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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.41, #3)
Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives of potential interest for biological and foldameric applications by Asta Žukauskaitė; Sven Mangelinckx; Vida Buinauskaitė; Algirdas Šačkus; Norbert De Kimpe (pp. 541-558).
A short synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates and alkyl 3-bromoazetidine-3-carboxylates was developed involving amination, bromination, and base-induced cyclization of alkyl 2-(bromomethyl)acrylates. The aziridines are the kinetically favored cyclization products and could be transformed into 3-bromoazetidine-3-carboxylic acid derivatives via thermal isomerization. The new small-membered azaheterocyclic α- and β-amino acid derivatives contain a bromo-substituted carbon center as a useful moiety for functionalization. Transformation of these functionalized azaheterocycles via nucleophilic substitution with carbon, sulfur, oxygen, and nitrogen nucleophiles and via elaboration of the amino and carboxyl group provided a broad range of new conformationally constrained aziridine-2- and azetidine-3-carboxylic acid derivatives, which are of interest from a biological point-of-view as well as for applications in the field of foldamers.
Keywords: Aziridine-2-carboxylic acids; Azetidine-3-carboxylic acids; β-Amino acids; α-Amino acids; Conformational constraint
Asymmetric synthesis of quaternary α-amino acid derivatives and their fluorinated analogues by Santos Fustero; María Sánchez-Roselló; Claribel Báez; Carlos del Pozo; José L. García Ruano; José Alemán; Leyre Marzo; Alejandro Parra (pp. 559-573).
In this work, we describe the asymmetric synthesis of a series of fluorinated and non-fluorinated quaternary α-amino acid derivatives. This methodology involves the diastereoselective addition of chiral 2-p-tolylsulfinyl benzylcarbanions to either imines containing a 2-furyl moiety or trifluoromethyl α-imino esters. Synthetic practicality of this method is demonstrated by short (two-steps) and convenient preparation of 2-(trifluoromethyl)indoline-2-carboxylates.
Keywords: Asymmetric synthesis; Sulfinylcarbanion; α,α-Disubstituted (quaternary)-α-amino acids; α,β-Dialkyl-α-amino acids; Trifluoromethylated α-amino acids; Sterically constrained amino acids
A straightforward route to enantiopure 2-substituted-3,4-dehydro-β-proline via ring closing metathesis by Alessandra Tolomelli; Luca Gentilucci; Elisa Mosconi; Angelo Viola; Enrico Paradisi (pp. 575-586).
The synthesis of unusual cyclic amino acids, that may be envisaged as proline analogs, is an area of great interest for their potential applications as scaffolds for the design of bioactive peptidomimetics or units for the creation of novel foldamers. We have carried out the preparation of cyclic dehydro-β-amino acids starting from allylic carbonates via a two-step allylic amination/ring closing metathesis (RCM) protocol. The introduction of the allylamino moiety has been carried out either without a catalyst, through an SN2′ reaction, or in the presence of iridium complexes. The backbone of the allylamino intermediates contains two unsaturations, thus suggesting that RCM could be a valuable tool for the preparation of dihydropyrrole scaffolds. A similar reaction has been already reported in the literature for racemic aromatic-substituted substrates, but no examples of enantiopure derivatives bearing aliphatic chains have been reported. The reaction was optimized by testing different Grubbs’ catalysts and carbamate nitrogen protecting groups. Moreover, in view of a future application of these dehydro-β-amino acids as central core of peptidomimetics, the malonate chain was also used to protect nitrogen prior to RCM.
Keywords: Dehydro-β-proline; Allylic amination; Iridium catalysis; Ring closing metathesis; Grubbs’ catalyst
A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids by Valérie Declerck; David J. Aitken (pp. 587-595).
The synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids has been refined to improve both the efficiency and the simplicity. These improvements provide a shorter and easier access to the racemic cis-cyclobutane β-amino acid core. Derivatization of this material with a chiral non-racemic oxazolidin-2-one allows easy diastereoisomeric separation and presents the advantage of allowing the non-destructive cleavage of the chiral auxiliary either by hydrolysis or by ammonolysis, thus providing an efficacious access to N-protected derivatives of all four stereoisomers of Boc-2-aminocyclobutanecarboxylic acid.
Keywords: 2-Aminocyclobutanecarboxylic acids; Photochemical [2 + 2] cycloaddition; Chiral resolution; Epimerization; Oxazolidin-2-one
Monoterpene-based chiral β-amino acid derivatives prepared from natural sources: syntheses and applications by Zsolt Szakonyi; Ferenc Fülöp (pp. 597-608).
