Peptidomimetics- Propargylamide-Based Isosteres of Peptide Structures

Matthias Wünsch
In medicinal chemistry, the importance of peptidomimetics as small-molecular, orally bioavailable PPI disruptors increases with the structural elucidation of PPI interfaces. However, the design of peptidomimetics, which accurately represent the peptide-template requires a sophisticated diversity of structural devices and reactions. In this thesis, a versatile peptidomimetic scaffold consisting of 3-amino-prop-1-yn-1-yl-benzoates is contributed. This structure is obtained by connection of
more » ... onnection of enantiomerically pure propargylamides with halo-benzoates by Sonogashira cross-coupling. To access a variety of side chains, an array of propargylamides is prepared asymmetrically, comprising all kinds of functional groups (Chapter II). Variation of the aromatic substitution pattern, application of heteroarenes and olefins (by hydroalkynylation of propynoates) in the C terminal moiety enables the introduction of versatile side chains and a well-defined curvature in the backbone. Conformational preferences are analyzed by NMR- and CD spectroscopy, MD simulations and X ray crystal structure analysis. Oligomerization of the peptidomimetic scaffolds is performed to investigate their properties as structural helix mimetics. Additionally, interesting dipeptide analogous peptidomimetics with unique properties are presented (Chapter III). Particularly rigid peptidomimetic structures based on naphthalene-, biphenyl-, azobenzene- and hydrazine scaffolds direct N and C termini into the same direction and are therefore applied as sterically enforced turn motif mimetics. Their introduction in peptide chains to induce a hairpin formation is studied by 1H NMR spectroscopy, temperature coefficient, CD spectra and X ray structure analysis (Chapter IV). para-Substituted peptidomimetics are applied as isosteres of the natural HDAC substrate (e.g. acetylated lysine). By functionalization with a hydroxamic acid, potent HDAC inhibitors can be generated. From a SAR study, interesting information on the influence of the aroma [...]
doi:10.4119/unibi/2930809 fatcat:5burhgke25cg5hsij5vom57bji