nitrogen is relatively rapid for all three peptides at pH < 4. After reaching a concentration maximum within 10–50 h, the resulting κ²N ′_met,S six-membered chelate slowly isomerizes to the thermodynamically preferred κ²N  ¹,S macrochelate and in the case of the tetra- and penta-peptides to the less favoured κ²N  ³,S complex as well. The speed of this reaction is significantly faster for the latter i + 4 spacing of the ligating residues, which brings the thioether S and imidazole donor atoms into close proximity for an α helix conformation. Although time dependent studies indicated that the macrochelates are formed at a comparable rate to the κ²N ′_met,S complexes in alkaline solution, a clear thermodynamic preference for the smaller methionine chelate is apparent for the longer peptides.

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