Metallkomplexe mit dualer Funktionalität : Eine Studie über die zelluläre Wirkungsweise photozytotoxischer Kinaseinhibitoren

Light as a therapeutic instrument is common since the ancient Egyptians and it is still a promising approach to attain the site-specific activation of chemotherapeutics in modern cancer therapy. Especially the photodynamic therapy, which is based on the cytotoxic effect of a light-activated singlet oxygen producer, has become a promising alternative for selective cancer treatment. This work examines the photocytotoxic properties of organometallic iridium and rhenium complexes, in order to determine their potential as novel photodynamic agents. As essential requirement both kinds of metal complexes exhibit a strong antiproliferative effect on different cancer cell lines, after the irradiation with visible light. This is the result of several cell viability studies with complex concentrations in the nanomolar range. By contrast there is no toxic effect in the dark under these conditions. Similar to clinically approved photosensitizers, the here introduced complexes exhibit a cellular reaction within minutes after irradiation, which is accompanied by several typical apoptotic phenomena like cell shrinking, bleb formation, loss of adhesion and caspase activation. 24 h after irradiation the fragmentation of the DNA can be observed too. Especially the detailed analysis of the caspase activation led to the conclusion, that the irradiated complexes initiate the intrinsic apoptotic signaling pathway. Elicitor of this photocytotoxic effect is the generation of singlet oxygen, which could be determined under irradiated conditions in a cell-free detection-assay. This formation of reactive species is another elementary feature that the complexes share with common photosensitizers. However, a detail which makes them special and distinguishes them from other photoactive compounds is their additional function as kinase inhibitors. This property is based on the particular design of the pyridocarbazole ligand, which is a part of all examined complexes. This structure is inspired by the natural kinase inhibitor staurosporine and enables the complexes to bind in the active site of this protein class. Supported by the other coordinated ligands the herein presented iridium complex AW0234 represents a selective inhibitor for the receptor tyrosine kinase VEGFR and shows a significant antiangiogenic effect in three-dimensional endothelial spheroids. For the rhenium complexes it was possible to detect a nanomolar inhibition of the cytosolic protein kinase Pim1, which is also well-known for its implication in different tumor diseases. Consequently the complexes demonstrated in this work represent potential therapeutic agents with a dual anti-cancer activity that combines the advantages of the photodynamic therapy with the inhibition of protein kinases.