Aminopyrazole Oligomers for β-SheetStabilization of Peptides

Abstract

A general concept for the stabilization of β-sheetsby designed artificial ligands is introduced. The ligands have twokey features: they contain acylated 3-aminopyrazoles with a DAD hydrogenbond donor and acceptor pattern, and they were synthesized as oligomersin order to multiply their hydrogen bond interactions with peptidesin the β-sheet conformation. Dimeric aminopyrazoles wereaccessible by reaction of the N1-Boc-protectedaminopyrazole derivative 1 with severalacid dichlorides followed by a standard deprotection procedure withtrifluoroacetic acid. For the oligomers, N1-PMBprotection of new pyrazole amino acids followed by an iterativeextension protocol with peptide coupling using PyClop or Mukaiyama’sreagent led to the target compounds. All protecting groups weresubsequently removed in a final deprotection step with warm trifluoroaceticacid. 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 orderto elucidate their conformational preference in solution and thesolid state. The emerging picture was the same for all methods: bothligands adopt a flat conformation with a high degree of pre-orientationand the correct DAD pattern for optimal interaction with peptidesin their extended conformation. Aggregation assays with the Prionprotein and the Alzheimer’s peptide Aβ (1-40)show highly promising results for some of the dimeric and oligomericligands at very low concentrations.

amino acids - peptides - molecular recognition - bioorganic chemistry - drugs - protecting groups

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Due to the low crystal quality, thecrystal structure of 3b has not been fullyrefined.

<A NAME="RT06403SS-21">21</A>

Professor Dr. D. Riesner, Institutfür Physikalische Biologie, Universität Düsseldorf.

<A NAME="RT06403SS-22">22</A>

CCDC 214082 contains the supplementarycrystallographic data for this paper. These data can be obtainedfree of charge via www.ccdc.cam.ac.uk/conts/retrieving.html(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:[phone]; e-mail: [e-mail]).