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
1b
Carrell RW.
Lomas DA.
Lancet
1997,
350:
134
2a
Riesner D.
Kellings K.
Post K.
Wille H.
Serban H.
Baldwin M.
Groth D.
J. Virol.
1996,
70:
1714
2b
Pitschke M.
Prior R.
Haupt M.
Riesner D.
Nat. Med. (NY)
1998,
4:
832
3
Schrader T.
Kirsten C.
Chem. Commun.
1996,
2089
4
Schrader T.
Kirsten CN.
J. Am. Chem. Soc.
1997,
119:
12061
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
7
Robins RK.
Furcht FW.
Grauer AD.
Jones JW.
J. Am.Chem Soc.
1956,
78:
2418
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.
9a Removalwith TFA/anisole or TFA: Subramanyam C.
Synth.Commun.
1995,
25:
761
9b With DDQ: Singh SB.
Tetrahedron Lett.
1995,
35:
2009
10
Coste J.
Frerot E.
Jouin P.
J.Org. Chem.
1994,
59:
2437
11
Mukaiyama T.
Angew.Chem., Int. Ed. Engl.
1979,
18:
707 ; Angew. Chem. 1979 , 91 , 798
12
Nakhle BM.
Trammell SA.
Sigel KM.
Meyer TJ.
Erickson BW.
Tetrahedron
1999,
55:
2835
13
Wang Y.
Inguaggiato G.
Jasamai M.
Shah M.
Hughes D.
Slater M.
Simons C.
Bioorg. Med.Chem.
1999,
7:
481
14
Rodriguz-Franco MI.
Dorronsoro I.
Hernandez-Higueras AI.
Antequera G.
TetrahedronLett.
2001,
42:
863
15
Takahashi S.
Kuroyama Y.
Sonogashira K.
Hagihara N.
Synthesis
1980,
627
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
17
Ribeiro AA.
Goodman M.
Naider F.
Int.J. Peptide Protein Res.
1979,
14:
414
18 For detailed crystallographic information,refer to the Cambridge Crystallographic Database, where structure 3f has been deposited with full data.
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
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).