Synthesis and conformational preferences of unnatural tetrapeptides containing l-valine units

Balducci, Daniele; Bottoni, Andreà; Calvaresi, Matteo; Porzi, Gianni; Sandri, Sergio

doi:10.1016/j.tetasy.2006.12.006

Cited by 8 publications

(28 citation statements)

References 27 publications

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“…[23] A combined molecular modeling and solution and crystal-state conformational study of acyl-l-Val-l-Xxx-NHR peptides (in which Xxx is 4-methylene-l-(aMe)Pro) suggests the absence of any C=O···HÀN intramolecular hydrogen bond in this sequence. [24,25] According to the X-ray diffraction data, the 4-substituted l-(aMe)Pro residue is a right-handed helix.…”

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confidence: 99%

Is the Backbone Conformation of C^α‐Methyl Proline Restricted to a Single Region?

Poli

Moretto

Crisma

et al. 2009

Chemistry A European J

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C(alpha)-methyl-L-proline, or L-(alphaMe)Pro, is probably the most conformationally constrained alpha-amino acid. In particular, its omega and phi torsion angles are restricted to about 180 and -60 degrees, respectively, and only three ranges of values are theoretically available for psi in mono- or longer peptides, namely, about -30 degrees (cis', 3(10)/alpha-helical structure), 60 degrees (inverse gamma turn), or 140 degrees (trans', poly(L-Pro)(n) II structure). In this work, we examined the tendency of a number of N(alpha)-acyl dipeptide N'-alkylamides of the type RCO-(alphaMe)Pro-Xxx-NHR' or RCO-Xxx-(alphaMe)Pro-NHR', in which Xxx is L (or D)-Ala, Aib (alpha-aminoisoburyric acid), or L (or D)-(alphaMe)Pro, long enough to fold into intramolecularly hydrogen-bonded gamma or beta turns. The results are compared with those obtained for the corresponding dipeptides based on Pro, a well-known turn-forming residue. For the crystal-state 3D-structural analysis we used X-ray diffraction, whereas our solution conformational analysis was heavily based on the FTIR absorption and (1)H and (13)C NMR spectroscopy techniques. We conclude that (alphaMe)Pro is able to explore both trans' and cis' psi areas of the conformational space, but in (alphaMe)Pro the latter is overwhelmingly more populated, in marked contrast to the Pro preference. This finding is a clear indication that in (alphaMe)Pro the major 3D-structural determinant is the C(alpha)-methyl group. The circular dichroism (CD) signature of a peptide type III' beta-turn conformation is also proposed.

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confidence: 99%

Is the Backbone Conformation of C^α‐Methyl Proline Restricted to a Single Region?

Poli

Moretto

Crisma

et al. 2009

Chemistry A European J

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“…The conformational analysis carried out on these unnatural peptides, pointed out the role of proline derivatives in originating β-and γ-folded conformers, thus acting as a scaffold promoting compact conformations. 16 In the present paper our aim is to study more extended unnatural peptides, containing in the middle of the chain a modified (S)-proline unit as a scaffold and to investigate the presence of stable conformations associated with reverse turn formation through intra-molecular hydrogen bonds, similar to those already observed. [16][17][18] We have synthesized new non-proteinogenic peptides incorporating, besides the modified (S)-proline, three L-valine units and two additional non proteinogenic α-aminoacids such as (2R)-methyl aspartic acid and (2S)-methylornitine.…”

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confidence: 78%

“…16 In the present paper our aim is to study more extended unnatural peptides, containing in the middle of the chain a modified (S)-proline unit as a scaffold and to investigate the presence of stable conformations associated with reverse turn formation through intra-molecular hydrogen bonds, similar to those already observed. [16][17][18] We have synthesized new non-proteinogenic peptides incorporating, besides the modified (S)-proline, three L-valine units and two additional non proteinogenic α-aminoacids such as (2R)-methyl aspartic acid and (2S)-methylornitine. These unnatural hexapeptides (1, 2a and 2b in Scheme 1) have been examined using spectroscopic techniques ( 1 H NMR and IR) and computational simulations based on molecular dynamics (MD).…”

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confidence: 78%

“…[16][17][18][19][40][41][42][43][44] Concerning the latter parameter we must outline that it does not always represent a key factor to establish the formation of hydrogen bonds, particularly in the case of cross-linked peptides.…”

