Platinum–nucleobase PtN4 complexes as chemotypes for selective peptide reactions with biomolecules

The reactions of a substitution-inert complex [Pt(dien)(9-EtGua)](NO3)2, I, on DNA and model tetrapeptides were examined. The tetrapeptides Ac-GAXG (gly-ala-meth-gly) and Ac-GWXG (gly-trp-meth-gly) (X = Met or Cys) were chosen to compare firstly the relative reactivity of the thioether versus thiol and secondly to compare the effect of possible stacking of the platinated nucleobase with tryptophan on substitution reactions. Characterization of predicted products was made using [PtCl(dien)]Cl. Melting point and ethidium bromide inhibition assays confirmed the lack of reactivity on DNA. 1H NMR, 195H NMR and ESI-MS spectroscopy techniques showed that the cysteine-containing peptides reacted significantly faster than those of methionine. The reactivity differences were confirmed using simply N-AcMet and N-AcCys. The presence of tryptophan enhanced the rate of reaction slightly for the methionine-containing peptides. Theoretical calculations on the [Pt(dien)(9-EtGua)]–GWMG/GAMG interactions show that the GWMG species is roughly 5 kcal/mol more stable than formation of the GAMG species (−9.3 and −3.9 kcal/mol) due to the additional π stacking interaction. The results show the utility of considering the PtN4 chemotype for selective reactions with peptides and templates for design of specific protein inhibitors.