Natural monoterpenes have proved to be good starting materials for the synthesis of β-amino acid derivatives. In the past decade, a number of well-known synthetic procedures have been applied for the preparation of monoterpene-based β-amino acid derivatives, e.g. from β-lactams via the 1,2-dipolar cycloaddition of chlorosulfonyl isocyanate to commercial or readily available monoterpenes [e.g. (+)- and (−)-α- or δ-pinene, (+)-3- and 2-carene, (+)- and (−)-apopinene], the conjugate addition of amides to monoterpene-based α,β-unsaturated esters or the transformations of (−)-cis-pinonoic acid prepared by the oxidative cleavage of (+)- and (−)-verbenone. β-Amino acid derivatives are excellent building blocks for versatile transformations, e.g. multicomponent reactions resulting in β-lactams, syntheses of 1,3-heterocycles and diaminopyrimidine derivatives or the formation of peptides containing an H12 helix. 1,3-Amino alcohol derivatives prepared from β-amino esters have been applied as chiral catalysts in enantioselective transformations. Several of these compounds are of noteworthy pharmacological importance, such as tyrosine kinase Axl inhibitor diaminopyrimidine-coupled β-aminocarboxamides, MDR inhibitor thiourea derivatives of β-amino esters or 2-imino-1,3-oxazines, which exhibit marked growth inhibitory activity on multiple cancer cell lines. The present review summarizes recent developments relating to the syntheses, applications and pharmaceutical importance of monoterpene-based β-amino acids and their derivatives.
Keywords: Beta-amino acid; Monoterpene; Chiral; Asymmetric synthesis; Chiral catalyst
Formation of gels in the presence of metal ions by Nicola Castellucci; Giuseppe Falini; Gaetano Angelici; Claudia Tomasini (pp. 609-620).
A small library of stereoisomeric pseudopeptides able to make gels in different solvents has been prepared and their attitude to make gels in the presence of several metal ions was evaluated. Four benzyl esters and four carboxylic acids, all containing a moiety of azelaic acid (a long chain dicarboxylic acid) coupled with four different pseudopeptide moieties sharing the same skeleton (a phenyl group one atom apart from the oxazolidin-2-one carboxylic group), were synthesized in solution, by standard coupling reaction. The tendency of these pseudopeptides to form gels was evaluated using the inversion test of 10 mM solutions of pure compounds and of stoichiometric mixtures of pseudopeptides and metal ions. To obtain additional information on the molecular association, the gel samples were left dry in the air to form xerogels that were further analyzed using SEM and XRD. The formation of gel containing Zn(II) or Cu(II) ions gave good results in term of incorporation of the metal ions, while the presence of Cu(I), Al(III) and Mg(II) gave less satisfactory results. This outcome is a first insight in the formation of stable LMWGs formed by stoichiometric mixtures of pseudopeptides and metal ions. Further studies will be carried out to develop similar compounds of pharmacological interest.
Keywords: Low molecular weight gelators; Pseudopeptides; Metal ions; Azelaic acid; Pseudoprolines
Toward the rational design of molecular rotors ion sensors based on α,γ-cyclic peptide dimers by María Jesús Pérez-Alvite; Manuel Mosquera; Luis Castedo; Juan R. Granja (pp. 621-628).
A dimer-forming self-assembling cyclic hexapeptide with a control register and a large association constant in water is described. The self-assembly process is followed by pyrene-excimer emission and the main diastereomeric dimer present in solution is switched by controlled addition of divalent cations (e.g., Ca, Mg) or oxalic acid.
Keywords: Self-assembling; Cyclic peptide; Molecular rotor; γ-Amino acid; Dimer; Excimer
Chiral, fully extended helical peptides by Marco Crisma; Alessandro Moretto; Cristina Peggion; Lavinia Panella; Bernard Kaptein; Quirinus B. Broxterman; Fernando Formaggio; Claudio Toniolo (pp. 629-641).
The synthesis of the N-protected (blocked) homo-peptide esters from the chiral Cα-ethyl, Cα-n-pentylglycine was performed in solution to the hexapeptide level. The conformational propensity exhibited by these oligomers in chloroform solution and in the crystal state was assessed by use of FTIR absorption, NMR, and X-ray diffraction. The results indicated that fully extended helical structures (2.05-helices) are overwhelmingly adopted irrespective of the peptide main-chain length. This oligomeric series is of great interest as it is characterized by the longest C i α ,…, C i+1 α (per residue) separation achievable in the class of chiral, rigid, helical peptide spacers based on α-amino acids.
Keywords: Fully extended helix; Homo-oligopeptides; Infrared absorption; Nuclear magnetic resonance; Cα-Tetrasubstituted α-amino acids; X-ray diffraction
C-3 branched δ-3,5-cis- and trans-THF sugar amino acids: synthesis of the first generation of branched homooligomers by Michela I. Simone; Alison A. Edwards; George E. Tranter; George W. J. Fleet (pp. 643-661).
