Purder, Patrick (2023)
Studies on FKBP ligands and inhibitors for GS-like enzymes.
Technische Universität Darmstadt
doi: 10.26083/tuprints-00022875
Dissertation, Erstveröffentlichung, Verlagsversion

Kurzbeschreibung (Abstract)

The first half of this dissertation is dedicated to the development of novel FKBP ligands, aiming to improve binding affinity, selectivity between selected members of the FKBP family, and metabolic stability. The basis of this project is the molecular 3,10-diazabicyclo[4.3.1]decan-2-one scaffold, which proved to be privileged for FKBP binding. Three attachment points were found to allow beneficial derivatization of this scaffold, which are atoms 3, 5 and 10 (Figure 1a). In this work, a structurally similar but non-binding negative control was developed to be used in biochemical and biological experiments with FKBP ligands. Next, FKBP ligands with a carboxylic acid in the R1 position and hydroxy groups in the R3 position were synthesized with the purpose of creating more water-soluble ligands for biochemical experiments. These compounds also presented an increased metabolic stability. Furthermore, the typically used phenyl sulfonamides in the R2 position were substituted with benzyl sulfonamides, a moiety that was reported to show good binding in other pipecolate-based scaffolds. However, benzyl sulfonamides are not suited in the 3,10-diazabicyclo[4.3.1]decan-2-one scaffold. As an extension of my master thesis, the R2 residue was extended in the para position. One motif was found to show a strong enhancement in FKBP12 binding and selectivity, which was further analyzed and optimized. Furthermore, the influence of the highly conserved sulfonamide in R2 was addressed. Analogous sulfenamide, sulfinamides and sulfonimidamides were synthesized to gain structure-affinity relationship information. The sulfonimidamide handle was used to expand the ligand, and this ligand series indicated a novel FKBP12 binding mode. Finally, all synthesized FKBP ligands were tested for Mip binding and selected compounds showed in vitro activity against Legionella pneumophila. The second half of this dissertation describes the design and synthesis of methionine sulfoximine analogs (Figure 2). The recently characterized glutamine synthetase-like enzyme GlnA4 could be targeted and the best inhibitor showed in vitro inhibition of GlnA4 in Streptomyces coelicolor. Lastly, the synthesis of homocysteine sulfonimidamide is described, which aimed to improve glutamine synthetase binding compared to the gold standard inhibitor MSO. Unfortunately, it showed no improved GS inhibition.

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