Mark Wehner

Aminopyrazole Oligomers for β-SheetStabilization of Peptides

A general concept for the stabilization of β-sheets by designed artificial ligands is introduced. The ligands have two key features: they contain acylated 3-aminopyrazoles with a DAD hydrogen bond donor and acceptor pattern, and they were synthesized as oligomers in order to multiply their hydrogen bond interactions with peptides in the β-sheet conformation. Dimeric aminopyrazoles were accessible by reaction of the N1-Boc-protected aminopyrazole derivative 1 with several acid dichlorides followed by a standard deprotection procedure with trifluoroacetic acid. For the oligomers, Nl-PMB protection of new pyrazole amino acids followed by an iterative extension protocol with peptide coupling using PyClop or Mukaiyamas reagent led to the target compounds. All protecting groups were subsequently removed in a final deprotection step with warm trifluoroacetic acid. Two dimeric key compounds 3b and 3f were examined by NMR at various temperatures, in NOESY experiments as well as by X-ray crystallography in order to elucidate their conformational preference in solution and the solid state. The emerging picture was the same for all methods: both ligands adopt a flat conformation with a high degree of pre-orientation and the correct DAD pattern for optimal interaction with peptides in their extended conformation. Aggregation assays with the Prion protein and the Alzheimers peptide Aβ (1-40) show highly promising results for some of the dimeric and oligomeric ligands at very low concentrations.

Conformationally Rigid Hosts Containing Phosphonic Units

We present here a new class of cleft-like receptor molecules containing two or four phosphonates anions, tailored for multipoint binding of their substrates. Depending on the accessibility of the cleft, these hosts are water soluble and selective for short or long f , y -diammonium compounds. Due to their inherent chirality, we found that only those host-guest combinations which allow a three-point-interaction were effective.