This article describes the efficient synthesis of the first generation of branched sugar amino acid (SAA) oligomers in solution phase via two main routes: by the use of a standard coupling reagent and via the use of active ester intermediates. Benzyl-protected dimeric carbopeptoid and methyl-protected dimeric and tetrameric, hexameric and octameric carbopeptoids were obtained from a branched δ-3,5-trans-tetrahydrofuran (THF) SAA and methyl-protected dimeric and tetrameric carbopeptoids were synthesised from a branched δ-3,5-cis-THF SAA. These systems are of interest because of their potential to display foldameric properties reminiscent of those observed in α-peptides and proteins. Amongst their many uses, foldamers provide simpler models in the study of the factors which induce the folding and unfolding of proteins and, ultimately, potential insights into their functioning.
Keywords: Sugar amino acids; Branched carbohydrates; Secondary structure; Foldamers; Carbopeptoids
Cyclic α,β-peptoid octamers with differing side chain patterns: synthesis and conformational investigation by Emiliana De Santis; Thomas Hjelmgaard; Sophie Faure; Olivier Roy; Claude Didierjean; Bruce D. Alexander; Giuliano Siligardi; Rohanah Hussain; Tamás Jávorfi; Alison A. Edwards; Claude Taillefumier (pp. 663-672).
The solution-phase synthesis and cyclisation of three α,β-peptoid octamers with differing side chain patterns is reported. One of these, compound C, showed a significantly greater resolution by NMR relative to the other two structurally related octamers. This observation was studied in detail by circular dichroism at a synchrotron light source to facilitate the correlation between the side chain patterns and conformational preference of these three peptoids. The X-ray crystal structure of cyclic octamer C, the first high-resolution structure for the α,β-peptoid backbone, was also obtained from methanol. Combined solid- and solution-phase studies allowed the identification of the N-2-(benzyloxy)ethyl side chain on the β-residue of the heterogeneous backbone as a key structural feature driving the increased conformational stability for octamer C.
Keywords: Peptidomimetics; α,β-peptoids; Circular dichroism; X-ray crystallography
Synthesis and structural study of highly constrained hybrid cyclobutane-proline γ,γ-peptides by Raquel Gutiérrez-Abad; Daniel Carbajo; Pau Nolis; Carles Acosta-Silva; Juan A. Cobos; Ona Illa; Miriam Royo; Rosa M. Ortuño (pp. 673-686).
Two diastereomeric series of hybrid γ,γ-peptides derived from conveniently protected derivatives of (1R,2S)- and (1S,2R)-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid and cis-4-amino-l-proline joined in alternation have efficiently been prepared through convergent synthesis. High-resolution NMR experiments show that these compounds present defined conformations in solution affording very compact structures as the result of intra and inter residue hydrogen-bonded ring formation. (R,S)-cyclobutane containing peptides adopt more twisted conformations than (S,R) diastereomers. In addition, all these γ-peptides have high tendency to aggregation providing vesicles of nanometric size, which were stable when allowed to stand for several days, as verified by transmission electron microscopy.
Keywords: Hybrid γ,γ-peptides; Cyclobutane; cis-4-amino-l-proline; Hydrogen bonds; Secondary structures; Self-assembly; Vesicles
Foldamers containing γ-amino acid residues or their analogues: structural features and applications by Francelin Bouillère; Sophie Thétiot-Laurent; Cyrille Kouklovsky; Valérie Alezra (pp. 687-707).
Over the past 20 years, the field of foldamers has rapidly increased. Many β-peptides have already been described and shown interesting properties. γ-Peptides have more recently emerged but seem to be very interesting as well. In this review, we will cover every peptidomimetic oligomer that contains a γ-amino acid or an analogue and presents a structural feature. It includes γ-peptides but also hybrid α–γ peptides, β–γ peptides and analogues such as oligoureas or aminoxy acids. We will present the biological properties of these oligomers.
Keywords: Gamma-amino acid; Gamma-peptide; Foldamer; Hybrid peptide; Secondary structure
α/β-Peptide foldamers: state of the art by Ludwig K. A. Pilsl; Oliver Reiser (pp. 709-718).
Interplay between proteins, nucleic acids, carbohydrates and/or lipids is involved in almost every process in life on earth. As a consequence, a wide range of diseases results from abnormal interactions of such biomolecules. The main motivation of foldamer science is the development of scaffolds that are capable of adopting defined structures, mimicking parts of biological protagonists in their function. Among the most fundamental interactions in living beings are those between proteins, the so called protein–protein interactions (PPIs). Therefore, peptidic foldamers bear the promise to be an important tool for the inhibition of PPIs, as they are structurally most similar to the original proteins. The great number of possible permutations given by the combination of proteinogenic α-amino acid residues along with β-amino acids opens the door for a larger pool of accessible structures with potential applications. Despite the increasing amount of new secondary structure motifs, only few examples for tertiary and quaternary structure design, as well as inhibition of PPIs, have been realized so far. In this review, we summarize the current knowledge and recent progress made in the field of α/β-peptide foldamers beginning from secondary structure design up to highly sophisticated biological applications, such as protein surface recognition and inhibition of HIV cell entry.
