Design, synthesis and application of rigid rod-like foldamers using 6-aminoquinoline 2-carboxylate building blocks

Aftahy, Kathrin (2024): Design, synthesis and application of rigid rod-like foldamers using 6-aminoquinoline 2-carboxylate building blocks. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

β-barrel proteins represent a wide family of α-helical and β-sheet conformed molecules with distinct conformation and overall pore-like structures. Their biological functions are manifold. When targeting their mimetics, one way is to design and synthesize linear foldamer oligomer fragments that can be purified, assembled and macrocyclized. These fragments, however, – corresponding to the β-sheet molecule in a β-barrel proteins – comprise a wide aromatic surface. Accordingly, these molecules are prone to unspecific aggregation and thus, purification post synthesis may be challenging. Herein, we show different ways synthesizing these rod-like molecules based on 6- aminoquinoline 2-carboxylic acid units (hereafter referred to as Qp; see chapter 1 for details on this monomer). Firstly, we show that rod-like molecules based on Qp can be incorporated in lipid bilayer membranes. Furthermore, they propose a new tool to control geometry, bending rigidity and molecular composition of membranes by using ultra-short nanotubes (usNT). Moreover, they can be traced by single-molecule measurements via distinct current response and show binding affinity towards membrane proteins e.g., Annexin V and ENTH (see chapter 3 for more details). Secondly, we show that linearity disruptor groups i.e. DMB groups can change the conformation on linear foldamer oligomers. They enabled kinking of the foldamer backbone and changing the overall geometry through cis/trans isomerism. In this way, we show successful intramolecular macrocyclization of foldamer oligomers. Specifically, the shortest possible macrocyclic foldamer sequence is synthesized accordingly. Moreover, we show the ability of host-guest complexes with larger macrocycles (see chapter 5 for more details). Finally, we demonstrate that linear foldamers can be used for the design of macro cyclic foldamer-peptide hybrids which were obtained by hybridization with oligopeptides. In this context, we demonstrate that the foldamer’s conformation affect the conformation of its neighboring oligopeptide and overturn the whole conformation of these hybrids (see chapter 5 for more details). In conclusion, these results establish a scientific output on rigid and rod-like foldamers. Specifically, these results suggest that macrocyclic architectures consisting of 6-aminoquinoline 2-carboxylic acid units either – homomeric sequences or in hybrid models – show significant potential in the application in membrane models, molecular recognition or peptidomimetic designs.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 1. Februar 2024
• 1. Bericht­erstatter:in: Huc, Ivan