Download PDF
Synthesis 2003(12): 1815-1826
DOI: 10.1055/s-2003-41031
PAPER
© Georg ThiemeVerlag Stuttgart · New York

Aminopyrazole Oligomers for β-SheetStabilization of Peptides

P. Rzepecki, M. Wehner, O. Molt, R. Zadmard, K. Harms, T. Schrader*
Philipps-Universität Marburg, Department of Chemistry, Hans-Meerwein-Straße,35032 Marburg, Germany
Fax: +49(6421)2828917; e-Mail: schradet@mailer.uni-marburg.de;
Further Information

Publication History

Received 7 July 2003
Publication Date:
13 August 2003 (online)

    Permissions and Reprints All articles of this category

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

  • 1a Wisniewski T. Aucouturier P. Soto C. Frangione B. Amyloid  1998,  5:  212 
    CrossrefGoogle Scholar
  • 1b Carrell RW. Lomas DA. Lancet  1997,  350:  134 
    CrossrefGoogle Scholar
  • 2a Riesner D. Kellings K. Post K. Wille H. Serban H. Baldwin M. Groth D. J. Virol.  1996,  70:  1714 
    CrossrefGoogle Scholar
  • 2b Pitschke M. Prior R. Haupt M. Riesner D. Nat. Med. (NY)  1998,  4:  832 
    CrossrefGoogle Scholar
  • 3 Schrader T. Kirsten C. Chem. Commun.  1996,  2089 
    CrossrefGoogle Scholar
  • 4 Schrader T. Kirsten CN. J. Am. Chem. Soc.  1997,  119:  12061 
    CrossrefGoogle Scholar
  • 5 Schrader T, Riesner D, Nagel-Steger L, Aschermann K, Kirsten C, Rzepecki P, Molt O, Zadmard R, and Wehner M. inventors; DE102 21 052.7  application. 
  • 6 Some of Dervan’s minor groovebinders contain N-alkylated pyrazole amino acids: Zhan Z.-YJ. Dervan PB. Bioorg. Med.Chem.  2000,  8:  2467 
    Google Scholar
  • 7 Robins RK. Furcht FW. Grauer AD. Jones JW. J. Am.Chem Soc.  1956,  78:  2418 
    CrossrefGoogle Scholar
  • 9a Removalwith TFA/anisole or TFA: Subramanyam C. Synth.Commun.  1995,  25:  761 
    Google Scholar
  • 9b With DDQ: Singh SB. Tetrahedron Lett.  1995,  35:  2009 
    Google Scholar
  • 10 Coste J. Frerot E. Jouin P. J.Org. Chem.  1994,  59:  2437 
    CrossrefGoogle Scholar
  • 11 Mukaiyama T. Angew.Chem., Int. Ed. Engl.  1979,  18:  707 ; Angew. Chem. 1979, 91, 798
    CrossrefGoogle Scholar
  • 12 Nakhle BM. Trammell SA. Sigel KM. Meyer TJ. Erickson BW. Tetrahedron  1999,  55:  2835 
    CrossrefGoogle Scholar
  • 13 Wang Y. Inguaggiato G. Jasamai M. Shah M. Hughes D. Slater M. Simons C. Bioorg. Med.Chem.  1999,  7:  481 
    CrossrefGoogle Scholar
  • 14 Rodriguz-Franco MI. Dorronsoro I. Hernandez-Higueras AI. Antequera G. TetrahedronLett.  2001,  42:  863 
    Google Scholar
  • 15 Takahashi S. Kuroyama Y. Sonogashira K. Hagihara N. Synthesis  1980,  627 
    Article in Thieme ConnectGoogle Scholar
  • 16 The aminopyrazole nucleus is incorporatedin Viagra; 3-aminopyrazoles have been tested as antiinflammatory agents: Gadad AK. Kittur BS. Kapsi SG. Mahajanshetti CS. Rajur SB. Arzneim.-Forsch.  1996,  46:  1082 
    Google Scholar
  • 17 Ribeiro AA. Goodman M. Naider F. Int.J. Peptide Protein Res.  1979,  14:  414 
    Google Scholar
  • 19 A similar DAD pattern has been observedin a crystal structure for a related aminopyrazole derivative: Saweczko P. Enright GD. Kraatz HB. Inorg. Chem.  2001,  40:  4409 
    CrossrefGoogle Scholar
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:+44 1223336033; e-mail: deposit@ccdc.cam.ac.uk).