X‐ray structure analysis reveals β‐turn mimicry by N‐amino‐imidazolidin‐2‐ones^†

Abstract

The conformation of the N-amino-imidazolidin-2-one (Aid) peptidomimetic was investigated using NMR spectroscopy and X-ray crystallography. In solution, the tetrapeptide model p-bromobenzoyl-Aid-l-Phe-N'-iso-propylamide (1) exhibited shielded and solvent exposed amide protons indicative of a turn conformation. In the crystal lattice of 1, four turn conformers were present in the unit cell differing primarily by the ring puckering of the Aid residue. Two pairs of β-turn conformers were observed each possessing an intramolecular ten-member hydrogen bond between the benzamide carbonyl and iso-propylamine NH moieties. The pairs had types II and II' β-turn geometry that differed slightly about the ϕ and ψ torsion angles. Moreover, the X-ray analysis of 1 has been compared with that of the related unsaturated N-amino-imidazolin-2-one (Nai) analogs indicating the influences of ring flattening and substituents on conformation. Insertion of the preorganized Aid structure into biologically active peptides has thus been shown to offer a potentially valuable means for exploring the importance of turn geometry for activity, particularly in drug discovery.

Azapeptide Synthesis Methods for Expanding Side-Chain Diversity for Biomedical Applications

“…X-ray crystallography of Aid peptide 76 indicated two pairs of 10-membered hydrogen-bonded conformers in the unit cell, each pair having respectively dihedral angles approaching ideal type II′ and type II β-turns (Figure ). In solution, NMR titration studies on 76 supported a 10-membered hydrogen bond between the benzamide carbonyl and the solvent-shielded isopropylamide NH. Like its Nai counterpart, the saturated Aid residue was situated at the i + 1 position in the β-turn but adopted both type II′ and type II geometries because of greater ring pucker flexibility.…”

Synthesis and Structural Characterization of β-Turn Mimics Containing (Z)-Chloroalkene Dipeptide Isosteres

“…It was found that a 16-fold dilution of the solution from 10 to 0.6 mM caused only a small shift in the N–H proton signals, suggesting that no intermolecular H-bonding-driven aggregation was present in the range of the concentrations tested. This was based on the fact that, when the concentration in DMSO- d 6 relative to that in CDCl 3 is increased, the donor proton causes a downfield shift due to the H-bonding with DMSO- d 6 . Since this effect is weakened by the presence of internal H-bonding, it can be used as an index with which to analyze the presence of H-bonding.…”

Synthesis and Biomedical Potential of Azapeptide Modulators of the Cluster of Differentiation 36 Receptor (CD36)

“…Furthermore, the aza-variants of the α-amino γ-lactam, so called N -amino-imidazolidin-2-one (Aid) residues were introduced into GHPR-6 analogues (e.g., 91d , Figure 9 ) by a sequence featuring alkylation of semicarbazone 39 with 1,2-dibromoethane, liberation of semicarbazide 90 with hydroxylamine in pyridine, peptide elongation and resin cleavage ( Scheme 9 ) [ 57 ]. In model peptides, Aid residues have been shown by NMR spectroscopy and X-ray crystallography to adopt the i + 1 position of well-defined, compact β-turns possessing intramolecular ten-member hydrogen bonds within types II and II’ geometry contingent on ring puckering [ 58 ].…”

“…In general, replacement of Ala 3 by these covalent constraining residues gave Furthermore, the aza-variants of the -amino -lactam, so called N-amino-imidazolidin-2-one (Aid) residues were introduced into GHPR-6 analogues (e.g., 91d, Figure 9) by a sequence featuring alkylation of semicarbazone 39 with 1,2-dibromoethane, liberation of semicarbazide 90 with hydroxylamine in pyridine, peptide elongation and resin cleavage (Scheme 9) [57]. In model peptides, Aid residues have been shown by NMR spectroscopy and X-ray crystallography to adopt the i + 1 position of well-defined, compact -turns possessing intramolecular ten-member hydrogen bonds within types II and II' geometry contingent on ring puckering [58]. In summary, the application of covalent constraint employing azaPro, azaPip, Agl, Bgl and Aid residues added support to conclude that an active turn conformer existed within the central residues of the hexapeptide.…”