Oktaedrische Ruthenium(II)- und Rhodium(III)-Komplexe mit mehrzähnigen Liganden als Kinaseinhibitoren

Aufgabenstellung (gekürzt): Während klinisch zugelassene bioaktive Substanzen vornehmlich organische Moleküle sind, werden anorganische Verbindungen hauptsächlich wegen der Reaktivität des Metallzentrums wie in DNA-bindenden Cytostatika (z.B. Cisplatin) oder in Kontrastmitteln (z.B. Gd(III)-Komplex...

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Bibliographic Details
Main Author: Mollin, Stefan
Contributors: Meggers, Eric (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2012
Chemie
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Table of Contents: In recent years, Meggers et al. developed a novel strategy, wherein inert metal complexes were designed as protein kinase inhibitors. Here, the ability of octahedral metal complexes is used to organize organic ligands in three-dimensional space to form structures with unique and defined shapes. Based on the natural product staurosporine, a potent but unselective kinase inhibitor, MEGGERS et al. designed half-sandwich complexes initially. Later, octahedral complexes were developed to achieve a number of potent and selective kinase inhibitors. To increase the activity and selectivity of kinase inhibitors and to control the stereochemistry of octahedral complexes, one approach is the introduction of multidentate ligands. Therefor several novel tri- and tetradentate ligands were synthesized and introduced in different octahedral metal complexes. A few Ru(II) complexes were developed containing the novel multidentate ligands. Hereby, some compounds were found with interesting biological activities. For this, studies regarding the activity towards human cell lines and the affinity towards a panel of kinases were investigated. In this thesis, first octahedral lipid kinase inhibitors were synthesized and tested against PI3Kalpha and PI3Kgamma. After testing a series of different bi-, tri- and tetradentate ligands within the Ru(II) complexes, the pyridocarbazole pharmacophor ligand was further optimized. Rhodium(III) was established as new metal center for kinase inhibitor design. Thus, Rh(III)-pyridocarbazol complexes were synthesized with a variety of tridentate ligands. The novel structures were investigated by several x-ray structures and regarding their activity against the protein kinase PIM1. In addition, further Rh(III) complexes were developed with novel pharmacophor ligands like phenylquinolines. Here, enantiopure complexes could be synthesized through the addition of chiral ligands. The resulting enantiopure compounds were tested for inhibition of protein kinases.