Interaction of half-sandwich Rh(III) ion and some of its complexes with endogenous imidazole derivatives

An increasing number of {Rh(η⁵-Cp*)}²⁺ complexes are reported to possess promising medical, mostly anticancer activities. In parallel, growing interest has also focused on the interactions between {Rh(η⁵-Cp*)}²⁺-based metallodrugs and macromolecular components of biological fluids, since the biospeciation of these potential metallodrugs may strongly influence their overall pharmacological properties. Less attention was paid to the interaction of {Rh(η⁵-Cp*)}²⁺ complexes with low molecular mass (LMM) constituents of biological fluids, which may also have significant impact on their biospeciation. From this point of view, the biogenic imidazole derivatives are the most important, since the primary binding sites of proteins for {Rh(η⁵-Cp*)}²⁺ cation are the surface histidine groups. Several imidazole containing endogenous LMM components are known, which have relevant concentrations in certain biological fluids, such as plasma. Therefore, here we report systematic solution thermodynamic and solution structural (potentiometric, UV-Vis, ESI-MS and ¹H NMR) study on the interaction of {Rh(η⁵-Cp*)}²⁺ cation with thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH₂, L¹), carnosine (β-alanyl-histidine, L²), carcinine (β-alanyl-histamine, L³), histidine (L⁴) and the human growth modulator tripeptide GHK (Gly-His-Lys, L⁵). The results indicate, that these biogenic ligands, especially histidine and GHK, possess very high binding ability towards {Rh(η⁵-Cp*)}²⁺ cation, higher than for the well-known histidine-peptide binder copper(II). In addition, we also studied the interaction of two simple [Rh(η⁵-Cp*)(A)Cl]⁺ complexes (where A = 2,2'-bipyridyl (bpy) or ethylenediamine (en)), as mimics of potentially anticancer compounds, with the above listed endogenous imidazole derivatives. Beside the formation of ternary [Rh(η⁵-Cp*)(A)(L)] complexes, histidine and GHK, having exceptionally high {Rh(η⁵-Cp*)}²⁺ binding ability, are also able to displace en or bpy from the coordination sphere of Rh(III). Moreover, histidine and GHK successfully compete even with human serum albumin under near physiological conditions, and thus may have fundamental effect on the blood transport and biodistribution of any {Rh(η⁵-Cp*)}²⁺-based bioactive compounds.