On the interaction of N-heterocyclic carbene Ir+I complexes with His and Cys containing peptides

Abstract

In contrast to their rhodium(I) and iridium(III) analogues, examples of iridium(I) complexes are only poorly investigated in the context of anti-cancer research. Recently we reported on the cytotoxic activity of [Ir(+I)(COD)(NHC)Cl] complexes (NHC: N-heterocyclic carbene, COD: 1,5-cycloactodiene) and their unusual oxidative interaction with cytochrome c and lysozyme. To get further insight into the molecular basis of this interaction a methylated histidine (His) derivative was synthesized, which could be used in solid phase peptide chemistry leading to a peptide-imidazolium salt. This peptide-imidazolium salt was then used to synthesize the corresponding [Ir(NHC-peptide)(COD)Cl] complex, which serves as a model system to determine the influence of a biomolecule directly bound to the metal center by means of NMR spectroscopy, ESI mass spectrometry and HPLC. The results help to explain earlier findings for protein interaction of such Ir(NHC) fragments as they suggest decomposition of the complexes in solution: After loss of the chlorido and the COD ligand, the Ir–NHC-peptide fragment remains intact coordinated to solvent molecules, but would then eventually decompose completely. By reacting short model peptides (containing Cys and His residues for metal coordination) with another [Ir(COD)(NHC)Cl] complex known for its interaction with the proteins stated above, we were further able to capture the Ir–NHC fragment in a chelating motif comprising the functional His or Cys amino acids. Also, we observed an oxidation of the iridium center from +I to +III at this stage. Particularly interesting bimetallic peptide-bridged adducts were found for Cys-containing peptides, which leads to interesting new insights into the molecular mechanism of anti-cancer activity of this class of compounds as bimetallic species that were not discussed previously in the literature in this context.