Interaction of Ferrocenoyl-Dipeptides with 3-Aminopyrazole Derivatives: β-Sheet Models? A Synthetic, Spectroscopic, Structural, and Electrochemical Study

Abstract

The use of 3-aminopyrazole derivatives as beta-sheet templates is investigated using a series of ferrocenoyl (Fc)-dipeptides (Fc-Gly(2)-OEt, Fc-Ala(2)-OBzl, Fc-Leu-Phe-OMe, Fc-Val-Phe-OMe, Fc-Phe(2)-OMe, Fc-Leu(2)-OMe, Fc-Val(2)-OMe). The synthesis and full characterization are reported. The solid-state structures of Fc-Gly(2)-OMe and Fc-Leu-Phe-OMe show extensive hydrogen bonding of the podand peptide substituents, resulting in the formation of supramolecular Fc-dipeptide assemblies. For Fc-Gly(2)-OMe, this can be described as a parallel beta-sheet, whereas intermolecular interactions in Fc-Leu-Phe-OMe result in the formation of supramolecular helical structures. The saturation titrations of Fc-dipeptides with 3-amino-5-methylpyrazole (3-AMP) and 3-trifluoroacetylamido-5-methylpyrazole (3-TFAc-AMP) show a 1:1 interaction of the Fc-peptide with the aminopyrazole derivatives. IR measurements in solution confirm binding to the top face of the Fc-dipeptide and the involvement of the Fc-C=O and the ester C=O groups in establishing H-bonding interactions with the 3-TFAc-AMP. However, binding constants in chloroform are low and range from 8 to 27 M(-1), which correspond to binding energies of 5-7 kJ mol(-1). In higher polarity solvents, such as acetonitrile or acetone, the binding constants are below 5 M(-1), emphasizing the limited utility of 3-AMP derivatives as beta-sheet templates. Electrochemical measurements confirm the weak interactions between the various Fc-dipeptides and 3-TFAc-AMP. Typical shifts in the redox potential of the Fc moiety are in the range 0-20 mV. Attempts to modify 3-AMP at the 3-position by carbodiimide coupling with amino acid derivatives and, thus, enhance the binding to the Fc-peptides resulted in 2-amino acid substituted 3-AMP derivatives. Substitution at the 2-position blocks the binding site, and no interactions with Fc-dipeptides are observed.