title: Control of ligand-exchange processes and the oxidation state of the antimetastatic Ru(III) complex NAMI-A by interactions with human serum albumin.
abstract: The behaviour of the antimetastatic Ru(III) complex imidazolium [trans-RuCl₄(1H-imidazole)(DMSO-S)] (NAMI-A) under physiological conditions and its interactions with human serum albumin (hsA) have been studied using electron paramagnetic resonance spectroscopy (EPR). In physiological buffer at pH 7.4, these experiments demonstrate that the DMSO ligand is replaced rapidly by water, and spectra from the subsequent formation of five other Ru(III) complexes show further aquation processes. Although EPR spectra from mono-nuclear Ru(III) complexes are visible after 24 h in buffer, a significant decrease in the overall signal intensity following the first aquation step is consistent with the formation of oxo-bridged Ru(III) oligomers. Incubation with hsA reveals very rapid binding to the protein via hydrophobic interactions. This is followed by coordination through ligand exchange with protein side chains, likely with histidine imidazoles and at least one other specific site. Similar behaviour is observed when the complex is incubated in human serum, indicating that hsA binding dominates speciation in vivo. The addition of ascorbic acid to NAMI-A in buffer leads to quantitative reduction, producing EPR-silent Ru(II) complexes. However, this process is prevented when the complex binds coordinatively to hsA. Together, these results demonstrate the key role that hsA plays in defining the species found in vivo following intravenous treatment with NAMI-A, through prevention of oligomerization and maintenance of the oxidation state, to give protein-bound mono-nuclear Ru(III) species.
authors.affiliation: Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, V5A 1S6, Canada.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Webb
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Walsby
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009942:Organometallic Compounds / Q000737:chemistry*; D010084:Oxidation-Reduction; D011485:Protein Binding; D012428:Ruthenium / Q000737:chemistry*; D017975:Ruthenium Compounds; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D012709:Serum Albumin; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D012428:Ruthenium; D004121:Dimethyl Sulfoxide