Chirality-Driven Folding of Short β-Lactam Pseudopeptides

Abstract

Novel enantiopure pseudopeptide models containing a central -(-lactam)-(Aa)-scaffold characterized by the combined presence of an -alkyl--amino--lactam (i+1) residue and a -substituted (i + 2) amino acid have been readily synthesized from -alkyl serines. The conformational analysis of such -lactam pseudopeptides conducted in CDCl3 and DMSO-d6 solutions using 1D-and 2D-NMR techniques revealed an equilibrium between -II turn and -turn conformers, which was ultimately modulated by the relative configuration of the -(-lactam)-(Aa)-residues. Long-range chiral effects on the -lactam pseudopeptide conformers were also found when two (i) and (i + 3) chiral residues were attached to the termini of a central -(-lactam)-(Aib)-segment. In such mimetics, heterochiral (i) and (i + 3) residues reinforced a -II turn conformer, whereas homochiral corner residues stabilized an overlapped -II/ -I double turn motif. No -hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, -turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level, and finally, a conformation equilibrium model based on steric inter-residual interactions around the -(-lactam)-(i + 2)-segment was proposed to account for the observed chiral effects. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 substituted (i+2) amino acid have been readily synthesized from α-alkyl serines. The conformational analysis of such β-lactam pseudopeptides conducted in CDCl 3 and DMSO d6 solutions using 1D and 2D-NMR techniques revealed an equilibrium between β-II turn and γ-turn conformers, which was ultimately modulated by the relative configuration of the -(β-lactam)-(Aa)-residues. Long range chiral effects on the α-lactam pseudopeptide conformers were also found when two (i) and (i+3) chiral residues were attached to the termini of a central -(β-lactam)-(Aib)-segment. In such mimetics, heterochiral (i) and (i+3) residues reinforced a β-II turn conformer, whereas homochiral corner residues stabilized an overlapped β-II/ β-I double turn motif. No β-hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, β-turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level and, finally, a conformation equilibrium model based on steric inter-residual interactions around the -(β-lactam)-(i+2)-segment was proposed to account for the observed chiral effects.

Synthesis and Analysis of the Conformational Preferences of 5‐Aminomethyloxazolidine‐2,4‐dione Scaffolds: First Examples of β2‐ and β2, 2‐Homo‐Freidinger Lactam Analogues

“…It can be expected that substitution of Phe 3 with other amino acids could modify the stability and geometry of the folded conformation 8a. 11c It was shown that peptides incorporating a central lactam‐Gly pair can exhibit high conformational heterogeneity around the lactamGly bond, depending on the presence and relative disposition of the substituents of the lactam scaffold 8a. 11b…”

Synthesis, Pharmacological, and Biological Evaluation of MIF-1 Picolinoyl Peptidomimetics as Positive Allosteric Modulators of D2R

“…Later on, other studies showed that this neuropeptide is able to alleviate the behavioral changes caused by PD in animal models. , Given the therapeutic potential of MIF-1 in neurodegenerative processes, its bioactive conformation was investigated. X-ray crystallography and structure–activity relationship studies using constrained peptidomimetics suggest that MIF-1 adopts a type-II β-turn formed by intramolecular hydrogen bonding between the carbonyl oxygen atom of the l -proline residue and the trans amide proton of the glycinamide residue (depicted as dashed blue lines in Figure ).…”

Discovery of New Potent Positive Allosteric Modulators of Dopamine D2 Receptors: Insights into the Bioisosteric Replacement of Proline to 3-Furoic Acid in the Melanostatin Neuropeptide

“…While 6a is expected to adopt preferentially a classical γ-turn conformation, the existence of other turn motifs (including the postulated type II β-turn) or extended conformations cannot be ruled out due to its high flexibility. In fact, Aizpurua and co-workers disclosed MIF-1 peptidomimetics containing a β-lactam as a l -leucine surrogate in equilibrium between type II β-turn and γ-turn conformations …”

“…In fact, Aizpurua and coworkers disclosed MIF-1 peptidomimetics containing a βlactam as a L-leucine surrogate in equilibrium between type II β-turn and γ-turn conformations. 19 Moreover, using conformationally rigid peptidomimetics containing indolizidinone and spirobicyclic scaffolds, Johnson's lab has shown that other β-turn conformations such as VI βturn may be able to accommodate key pharmacophores in the same topological space. 2 However, in the case of 4a, β-turn conformations are excluded since the C-terminal carboxamide is absent (cf.…”

“…In fact, MIF-1 is a promising anti-Parkinson agent, as corroborated by the results obtained from animal models of PD. , The biological repertoire of MIF-1 is extensive, being described interactions with other drugs. For example, MIF-1 is known to antagonize dyskinesia induced by antipsychotic drugs and morphine-induced catalepsy. − Previous studies focused on the structure–activity relationships of MIF-1 using highly constrained derivatives, and data obtained from X-ray crystallography suggest that this neuropeptide adopts a type II β-turn. To adopt this bioactive conformation, MIF-1 establishes an intramolecular hydrogen bond between the carbonyl oxygen of the prolyl residue and the trans amide hydrogen of the glycinamide moiety (illustrated as a dashed blue line in Figure ).…”