α-γ hybrid peptides that contain the conformationally constrained gabapentin residue: characterization of mimetics of chain reversals

Abstract

The crystal structures of four dipeptides that contain the stereochemically constrained γ-amino acid residue gabapentin (1-(aminomethyl)cyclohexaneacetic acid Gpn) are described. The molecular conformation of Piv-Pro-Gpn-OH (1), reveals a -turn mimetic conformation, stabilized by a ten atom C-H...O hydrogen bond between the Piv CO group and the pro S hydrogen of the Gpn CH₂-CO group. The peptides Boc-Gly-Gpn-OH (2), Boc-Aib-Gpn-OH (3), and Boc-Aib-Gpn-OMe (4) form compact, folded structures, in which a distinct reversal of polypeptide chain direction is observed. In all cases, the Gpn residue adopts a gauche,gauche (g,g) conformation about the C^γ-Cβ (θ¹) and C^α-(θ²) bonds. Two distinct Gpn conformational families are observed. In peptides 1 and 3, the average backbone torsion angle values for the Gpn residue are φ = 98°, θ¹ = -62°, θ² = -73°, and ψ = 79°, while in peptide 2 and 4 the average values are φ = -103°, θ¹ = -46°, θ² = -49°, and ψ = -92°. In the case of 1 and 3, an intramolecular nine-membered O-H...O hydrogen bond is formed between the C=O of the preceding residue and the terminal carboxylic acid OH group. All four α-γ dipeptide sequences yield compact folded backbone conformations; this suggests that the Gpn residue may be employed successfully in the design of novel folded structures.