Item type:Thesis, Open Access

Entwicklung metallbasierter Enzyminhibitoren für Serinproteasen, Carboanhydrasen und Poly(ADP-ribose)-Polymerasen

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2013-10-07

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Philipps-Universität Marburg
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Abstract

Several metal-based enzyme inhibitors have been designed using molecular modeling software, synthesized and evaluated biochemically. The scaffold was based on tethering a pharmacophore functional group with a high affinity to the active site of the target enzyme to a tetrahedral or octahedral coordination unit. As the [Ru(bpy)3]2+ moiety is known to produce singlet oxygen if exposed to light a chromophore assisted light inactivation (CALI) approach was used to increase the inhibition of [Ru(bpy)3]2+ moiety-based trypsin inhibitors. The isolation of complexes with a high enantiopurity allowed us to examine the influence of the stereo configuration upon enzyme affinity and a high stereo preference of the active site was observed. To demonstrate that helically-chiral complexes can be used as structural scaffolds not only for trypsin, but for other enzymes as well, inhibitors of carbonic anhydrases and poly(ADP-ribose)-polymerase 1 (PARP1) were examined. Based on molecular modeling results several iridium(III) complex-based carbonic anhydrase II inhibitors were developed with IC50-values as low as 34 nM. A similar approach for PARP1 resulted in an excellent ruthenium(II) complex-based inhibitor with an IC50-value of 3-6 nM.

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Dates
Created: 2013Issued: 2013-10-07Updated: 2013-10-07
DOI
https://doi.org/10.17192/z2013.0471
Faculty
Fachbereich Chemie
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
inhibitororganometallischenzymemetalmetallorganisch
DFG-subjects
InhibitorMetallIridiumRutheniumEnzym
DDC-Numbers
540
License
https://rightsstatements.org/vocab/InC-NC/1.0/
URI
https://open.uni-marburg.de/handle/10.17192/z2013.0471
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Göbel, Peter Jussi: Entwicklung metallbasierter Enzyminhibitoren für Serinproteasen, Carboanhydrasen und Poly(ADP-ribose)-Polymerasen. : Philipps-Universität Marburg 2013-10-07. DOI: https://doi.org/10.17192/z2013.0471.

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