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.

Key words

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

References

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8

This is a general problem often observedwith pyrazole derivatives: In agreement with the HSAB principle,hard acids such as acid chlorides preferentially attack the hard baseNH₂,while softer acids (such as anhydrides) perform acylationof the softer ring nitrogen.

18

For detailed crystallographic information,refer to the Cambridge Crystallographic Database, where structure 3f has been deposited with full data.

20

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

21

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

22

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]).