Entwicklung metallorganischer Enzyminhibitoren für Histondeacetylasen und Carboanhydrasen

Die Entwicklung neuer chemischer Verbindungen als synthetische Wirkstoffe in biologischen Systemen ist ein Hauptforschungsgebiet der Chemischen Biologie sowie der medizinischen Forschung. Während die meisten klinisch zugelassenen Substanzen vornehmlich rein organische Moleküle sind, befinden sich di...

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Bibliographic Details
Main Author: Ritterbusch, Florian
Contributors: Meggers, Eric (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2012
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The development of new chemical compounds as synthetic therapeutics for biological systems is an important field of medicinal chemistry. Most clinically used substances are purely organic compounds, while metals are preferred classical tools in nuclear medicine. Bioorganometallic chemistry, a combination of bioinorganic and organometallic chemistry, represents a rapidly growing field within chemical biology. Meggers et al. have investigated the application of chemically inert organometallic complexes as kinase inhibitors, where the metal has only a structural function. Through varying the ligands around the metal center it is possible to generate rigid structures that fill the enzyme pocket in a unique fashion and overcome the limited tetrahedral geometry of classic organic compounds. The principal purpose of this dissertation was to demonstrate the generality of this design strategy of using metal complexes as enzyme inhibitors for other protein targets. For this approach, histone deacetylases and carbonic anhydrases were chosen. Several broad-spectrum inhibitors, with related structural motifs for each enzyme class, were used as templates for the development and synthesis of bidentate pharmacophore ligands. These ligands were used to prepare a small library of metal complexes, which were subsequently tested for their biological activity. Overall, the results contained in this dissertation demonstrate the potential of metal complexes as potent inhibitors of histone deacetylases and carbonic anhydrases. This is a promising starting point for development of further isoform selective compounds.