Metal complexes with sulfur ligands as cytotoxic agents
A series of Pt(II) complexes with a ligand system based on ß-hydroxydithiocinnamic esters are described as potential cytotoxic agents. The pharmacophore was adapted by using different substituents at the aromatic moiety and by varying the alkyl chain lengths at the dithioester unit. Coordination towards a Pt(II) center afforded neutral (O,S) bidentate complexes where the ligand sphere is completed by a chlorido ligand and DMSO, which coordinates via its S atom. To achieve different polarities and hence degrees of aqueous solubility, the metal complexes’ behavior in aqueous solution was assessed by UV-vis spectroscopy, giving information on aquation processes and solubility behavior. The compounds’ biological activity against representative cancer cell lines was assessed. Fluorescence microscopy provided first visual impression of cellular response to the reported compounds. Biomolecule interaction studies were then conducted using ESI mass spectrometry and UV-visible spectroscopy. A panel of model proteins was investigated and stable binding of the (O,S)Pt unit towards amino acid side chains revealed. Binding motifs were furthermore analyzed by X-ray crystallographic studies. Subsequently, the compounds’ binding ability towards DNA was probed using 9-methylguanine and single-strand oligonucleotides. Also in this case, stable coordination of the (O,S)Pt unit was found. To enable an enhanced compound targeting towards cancer cells with peptide conjugates, synthetic pathways towards the formation of bioconjugates were explored. Two general methods to link the (O,S)Pt pharmacophore to a model peptide were applied, 1,3-dipolar azide-alkyne cycloaddition and the linking via amide bonds. To this aim, the ligand system was derivatized with alkyne-, azide-, and carboxy substituents and reacted with Leu5-Enkephalin bearing the respective complimentary functional group.