Intermolecular β-Sheet Stabilization with Aminopyrazoles

Abstract

3-Aminopyrazole derivatives are the first artificial templates that stabilize the β-sheet conformation in N/C-protected dipeptides by purely intermolecular interactions. In the complex two aminopyrazole molecules lie exactly above and below the peptide backbone. Binding to the top face of the peptide is strongly favored because it forms three cooperative hydrogen bonds simultaneously to the receptor molecule, whereas the bottom face has only two. Polymerizable 3-amino- and 3-amidopyrazoles have been made accessible in excellent yields by a general route starting from p-toluic acid. With 1H NMR titrations binding constants for the 1:1 complex of up to 880 M-1 have been determined in chloroform. The association constants are strongly influenced by the electronic character of the aminopyrazole derivative as well as by the steric demand of the peptide residues. Variable temperature studies prove that the complex is formed by dynamic hydrogen bonds and confirmed the preferential binding of the receptor molecules at the top face. By detailed Karplus-analysis of the NH-α-CH coupling constants in the complex a remarkable correlation between the dihedral angle θ and the degree of complexation was found, which shows that several amidopyrazoles are capable of forcing the dipeptide into an almost ideal β-sheet conformation. In glycine-containing dipeptides the third hydrogen bond slows down the free rotation around the C−C/C−N bond to almost zero. Intramolecular nuclear Overhauser enhancements (NOE) provide additional evidence for the peptide's extended conformation, while strong reciprocal intermolecular NOEs give the final proof of the existence of the critical third hydrogen bond and the postulated mutual orientation of the complexation partners. First 1H NMR titrations with tripeptides show very promising results concerning the application of this concept to oligopeptides.

The Synthesis, Structure and Properties of N-Acetylated Derivatives of Ethyl 3-Amino-1H-pyrazole-4-carboxylate

“…Compound 1 crystallized as monoclinic in the space group P2 1 /n, aϭ8.227 (2) Å, bϭ8.283(1) Å, cϭ11.111(2 Ethyl 1-Acetyl-3-amino-1H-pyrazole-4-carboxylate (2) To a suspension of 1 (775 mg, 5 mmol) and DMAP (121 mg, 1 mol) in DMF (0.5 ml) was added Ac 2 O (0.71 ml, 7.5 mmol), after 1 h at room temperature a white precipitate was filtered off and washed with DMF (1 ml) to furnish 2 (550 mg, 56% isolated yield), mp 110°C; TLC: Rf 0.86; HPLC: t R 3.0 min, 99% purity; 1 H-NMR (DMSO-d 6 …”

“…In order to determine the position of hydrogen at nitrogen atoms in compounds 1 and 5 in solution we performed NMR analysis and calculations. Compound 1 in the CDCl 3 and DMSO-d 6 solutions is a mixture of tautomers, according to NOESY, multinuclear HMBC and HSQC spectra and as well as calculations (Table 3). In addition, it was shown that 5 in DMSO-d 6 contains a mixture of tautomers which was corroborated by calculations ( Table 3).…”

Hydrogen-bonding interactions in ferrocene-peptide conjugates containing valine

“…The assignment of amide NH protons is shown in Scheme 2 and the result of the VT 1 H NMR is summarized in Table 3 (see Supporting information for plots of chemical shifts versus temperature). The amide protons that are involved in intramolecular or intermolecular hydrogen bonding experience temperature dependent chemical shifts [25]. For example, the temperature coefficients of compound 1 (see Fig.…”

Wechselwirkung kleiner, geschützter Peptide mit Aminopyrazolderivaten: effektive Verkappung von β‐Faltblattmodellen in der Gasphase

“…Diese starren Heterocyclen wurden in Lösung auf ihre Fähigkeit zur Erkennung des Peptidrückgrats mit NMR-und IR-spektroskopischen Methoden sowie mit Kraftfeldrechnungen untersucht. [4][5][6][7][8] Um mit einer möglichen Peptiddimerisierung konkurrieren zu können, muss mit der Bildung eines Peptid- Ein entscheidender Vorteil der Molekularstrahlexperimente besteht in der Möglichkeit, isolierte Cluster massen-, isomeren-und zustandsselektiv zu analysieren. Die R2PI-Methode (R2PI: resonance enhanced two photon ionization), [9] bei der das Molekül durch ein UV-Photon zunächst angeregt und anschließend durch ein zweites UV-Photon ionisiert wird, ermöglicht eine Diskriminierung auch zwischen einander sehr ähnlichen Isomeren, z.…”