Smart drugs: Towards synergistic effects of biologically active ligand systems and metal centers

Abstract

Transition metal complexes feature a prominent role in the treatment and diagnosis of a variety of diseases and conditions. As many metal ions are biologically relevant and metal compounds exhibit biological activity, the complexation to pharmacological active ligands has been suggested to provide a means to create synergistic effects between ligand and metal centre, increase solubility of the bioactive ligand and reduce systemic toxicity. To exploit these advantages, the selection of the ligand is of utmost importance. In this doctoral thesis, an extensive series of naphthoquinone-, flavone- and quinolinebased organoruthenium(II) compounds were synthesised and characterised in terms of their chemical structure and their biological activity against different cancer cell lines. Flavones, naphthoquinones and quinolines are examples of biologically active compounds with a broad variety of pharmacological properties and the ability to coordinate to metal centres. The preparation of the compounds was complemented by mode of action studies to elucidate structure-activity relationships. Expansion on the structural diversity of O,O-chelating 3-hydroxyflavones and their ruthenium complexes showed that substitution of the ligand has a substantial impact on the anticancer activity, while electronic effects and lipophilicity seem less important. With the aim to increase the stability of the complexes, the preparation of N,O-coordinating 3-(alkylamino)flavones was attempted. Surprisingly the conversion of 3-tosylflavone with primary amines led to formation of Z- and E-1’-(alkylamino)aurones instead of the expected flavones. When using 2-hydroxynaphthoquinones as ligands, Ru complexes resembling those of 3-hydroxyflavones were obtained. Conversion of these naphthoquinones into the respective oximes to give N,O-chelating ligands and coordination to Ru(η6-p-cymene) surprisingly resulted in a rearrangement to yield nitroso-naphthalene complexes. This conversion led to ligands with higher anticancer activity, but the nitroso-naphthalene complexes were less potent anticancer agents than the O,O-coordinating naphthoquinone derivatives. The most potent anticancer agents developed were based on 8-hydroxyquinoline. Surprisingly, coordination of these ligands to a ruthenium centre did not enhance their biological activity, which notably also did not correlate with cellular accumulation. The excellent stability profile in an acidic environment and the lipophilicity of the compounds make them ideal candidates for development as orally administrable anticancer drugs.