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β-Turns are one of the most common secondary structures found in proteins. In the interest of developing novel β-turn inducers, a diastereopure azepane-derived quaternary amino acid has been incorporated into a library of simplified tetrapeptide models in order to assess the effect of the azepane position and peptide sequence on the stabilization of β-turns. The conformational analysis of these peptides by molecular modeling, NMR spectroscopy, and X-ray crystallography showed that this azepane amino acid is an effective β-turn inducer when incorporated at the i + 1 position. Moreover, the analysis of the supramolecular self-assembly of one of the β-turn-containing peptide models in the solid state reveals that it forms a supramolecular helical arrangement while maintaining the β-turn structure. The results here presented provide the basis for the use of this azepane quaternary amino acid as a strong β-turn inducer in the search for novel peptide-based bioactive molecules, catalysts, and biomaterials.

Modulation of interactome networks, essentially protein-protein interactions (PPIs), might represent valuable therapeutic approaches to different pathological conditions. Since a high percentage of PPIs are mediated by α-helical structures at the interacting surface, the development of compounds able to reproduce the amino acid side-chain organization of α-helices (e.g. stabilized α-helix peptides and β-derivatives, proteomimetics, and α-helix small-molecule mimetics) focuses the attention of different research groups. This appraisal describes the recent progress in the non-peptide α-helix mimetics field, which has evolved from single-face to multi-face reproducing compounds and from oligomeric to monomeric scaffolds able to bear different substituents in similar spatial dispositions as the side-chains in canonical helices. Grouped by chemical structures, the review contemplates terphenyl-like molecules, oligobenzamides and heterocyclic analogues, benzamide-amino acid conjugates and non-oligomeric small-molecules mimetics, among others, and their effectiveness to stabilize/disrupt therapeutically relevant PPIs. The X-ray structures of a couple of oligomeric peptidomimetics and of some small-molecules complexed with the MDM2 protein, as well as the state of the art on their development in clinical trials, are also remarked. The discovery of a continuously increasing number of new disease-relevant PPIs could offer future opportunities for these and other forthcoming α-helix mimetics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

α7 Nicotinic acetylcholine receptors (nAChRs) are ion channels implicated in a number of CNS pathological processes, including pain and psychiatric, cognitive and inflammatory diseases. Comparing with orthosteric agonism, positive allosteric modulation of these channels constitutes an interesting approach to achieve selectivity versus other nicotinic receptors. We have recently described new chalcones and 1,3-diphenylpropanones as positive allosteric modulators (PAMs) of α7 nAChRs, which proved to have good analgesic activities but poor pharmacokinetic properties. Here we report the preparation of amino acid and peptide derivatives as prodrugs of these modulators with the aim of improving their in vivo biological activity. While the valine derivative showed very short half life in aqueous solutions to be considered a prodrug, Val-Val and Val-Pro-Val are suitable precursors of the parent 1,3-diphenylpropanones, via chemical and enzymatic transformation, respectively. Compounds 19 (Val-Val) and 21 (Val-Pro-Val), prodrugs of the 2',5',4-trihydroxy-1,3-diphenylpropan-1-one 3, showed significant antinociceptive activity in in vivo assays. The best compound, 21, displayed a better profile in the analgesia test than its parent compound 3, exhibiting about the same potency but long-lasting effects., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A suitably protected Orn-derived (3S,4S)-β-lactam was used as common intermediate in the synthesis of conformationally constrained (3S,4S)-2-oxoazepane α,α- and (2S,3S)-2-oxopiperidine-β(2,3,3)-amino acid derivatives. Compared to alternative procedures using an N-p-methoxybenzyl group at the 2-azetidinone, the incorporation of a p-methoxyphenyl moiety is crucial for the excellent stereochemical outcomes in the preparation of these heterocyclic amino acids. Chemoselective 7- or 6-exo-trig cyclization was achieved through alternative sequences of Pmp-deprotection/Boc-activation, followed by inter- and intramolecular β-lactam ring opening, respectively.

1,2-Diamine derivatives are valuable building blocks to heterocyclic compounds and important precursors of biologically relevant compounds. In this respect, amino acid-derived β-keto esters are a suitable starting point for the synthesis of β,γ-diamino ester derivatives through a two-step reductive amination procedure with either simple amines or α-amino esters. AcOH and NaBH(3)CN are the additive and reducing agents of choice. The stereoselectivity of the reaction is still an issue, due to the slow imine-enamine equilibria through which the reaction occurs, affording mixtures of diastereoisomers that can be chromatographically separated. Transformation of the β,γ-diamino esters into pyrrolidinone derivatives allows the configuration assignment of the linear compounds, and constitutes an example of their potential application in the generation of molecular diversity.

A simple method for the synthesis of an azepane quaternary amino acid in enantiopure form is described. Theoretical, NMR, and X-ray studies indicated that this azepane-derived amino acid is an effective stabilizer of 3(10) helical structures in short peptides.

To explore further the chemistry of amino acid-derived β-lactams, their conversion to α,α-heterocyclic quaternary amino acid derivatives is investigated. The latter derivatives, containing 2-oxoazepane as the α,α-substituent, are synthesized by a simple Pd-C-catalyzed hydrogenolysis of Orn(Z)-derived 2-azetidinones. The rearrangement from four- to seven-membered lactam ring is driven by the key intramolecular opening of the 1-Boc-β-lactam, initiated by 7-exotrig ring closure from the NH(2) of the Orn side chain. The synthetic route is applied to the stereoselective preparation of enantiomerically pure 4-amino-3-methyl-2-oxoazepane-4-carboxylate derivatives, for which the structure and configuration is confirmed by X-ray diffraction. Molecular modeling and NMR experiments indicate that these quaternary amino acids are able to drive the adoption of β-turn secondary structures when incorporated in model dipeptide derivatives.

Two solid-phase approaches, involving the base-assisted intramolecular alkylation of N-chloroacetyl-Phe derivatives anchored to appropriate solid supports, were investigated for the preparation of novel beta-lactams. When a BAL-type strategy was used, the resin-bound azetidinones were easily formed, as established by MAS-NMR, but final compounds could not be removed from the resin, unless a suitable two linkers system was used. In the second approach, in which the Phe residue is anchored to a Wang-type resin through the carboxylate group, the corresponding 1,4,4-trisubstituted 2-azetidinone was obtained in moderate to good yield and high purity.

The first general approach toward the asymmetric synthesis of 4-alkyl-4-carboxy-2-azetidinones derived from amino acids is described. The stereoselective construction of the beta-lactam ring was achieved through base-mediated intramolecular cyclization of the corresponding N(alpha)-chloroacetyl derivatives bearing (+)- or (-)-10-(N,N-dicyclohexylsulfamoyl)isoborneol as chiral auxiliary (ee up to 82%).

A systematic study on the base-assisted intramolecular alkylation of N-benzyl-N-chloroacetyl amino acid derivatives is described. This study resulted in the first concise and versatile route to the preparation of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones, to be included into the scarce family of beta-lactams with quaternary centers at the C(4) position. Particularly noteworthy is that the intramolecular N(alpha)-C(alpha)-cyclization of Phe and Leu derivatives afforded the corresponding beta-lactam derivatives with moderate enantioselectivity (up to 56%). It is suggested that, in these particular cases, the cyclization reaction proceeds by way of planar enolate intermediates, which possess dynamic chirality. The described sequence of reactions, that is compatible with commonly used protecting moieties for the alpha-carboxy group, cannot be applied to dipeptides, since the cyclization to the six-membered 2,5-diketopiperazine ring occurs preferentially.