Stereochemistry of gabapentin and several derivatives: solid state conformations and solution equilibria

Gabapentin (1-(aminomethyl)cycloheaxaneacetic acid; Gpn) is a widely used anti-epileptic drug. The target site of action of Gpn remains controversial. Gpn can exist in two isomeric chair forms. The crystal structures of Gpn 1 and eight derivatives, Gpn hydrochloride 2, Gpn lactam 3, Boc-Gpn-OH 4, Ac-Gpn-OH 5, Piv- Gpn-OH 6, Tosyl-Gpn-OH 7, Boc-Gpn-OSu 8 and Boc-Gpn-NHMe 9, are described. The aminomethyl group occupies an axial position in 1, 3, 6 and 7, while it lies in an equatorial orientation in 2, 4, 5 and 8. The structure of Boc-Gpn-NHMe 9 reveals that the crystals contain both chair forms of the derivative in the ratio 0.7:0.3, favouring the aminomethyl group in an axial position. In all cases, the torsional angles about the Cα–Cβ (θ1) and Cβ–Cγ (θ2) bonds of the g-amino acid residue are characteristic of a gauche, gauche (g, g) conformation. In solution, NMR studies establish rapid conformational exchange, as anticipated, at room temperature. Low temperature NMR studies permit conformational freezing and determination of the freeenergy difference between the two 1,1-disubstituted cyclohexane conformers. The largest free-energy difference is observed in the free amino acid (0.38 kcal mol–1), with the most stable conformer having the aminomethyl group in the equatorial position. The free-energy difference between the two forms is significantly reduced in the protected derivatives, with almost equal populations observed in solution for the fully protected neutral derivatives, Boc-Gpn-NHMe and Gpn lactam

Structural studies of model peptides containing beta-, gamma- and delta-amino acids

The crystal structures of five model peptides Piv-Pro-Gly-NHMe (1), Piv-Pro-beta Gly-NHMe (2), Piv-Pro-beta Gly-OMe (3), Piv-Pro-delta Ava-OMe (4) and Boc-Pro-gamma Abu-OH (5) are described (Piv:pivaloyl; NHMe: N-methylamide; beta Gly:beta-glycine; OMe:O-methyl ester; delta Ava:delta-aminovaleric acid; gamma Abu:gamma-aminobutyric acid). A comparison of the structures of peptides 1 and 2 illustrates the dramatic consequences upon backbone homologation in short sequences. 1 adopts a type II beta-turn conformation in the solid state, while in 2, the molecule adopts an open conformation with the beta-residue being fully extended. Piv-Pro-beta Gly-OMe (3), which differs from 2 by replacement of the C-terminal NH group by an O-atom, adopts an almost identical molecular conformation and packing arrangement in the solid state. In peptide 4, the observed conformation resembles that determined for 2 and 3, with the delta Ava residue being fully extended. In peptide 5, the molecule undergoes a chain reversal, revealing a beta-turn mimetic structure stabilized by a C-H center dot center dot center dot O hydrogen bond

Structural studies of model peptides containing β-, γ and δ-amino acids

The crystal structures of five model peptides Piv-Pro-Gly-NHMe (1), Piv-Pro-βGly-NHMe (2), Piv-Pro-βGly-OMe (3), Piv-Pro-δAva-OMe (4) and Boc-Pro-γAbu-OH (5) are described (Piv: pivaloyl; NHMe: N-methylamide; βGly: β-glycine; OMe: O-methyl ester; δAva: δ-aminovaleric acid; γAbu: γ-aminobutyric acid). A comparison of the structures of peptides 1 and 2 illustrates the dramatic consequences upon backbone homologation in short sequences. 1 adopts a type II β-turn conformation in the solid state, while in 2, the molecule adopts an open conformation with the β-residue being fully extended. Piv-Pro-βGly-OMe (3), which differs from 2 by replacement of the C-terminal NH group by an O-atom, adopts an almost identical molecular conformation and packing arrangement in the solid state. In peptide 4, the observed conformation resembles that determined for 2 and 3, with the δAva residue being fully extended. In peptide 5, the molecule undergoes a chain reversal, revealing a β-turn mimetic structure stabilized by a C-H···O hydrogen bond

Structural studies of model peptides \beta-, \gamma- containing and \delta- amino acids

