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In the first project (GANT project), structural proposals from a phenotypic screening were to be synthesised and tested for biological activity. After establishing the synthesis for the selected test molecules, these were successfully synthesized. For compound 1, complete analytical characterization and testing of biological activity was not possible because of insolubility. However, the results categorised most of the potential candidates as rather poor GLI inhibitors. As expected, the very potent and well-known GLI antagonist 39 showed very good inhibitory effects. For all other substances that were tested, only compound 6 had a low level of hh/GLI signalling. Based on these results, this project was postponed in favour of the other two projects in this thesis.
In the second project (Photoaffinity labeling of PPARβ/δ ligands), two active PA ligands 68 and 69 (Figure 152) were successfully synthesized for the photoaffinity labelling of PPARβ/δ by modifying the established synthesis route after previous unsuccessful attempts. The photosensitive groups could be introduced late-stage and the formation of regioisomers, which are difficult to separate, could be prevented by the effective use of the protecting group chemistry, which resulted in the successful synthesis. Unfortunately, it was not possible to bind one of the two ligands to the protein in order to identify the bound peptides down to individual labelled amino acids in the subsequent enzyme digestion in which a binding hypothesis could be formulated.
In the third project (Novel PRMT1 modulator), substance 80 was identified as a potential PRMT4/6 inhibitor through virtual screening. Contrary to expectations, this compound was inactive in the biological assay for PRMT4/6 but showed selective and agonistic PRMT1 activity. Within this work, the structure of the initial hit 80 was fully elucidated using analytical methods such as mass spectrometry and NMR spectroscopy. In addition, some very promising and potent activators of PRMT1 were synthesized, which are structurally different from those previously described in the literature. These include three compounds (80, 115 and 128; Figure 153) that bind very selectively to PRMT1 and lead to activation. By deriving structure-activity relationships starting from the initial hit 80, it was shown in various series that the planar isoquinoline-1,3(2H,4H)-dione backbone, the enamine partial structure and a nitrogen-substituted/alkylated benzylamine are essential for the activity. The compounds 131 x HCl, 184 x HCl, 192 x HCl, 193, 195, 200 and 202 (see figure 154) are high-affinity PRMT activators with different selectivity profiles and lead to an increased activity of 80-100%. Based on the derived SAR, a promising photoaffinity ligand could be designed, which carries the basic nitrogen necessary for the activity and would thus enable the first labeling experiments. Unfortunately, an initial synthesis was unsuccessful, but an alternative synthesis sequence was developed. A successful experiment would provide helpful information about the binding mode. At the time of writing this thesis, initial attempts were being made to obtain an X-ray crystal structure of some potent PRMT1 activators. In addition to photoaffinity labeling, these protein crystal structures would enable the establishment of a binding hypothesis and thus open up a structure-based drug design for the targeted further development of the corresponding molecules. Furthermore, the identification of the novel binding mode would make hit-to-lead optimisation accessible in order to provide starting points for the development of clinically usable PRMT1 activators.
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Dates
Created: 2024Issued: 2024-12-17Updated: 2024-12-17
Faculty
Fachbereich Pharmazie
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
PhotoaffinitätsmarkierungSignalwegTranskriptionsfaktorenMedizinalchemie, Liganden-basiertes Wirkstoffdesignsignalling pathwayGLI AntagonistenHedgehogProtein-Arginin-MethyltransferasenmethyltransferasesGLI antagonists, Peroxisome proliferator activated receptorsPeroxisom-Proliferator Aktivierte RezeptorenPhotoaffinity labellingTranscription factorsProtein argininesynthesis, Medicinal chemistry, Ligand-based drug design
DFG-subjects
LBDDPALLiganden-basiertes WirkstoffdesignSynthese
DDC-Numbers
540
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Iking, Christian: Design und Synthese neuartiger Transkriptionsmodulatoren. : Philipps-Universität Marburg 2024-12-17. DOI: https://doi.org/10.17192/z2024.0101.
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This item has been published with the following license: In Copyright