Pyridine Analogues of the Antimetastatic Ru(III) Complex NAMI-A Targeting Non-Covalent Interactions with Albumin

Abstract

A series of pyridine-based derivatives of the antimetastatic Ru(III) complex imidazolium [trans-RuCl(4)(1H-imidazole)(DMSO-S)] (NAMI-A) have been synthesized along with their sodium-ion compensated analogues. These compounds have been characterized by X-ray crystallography, electron paramagnetic resonance (EPR), NMR, and electrochemistry, with the goal of probing their noncovalent interactions with human serum albumin (hsA). EPR studies show that the choice of imidazolium ligands and compensating ions does not strongly influence the rates of ligand exchange processes in aqueous buffer solutions. By contrast, the rate of formation and persistence of interactions of the complexes with hsA is found to be strongly dependent on the properties of the axial ligands. The stability of noncovalent binding is shown to correlate with the anticipated ability of the various pyridine ligands to interact with the hydrophobic binding domains of hsA. These interactions prevent the oligomerization of the complexes in solution and limit the rate of covalent binding to albumin amino acid side chains. Electrochemical studies demonstrate relatively high reduction potentials for these complexes, leading to the formation of Ru(II) species in aqueous solutions containing biological reducing agents, such as ascorbate. However, EPR measurements indicate that while noncovalent interactions with hsA do not prevent reduction, covalent binding produces persistent mononuclear Ru(III) species under these conditions.

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

“…Initial rapid binding of KP1019 takes place in a non-covalent manner at the hydrophobic binding sites of HSA, however after a longer incubation time the type of the interaction is converted slowly to a protein-coordinated form [33]. Similar behavior of NAMI-A and its pyridine analogues was found recently based on mainly electron paramagnetic resonance spectroscopic measurements [34,35]. A binding ratio of four KP1019 complex anions on a single HSA molecule was determined by CD and confirmed by inductively coupled plasma atomic emission spectroscopic (ICP-AES) method [23].…”

Synthesis and X-ray Structural Analysis of the Ruthenium(III) Complex Na[trans-RuCl4(DMSO) (PyrDiaz)], the Diazene Derivative of Antitumor NAMI-Pyr

“…The Ru-N and Ru-S bond distances of 2.109(6) and 2.2924(17) Å, respectively, are very similar to those found in the related structures containing trans-RuNCl 4 S donor set. [33][34][35]37 Three of the chlorido ligands are terminal while Cl4 forms a bridge between the ruthenium and sodium atoms. The DMSO ligand also forms a bridge between a ruthenium centre (through its sulphur atom) and a sodium (through its oxygen) thus forming a five membered RuClNaOS ring in the crystal structure.…”

“…A pyridine-heterocycle unsubstituted analogue of 3, called NAMI-Pyr 37 and AziRu 38 ( Figure 3), has been reported to show interesting reactivity profiles towards biologically relevant targets. 9 Derivatives with functionalized pyridine ligand have also been investigated.…”

Spectroscopic studies on interactions of the tetrakis(acetato)chloridodiruthenium(II,III) complex and the Ru2(II,III)-NSAID-derived metallodrugs of ibuprofen and ketoprofen with human serum albumin

“…Ru(III)-N-heterocyclic drugs in human trials, upon intravenous administration, can readily bind to the protein, following ligand exchange via its side chain (Hys and Cys) to form stable proteinbound adducts [52,68]. Notably, differences in NAMI-A and KP1019 protein binding may account for their distinct biological activities and cellular uptake.…”

“…NAMI-A binding to HSA has been suggested to involve covalent interactions. However, it has also been found that the Ru(II)-reduced form of the complex favors protein binding, although the reduction is disfavored for the covalently bonded in relation to the non-covalently bonded species (which are readily reduced by ascorbic acid) [68][69][70][71]. Conversely, the binding of KP1019 to HSA occurs mostly in a noncovalent manner, probably due to favorable interactions of the indazole ligands with the hydrophobic domains of the protein [72].…”