The crystal structures of five model peptides Piv-Pro-Gly-NHMe (1), Piv-Pro-\beta Gly-NHMe (2), Piv-Pro- \beta Gly-OMe (3), Piv-Pro- \delta Ava-OMe (4) and Boc-Pro- \gamma Abu-OH (5) are described (Piv: pivaloyl; NHMe: N-methylamide; \beta Gly: \beta-glycine; OMe: O-methyl ester; \delta Ava: \delta -aminovaleric acid; \gamma Abu: \gamma -aminobutyric acid). A comparison of the structures of peptides 1 and 2 illustrates the dramatic consequences upon backbone homologation in short sequences. 1 adopts a type II \beta -turn conformation in the solid state, while in 2, the molecule adopts an open conformation with the \beta -residue being fully extended. Piv-Pro- \beta Gly-OMe (3), which differs from 2 by replacement of the C-terminal NH group by an O-atom, adopts an almost identical molecular conformation and packing arrangement in the solid state. In peptide 4, the observed conformation resembles that determined for 2 and 3, with the \delta Ava residue being fully extended. In peptide 5, the molecule undergoes a chain reversal, revealing a \beta -turn mimetic structure stabilized by a $C-H...O$ hydrogen bond

Polypeptide Helices in Hybrid Peptide Sequences

A new class of polypeptide helices in hybrid sequences containing alpha-, beta-, and gamma-residues is described. The molecular conformations in crystals determined for the synthetic peptides Boc-Leu-Phe-Val-Aib-beta Phe-Leu-Phe-Val-OMe 1 (beta Phe: (S)-beta(3)-homophenylalanine) and Boc-Aib-Gpn-AibGpn-OM2(Gpn:1-(aminomethyl)cycl hexaneacetic acid) reveal expanded helical turns in the hybrid sequences (alpha alpha beta)(n) and (ay), In 1, a repetitive helical structure composed Of C-14 hydrogen-bonded units is observed, whereas 2 provides an example of a repetitive C-12 hydrogen-bonded structure. Using experimentally determined backbone torsion angles for the hydrogen-bonded units formed by hybrid sequences, we have generated energetically favorable hybrid helices. Conformational parameters are provided for C-11, C-12, C-13, C-14, and C-15 helices in hybrid sequences

Ab initio structure determination of a peptide beta-turn from powder X-ray diffraction data

Ab initio crystal structure determination of the peptide Piv-Pro-Gly-NHMe directly from powder X-ray diffraction data, using the genetic algorithm technique for structure solution, has allowed the complete structural characterization of the Type II beta-turn conformation and the intermolecular interactions in this structure, and highlights the opportunities that now exist for structure determination of peptide systems when single crystals appropriate for single crystal X-ray diffraction experiments cannot be prepared

Design of Stable β‑Hairpin Mimetics through Backbone Disulfide Bonds

The synthesis and utilization of novel thiostatines (β-SH-substituted γ-amino acids) in the design of backbone-disulfide-stabilized β-hairpin mimetics, solution conformations of hybrid β-hairpins and Cys-disulfide-stabilized α-peptide analogue, their thiol exchange, and proteolytic stability are investigated. The results suggest that thiostatines can be used to design proteolytically stable water-soluble β-hairpin mimetics without deviating from overall β-hairpin conformation

C-H…O Hydrogen Bond Mediated Chain Reversal in a Peptide Containing a gamma-Amino Acid Residue, Determined Directly from Powder X-ray Diffraction Data

The finding that peptides containing beta-amino acid residues give rise to folding patterns hitherto unobserved in alpha-amino acid peptides[1] has stimulated considerable interest in the conformational properties of peptides built from beta, gamma, and delta residues,[2] as the introduction of additional methylene (CH2) units into peptide chains provides further degrees of conformational freedom. Studies of the influence of introducing omega-amino acids into regular polypeptide structures derived from alpha residues have demonstrated that extra methylene groups can be inserted into helical backbones and into the strand and turn segments of beta hairpins.[3] In regard to the influence of CH2 group insertion into the i +2 position of isolated peptide beta turns, we are investigating the conformational properties of a series of model sequences Piv-Pro-xxx-NHMe (defined in Scheme 1 and reference [4])