4,5-Disubstituted N-aminoimdazol-2-One Mimics of Peptide Turn Backbone and Side Chain Conformation

Abstract

Nai residues have been shown by NMR spectroscopy and X-ray crystallography to adopt turn conformations, and have been incorporated into biologically active peptides to study structure-activity relationships (Figure 1) [1,2]. The synthesis of Nai residues has entailed alkylation of aza-glycinyl dipeptides with propargyl bromide using tetraethyl ammonium hydroxide, followed by sodium hydride induced 5-exo-dig cyclisation and exoto endo-alkene epimerization. By performing a Sonogashira reaction on the aza-propargylglycine residue prior to ring formation, various aromatic and heteroaromatic ring systems have been introduced at the 4-position of the aminoimdazol-2-one residue. Although the use of strong base led to epimerization of aza-glycinyl dipeptide C-terminal α-amino esters, the Nai dipeptide enantiomers were effectively separated by chiral supercritical fluid chromatography [3]. After liberation of the carboxylic acid, the resulting Nai dipeptide building blocks have been inserted into longer peptide structures by standard coupling methods [1,2]. The current method for Nai peptide construction offers effective means for introducing substituents at the 4-position to mimic different amino acid side chains. Moreover, the 4-position substituents have been observed by crystallographic analyses to influence the conformation of the C-terminal α-amino acid residue side chain in model Nai peptides [2]. Considering the natural orientation of amino acid side chains in chi-space [4], the Nai 5-position represents a promising location for the attachment of substituents for peptide mimicry [5]. Evidence that the backbone and side chain geometry of natural amino acids involved in β-turns may be mimicked by 5-aryl Nai residues was derived from molecular modelling using HyperChem 8, which predicted that model Nai peptide 1 adopted a type II β-turn conformation in which the aromatic side chain χ torsion angle was oriented in a gauche (–) conformation (Figure 1). Aromatic residues are abundant at the central positions of turn conformations of naturally occurring bioactive peptides, such as somatostatin [6]. Constrained mimics of aryl amino acids that adopt turn conformations may thus offer interesting potential for studying structure-activity relationships [7]. Arylation of the Nai 5-position is thus being studied to provide rigidified aryl and heteroarylalanine residues for turn mimicry.