Entwicklung eines bifunktionalen Wirkstoffs: Antiangiogenese trifft Photozytotoxizität
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Philipps-Universität Marburg
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Abstract
Substitutionally inert metal complexes are promising emerging scaffolds for targeting enzyme active sites. Over the last several years, our research group has demonstrated that inert ruthenium(II) complexes can serve as highly selective nanomolar and even picomolar inhibitors of protein kinases. Octahedral metal coordination geometries in particular offer new gateways to design rigid, globular molecules with defined shapes that can fill protein pockets such as enzyme active sites in a unique fashion. However, the large number of possible stereoisomers does not only provide new structural opportunities, but also poses a formidable challenge because of the limited ability to control the stereochemistry in the cour- se of ligand exchange reactions. A continued progress in this area of inorganic medicinal chemistry therefore requires the development of strategies for the stereocontrolled synthesis of octahedrally coordinated metal complexes. Although most of our previous efforts were focused on ruthenium(II) complexes, we envisioned that octahedral iridium(III) complexes might be attractive scaffolds for two reasons: First, coordinative bonds with IrIII tend to be very inert and therefore IrIII complexes should be able to serve as stable scaffolds for the design of enzyme inhibitors. Second, octahedral IrIII complexes can be accessed from square-planar IrI complexes by stereoselective oxidative addition reactions. This factor provides a powerful tool to control the stereochemistry of octahedral IrIII complexes. Herein, we present the discovery of bioactive octahedral iridium(III) complexes, synthesized through oxidative addition as the key synthetic step. The organometallic compounds function as nanomolar and selective inhibitors of the protein kinase Flt4 (Fms-related tyrosine kinase 4), also known as VEGFR3 (vascular endothelial growth factor receptor 3). Flt4 is involved in angiogenesis and lymphangiogenesis and we demonstrate that these organoiridium compounds can indeed interfere with the development of blood vessels in vivo in two different zebrafish angiogenesis models and ex vivo in a 3D angiogenesis assay. The IC50 of the latest generation of organoiridium inhibitors is in the low nanomolar range and has improved solubility issues. In addition the organoiridium compound was found to be highly photocytotoxic. Such a dual and complementary anticancer activity in a single compound might lead to drug candidates with novel antitumor characteristics.
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Dates
Created: 2012Issued: 2012-07-11Updated: 2012-07-19
Faculty
Fachbereich Chemie
Publisher
Philipps-Universität Marburg
Language
ger
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DoctoralThesis
Keywords
AngiogenesisVEGFRKinasePhotocytotoxicityIridium Complex
DFG-subjects
PhotocytotoxicityIridiumAngiogenesisVEGFRBioinorganic chemistry
DDC-Numbers
540
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Wilbuer, Alexander (136546463): Entwicklung eines bifunktionalen Wirkstoffs: Antiangiogenese trifft Photozytotoxizität. : Philipps-Universität Marburg 2012-07-11. DOI: https://doi.org/10.17192/z2012.0494.
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This item has been published with the following license: In Copyright