Entwicklung metallorganischer Verbindungen für die Verwendung in der Krebstherapie

Rhenium(I)-Komplexe für die Photodynamische Therapie Die photodynamische Therapie (PDT) ist eine vielversprechende Methode für die Behandlung von Krebs. Hierbei wird ein Photosensibilisator (PS) in Anwesenheit von Sauerstoff belichtet, um verschiedene reaktive Sauerstoff-Spezies (ROS), wie 1O2, z...

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Bibliographic Details
Main Author: Wähler, Kathrin Marga
Contributors: Meggers, Eric (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2014
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Table of Contents: Rhenium(I) Complexes in Photodynamic Therapy Photodynamic therapy (PDT) has become a promising field in cancer treatment. This approach is based on a photosensitizer (PS) which is irradiated with visible light in the presence of oxygen to generate reactive oxygen species (ROS), like 1O2, ultimately leading to cell death. Until now many well-established PS depend on purely organic molecules like porphyrin derivatives, chlorines, phthalocyanines or porphycenes. However, metal complexes constitute an attractive class of compounds in PDT due to their ability to produce singlet oxygen in a more eifficient way. Furthermore, they have features such as structural diversity and complexity, tunable ligand exchange kinetics or unusual reactivities. This dissertation deals with the development of rhenium(I) complexes for photoactivated cancer therapy. In order to improve their stability and excitation wavelength the scaffold of the rhenium(I) complexes with a pyridocarbazole ligand was functionalized. By replacing the monodentate ligand against a strong sigma-donor, like trimethylphosphine or imidazole, no signs of decomposition can be monitored by 1H NMR spectroscopy. The introduction of a pi-donating substituent in the indole and a sigma-accepting substituent in the pyridine moiety of the pyridocarbazole ligand leads to a bathochromatic shift of the absorbance band. In this aspect a rhenium(I) complex, which initiates apoptosis in HeLa cells at wavelengths of > 620 nm, could be synthesized. To get an idea which mechanisms may occur in the cell further experiments were carried out. In this aspect the synthesis of a biotin-labeled complex is described which was localized in HeLa cells. The rhenium(I) compound seems to accumulate in different membranes of the cell and introduces the mechanism of lipid peroxidation which leads to cell death by apoptosis. Metal complexes with a pyridocarbazole ligand are well-known protein kinase inhibitors. Therefore the rhenium(I) compounds were tested for their inhibitory properties which led to IC50 values in the nanomolar range for the protein kinase Pim1 as model system at an ATP concentration of 10 µM. Thus, the organometallics show a dual function in a single drug which render them an attractive class of compounds for photodynamic as well as targeted therapy. Phenanthroline Complexes as Protein Kinase Inhibitors One project in the Meggers group deals with the design of metal complexes as selective and potent protein kinase inhibitors. The compounds are based on a pyridocarbazole ligand which forms hydrogen bonds to the hinge region of the ATP binding pocket. One major drawback of this system is the lengthy and complicated synthesis which causes problems for scale-up procedures. Furthermore, it tends to address only a few kinases within the human kinome. This thesis describes the design of a new pharmacophore ligand which is based on a phenanthroline system. The synthesized ruthenium(II) complex is a micromolar inhibitor for the protein kinases DYRK1A, Pim1 and Pim2 at an ATP concentration of 1 µM. A cocrystal structure of the compound with Pim1 reveals that the complex forms no hydrogen bonds with the hinge region of the ATP binding site, but instead with amino acid residues, which are located at the opposite site of the binding pocket. So the organometallic might be a promising lead structure for the development of potent and selective non-hinge-binding ATP-competitive inhibitors.