Reference

Aminopyrazole oligomers for b-sheet stabilization of peptides

Rzepecki, P.; Wehner, M.; Molt, O.; Zadmard, R.; Harms, K.; Schrader, T. (Philipps-Universitaet Marburg, Department of Chemistry, Marburg 35032, Germany). Synthesis, (12), 1815-1826 (English) 2003 Georg Thieme Verlag. CODEN: SYNTBF. ISSN: 0039-7881. DOCUMENT TYPE: Journal CA Section: 34 (Amino Acids, Peptides, and Proteins) Section cross-reference(s): 28 A general concept for the stabilization of b-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 b-sheet conformation. Dimeric aminopyrazoles, e.g. I, were accessible by reaction of the N1-Boc 3-amino-5-methylpyrazole with several acid dichlorides followed by a std. deprotection procedure with trifluoroacetic acid. For the oligomers, N1-PMB protection of new pyrazole amino acids followed by an iterative extension protocol with peptide coupling using PyClop or Mukaiyama's reagent led to the target compds. All protecting groups were subsequently removed in a final deprotection step with warm trifluoroacetic acid. Two dimeric key compds. I and II were examd. by NMR at various temps., in NOESY expts. as well as by X-ray crystallog. 650610-09-6 and 16024-58-1 which are cas registry numbers of substances are two of reagents here. in order to elucidate their conformational preference in soln. 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 Alzheimer's peptide Ab (1-40) show highly promising results for some of the dimeric and oligomeric ligands at very low concns. .