Expanding on the plecstatin anticancer agent class: exchange of the chlorido ligand for N-heterocyclic ligands

Abstract

Metal piano-stool complexes based on pyridinecarbothioamide (PCA) have shown promising antiproliferative and in vivo anticancer activity, in particular [Ru(cym)(p-F-PCA)Cl]PF₆ (cym is η⁶-p-cymene; plecstatin-1). The impact of modifications of the PCA and π-bound ligands on biological properties has been extensively investigated. Herein, we explored the influence of exchanging the chlorido ligand with the N-heterocycles 1-methylimidazole, 1-methylbenzimidazole and pyridine. In solution, an equilibrium between the protonated and deprotonated forms of the thioamide bond was observed, which was found dictated by the solvent system with both species detected in polar solvents. [Ru(cym)(PCA)Cl]⁺ complexes exhibit unique behaviour in an aqueous environment where they rapidly form dimeric species after substitution of the chlorido ligand for the sulfur donor of the PCA ligand of a second complex molecule. This was also observed for the synthesised complexes with the N-heterocyclic ligands being cleaved from the Ru centre allowing for dimerisation, which may be reversed by acidification of the solution resulting in the formation of equivalent mononuclear compounds. This behaviour explains the similar biological properties of the complexes with respect to that of plecstatin-1.