Section: Computational Proceduresmentioning

confidence: 99%

“…A computational strategy based on a two step protocol has been employed to explore the conformational space (phase space) of pseudopeptides 1, 2a and 2b and obtain structural information to rationalize the spectroscopic data. 16,18,21 In a first step a high-temperature quenched molecular dynamics (QMD) has been carried out to identify the most In the following we briefly describe the method used to build the diagrams of Figure 2. The free energy change associated with the passage between two different states of a system in thermodynamic equilibrium is given by ∆G = -RT ln (p 1 / p 2 ).…”

Section: -47mentioning

confidence: 99%

See 2 more Smart Citations

Conformational analysis of hexapseudopeptides mimicking reverse turn structures induced by a modified (S)-proline. A combined spectroscopic and molecular dynamics investigation. Part 4

et al. 2009

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Stereocontrolled Synthesis of Unnatural Tetrapeptides Containing L‐Valine Units. Part 3

Balducci

Porzi

2011

Helvetica Chimica Acta

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The stereoselective synthesis of the new nonproteinogenic branched tetrapeptides 9a -9d and 15a,b, containing two l-valine units and unnatural a-amino acids, was accomplished starting from the chiral synthon 1a, a monolactim ether easily obtained from l-valine.Introduction. -The present communication is a continuation of our studies directed at the stereoselective synthesis of pseudopeptides with the objective that the unnatural peptides, as some natural ones, could exhibit biological activity with the advantage of proteolytic stability. The presence of a-alkyl a-amino acids may influence the conformation of these unnatural peptides altering their properties [3]. Thus, we have focused our attention towards new peptidomimetic structures containing nonproteinogenic a-alkylated a-amino acids (modified proline or aspartic acid) and l-valine units [4]. This communication is connected with previous articles which addressed the stereocontrolled synthesis of unnatural tetrapeptides, C-terminal at both ends of the chain, containing l-valine units [1] [2]. Here, we report a versatile and simple approach to the stereoselective synthesis of branched unnatural tetrapeptides containing two lvaline units, one 2-methyl-d-aspartic acid and one other a-amino acid. The latter aamino acid was either (2R)-2,4-diaminobutanoic acid (in 9a), its (2R)-2-methyl (i.e., disovaline; in 9b), or its (2S)-2-methyl derivative (i.e., l-isovaline; in 15a), or dornithine (in 9c), its 2-methyl (in 9d), or the corresponding 2-methyl-l derivative (in 15b).The synthetic strategy adopted in the stereocontrolled synthesis of the title pseudotetrapeptides is based on the experience already acquired in previous approaches [1] [2] [4] making use of the chiral monolactim ether 1a, easily obtained from l-valine [5]. Schçllkopfs strategy, aimed to the asymmetric synthesis of nonproteinogenic dipeptides, was based on the use of the bis-lactim ether which is subsequently converted to the corresponding monolactim derivative [6].

show abstract

Synthesis and conformational preferences of unnatural tetrapeptides containing l-valine units

Cited by 8 publications

References 27 publications

Is the Backbone Conformation of C^α‐Methyl Proline Restricted to a Single Region?

Is the Backbone Conformation of C^α‐Methyl Proline Restricted to a Single Region?

Conformational analysis of hexapseudopeptides mimicking reverse turn structures induced by a modified (S)-proline. A combined spectroscopic and molecular dynamics investigation. Part 4

Stereocontrolled Synthesis of Unnatural Tetrapeptides Containing L‐Valine Units. Part 3

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Synthesis and conformational preferences of unnatural tetrapeptides containing l-valine units

Cited by 8 publications

References 27 publications

Is the Backbone Conformation of Cα‐Methyl Proline Restricted to a Single Region?

Is the Backbone Conformation of Cα‐Methyl Proline Restricted to a Single Region?

Conformational analysis of hexapseudopeptides mimicking reverse turn structures induced by a modified (S)-proline. A combined spectroscopic and molecular dynamics investigation. Part 4

Stereocontrolled Synthesis of Unnatural Tetrapeptides Containing L‐Valine Units. Part 3

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Is the Backbone Conformation of C^α‐Methyl Proline Restricted to a Single Region?

Is the Backbone Conformation of C^α‐Methyl Proline Restricted to a Single Region?