Keywords: Foldamers; β-Amino acids; α/β-Peptides; Peptide mimicry; Protein surface recognition; Protein–protein interactions
Synthesis and characterization of natural and modified antifreeze glycopeptides: glycosylated foldamers by Lilly Nagel; Carolin Plattner; Carsten Budke; Zsuzsanna Majer; Arthur L. DeVries; Thomas Berkemeier; Thomas Koop; Norbert Sewald (pp. 719-732).
In Arctic and Antarctic marine regions, where the temperature declines below the colligative freezing point of physiological fluids, efficient biological antifreeze agents are crucial for the survival of polar fish. One group of such agents is classified as antifreeze glycoproteins (AFGP) that usually consist of a varying number (n = 4–55) of [AAT] n -repeating units. The threonine side chain of each unit is glycosidically linked to β-d-galactosyl-(1 → 3)-α-N-acetyl-d-galactosamine. These biopolymers can be considered as biological antifreeze foldamers. A preparative route for stepwise synthesis of AFGP allows for efficient synthesis. The diglycosylated threonine building block was introduced into the peptide using microwave-enhanced solid phase synthesis. By this versatile solid phase approach, glycosylated peptides of varying sequences and lengths could be obtained. Conformational studies of the synthetic AFGP analogs were performed by circular dichroism experiments (CD). Furthermore, the foldamers were analysed microphysically according to their inhibiting effect on ice recrystallization and influence on the crystal habit.
Keywords: Bioorganic chemistry; Solid phase peptide synthesis; Microwave-enhanced synthesis; Glycopeptides; Ice recrystallization; Circular dichroism
A systematic study of fundamentals in α-helical coiled coil mimicry by alternating sequences of β- and γ-amino acids by Raheleh Rezaei Araghi; Carsten Baldauf; Ulla I. M. Gerling; Cosimo Damiano Cadicamo; Beate Koksch (pp. 733-742).
Aimed at understanding the crucially important structural features for the integrity of α-helical mimicry by βγ-sequences, an α-amino acid sequence in a native peptide was substituted by differently arranged βγ-sequences. The self- and hetero-assembly of a series of αβγ-chimeric sequences based on a 33-residue GCN4-derived peptide was investigated by means of molecular dynamics, circular dichroism, and a disulfide exchange assay. Despite the native-like behavior of βγ alternating sequences such as retention of α-helix dipole and the formation of 13-membered α-helix turns, the αβγ-chimeras with different βγ substitution patterns do not equally mimic the structural behavior of the native parent peptide in solution. The preservation of the key residue contacts such as van der Waals interactions and intrahelical H-bonding, which can be met only by particular substitution patterns, thermodynamically favor the adoption of coiled coil folding motif. In this study, we show how successfully the destabilizing structural consequences of α → βγ modification can be harnessed by reducing the solvent-exposed hydrophobic surface area and placing of suitably long and bulky helix-forming side chains at the hydrophobic core. The pairing of αβγ-chimeric sequences with the native wild-type are thermodynamically allowed in the case of ideal arrangement of β- and γ-residues. This indicates a similarity in local side chain packing of β- and γ-amino acids at the helical interface of αβγ-chimeras and the native α-peptide. Consequently, the backbone extended residues are able to participate in classical “knob-into-hole” packing with native α-peptide.
Keywords: α-Helical coiled coil; Foldamers; Chimeric peptides; β-Amino acids; γ-Amino acids
Helix-mediated protein–protein interactions as targets for intervention using foldamers by Thomas A. Edwards; Andrew J. Wilson (pp. 743-754).
Protein–protein interactions (PPIs) play a central role in virtually all biological processes and have been the focus of intense investigation from structural molecular biology to cell biology for the majority of the last two decades and, more recently, are emerging as important targets for pharmaceutical intervention. A common motif found at the interface of PPIs is the α-helix, suggesting that, in the same way as the “lock and key” model has evolved for competitive inhibition of enzymes, it should be possible to elaborate “rule-based” approaches for inhibition of helix-mediated PPIs. This review will describe the biological function and structural features of a series of representative helix-mediated PPIs and discuss approaches that are being developed to target these interactions with small molecules that employ non-natural amino acids.
Keywords: Protein–protein interactions; Chemical biology; Helix mimetics; Foldamers