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

A series of pyridine-based derivatives of the antimetastatic
Ru­(III)
complex imidazolium [trans-RuCl4(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.