The Chemistry of Anticancer Mononuclear and <i>N</i>‐Bridged Dinuclear 8‐Aminoquinoline Half‐sandwich Metal Complexes

Piano-stool complexes of ruthenium and other platinum group metals have shown promising preclinical results as anticancer agents, often with alternative modes of action to traditional platinum-based compounds. Quinoline is considered a privileged structure in medicinal chemistry and many complexes with potent anticancer activity have been reported. To assess the effect of incorporating bidentate 8-aminoquinoline-η²N-1,N-8 (AQH) ligands in half-sandwich piano-stool metal complexes of the general formula [M(L)(AQH)Cl]⁺, the respective Ru, Os (L=η⁶-p-cymene), Rh and Ir (L=η⁵-pentamethylcyclopentadienyl) complexes were prepared. Deprotonation of AQH during the reaction gave dinuclear [M(L)(AQ)]₂ ²⁺ complexes with the deprotonated μ-κ¹N-8-aminoquinolinato-η²N-1,N-8 (AQ) ligands acting as bridges between the metal centers. Conversion of the mononuclear Ru, Rh and Ir compounds to the dimetallic analogues was facilitated under basic conditions and improved for the Ru derivative by the addition of AgNO₃ to abstract the chlorido ligand. In in vitro anticancer activity studies, the dimetallic complexes were in general more potent than mononuclear analogues. The higher activity of the dimetallic compounds can be explained by higher uptake into cancer cells, as demonstrated for the respective Ru complexes, while zebrafish embryo studies demonstrated low toxicity, irrespective of the number of metal centers in the complexes.