The interaction of half-sandwich (η5-Cp*)Rh(III) cation with histidine containing peptides and their ternary species with (N,N) bidentate ligands

Our goal was to explore the possible interactions of the potential metallodrug (eta 5-Cp*)Rh(III) complexes with histidine containing biomolecules (peptides/proteins) in order to understand the most important thermodynamic factors influencing the biospeciation and biotransformation of (eta 5-Cp*)Rh(III) complexes. To this end, here we report systematic solution thermodynamic and solution structural study on the interaction of (eta 5-Cp*)Rh(III) cation with histidine containing peptides and their constituents ((N-methyl)imidazole, GGA-OH, GGH-OH, histidine-amide, HGG-OH, GHG-NH2), based on extensive 1H NMR, ESI-MS and potentiometric investigations. The comparative evaluation of our data indicated that (eta 5-Cp*)Rh(III) cation is able to induce the deprotonation of amide nitrogen well below pH 7. Consequently, at physiological pH the peptides are coordinated to Rh(III) by tridentate manner, with the participation of amide nitrogen. At pH 7.4 the (eta 5-Cp*)Rh(III) binding affinity of peptides follow the order GGA-OH < < GGH-OH < < histidine-amide < HGG-OH < GHG-NH2, i.e. the observed binding strength essentially depends on the presence and position of histidine within the peptide sequence. We also performed computational study on the possible solution structures of complexes present at near physio-logical pH. At pH 7.4 all histidine containing peptides form ternary complexes with strongly coordinating (N,N) bidentate ligands (ethylenediamine or bipyridyl), in which the peptides are monodentately coordinated to Rh(III) through their imidazole N1-nitrogens. In addition, the strongest chelators histidine-amide, HGG-OH and GHG-NH2 are also able to displace these powerful bidentate ligands from the coordination sphere of Rh(III). Superscript/Subscript Available

Automated summary

The study revealed that the (η5-Cp*)Rh(III) cation can induce deprotonation of amide nitrogen at physiological pH, leading to tridentate coordination with histidine-containing peptides. At pH 7.4, the binding strength of peptides with (η5-Cp*)Rh(III) depends on the presence and position of histidine in the sequence.