Quinolines as Privileged Scaffolds in Metal Complexes: Coordination Chemistry and Anticancer Activity

Abstract

Quinoline is considered a privileged structure in medicinal chemistry with many metal complexes containing bidentate 8 hydroxyquinoline (HQ) derived ligands having shown potent antiproliferative activity. Ru, Os, Rh and Ir quinoline based complexes with η6-p-cymene (cym) or η5-pentamethylcyclopentadienyl (Cp*) π bound ligands were developed here to explore the effect of modifying the ligand systems on reactivity and anticancer properties. Biotinylated HQ complexes were prepared through chlorido co ligand exchange of [M(cym/Cp*)(HQ)Cl] precursors to explore the potential for improved cancer cell targeting by exploiting sodium dependent multivitamin transporter (SMVT) overexpression. The complexes readily interacted with N-donor biomolecules, while molecular docking with streptavidin found strong overlaps with the biotin binding site. Potent antiproliferative activity of the Rh complexes was demonstrated, and whilst there was no clear relationship between activity and SMVT expression, the biotinylated compounds showed similar activity in cisplatin-sensitive and -resistant cells, and their toxicity toward zebrafish embryos was found to be low. As an alternative to HQ, complexes containing 8 aminoquinoline (AQH) ligands or deprotonated N bridging AQ ligands were developed. In vitro anticancer activity studies revealed a higher potency for dinuclear AQ containing complexes, which can likely be explained by higher uptake into cancer cells. Significant color changes at a rate determined by the metal center were observed for solutions of the compounds during analysis of mono to dinuclear complex conversion as well as relative stability. Oxidation of the AQH/AQ ligand was identified as a source of the color changes. The complexes did not bind to the 8 mer oligonucleotide, while interaction with peptides was dependent on the presence of L-histidine. Irrespective of the number of metal centers in the complexes, zebrafish embryo studies demonstrated low toxicity for the compound type. Additionally, an Ir(Cp*)(AQ butyramidato) complex displayed more potent antiproliferative activity than the Ru, Os, and Rh derivatives. As a result, further Ir complexes with AQ functionalized ligands containing either biotin, as a cancer cell vector, or indomethacin, as an anti inflammatory drug unit, were developed with either chlorido or triphenylphosphine co ligands. Molecular docking of the biotinylated complexes indicated a strong interaction with the biotin binding site of streptavidin and was supported by peripheral interactions between the protein and the metal(π bound) portion of the complexes. The metal ion was found to determine antiproliferative activity of the respective AQ butyramidato complexes which suggests that covalent interaction with a target may be involved in the mode of action.