Preparation and Structure ofβ-Peptides Consisting of Geminally Disubstitutedβ2,2- andβ3,3-Amino Acids: A Turn Motif forβ-Peptides

Seebàch, Dieter; Abele, Stefan; Sifferlen, Thierry; Hanggi, M.; Gruner, Sibylle A. W.; Seiler, Paul

doi:10.1002/(sici)1522-2675(19981216)81:12<2218::aid-hlca2218>3.0.co;2-0

Cited by 120 publications

(82 citation statements)

References 28 publications

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“…A dramatic example is the C 14 -helix formed in the all b-peptide Boc-(trans-ACHC) 6 CO 2 CH 2-Ph (Appella et al 1996). A C 10 hydrogen bond with a reversed hydrogen-bond directionality has also been characterized in the tripeptide Boc-(1-(aminomethyl) cyclohexanecarboxylic acid) 3 OMe (Seebach et al 1998c;Abele et al 1999).…”

Section: Reverse Turnsmentioning

confidence: 99%

Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of α-amino acids

Chatterjee

Roy

Balaram

2007

J. R. Soc. Interface.

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Half a century has passed since the hydrogen-bonded secondary structures of polypeptides and proteins were first recognized. An extraordinary wealth of conformational information is now available on peptides and proteins, which are formed of a-amino acid residues. More recently, the discovery of well-folded structures in oligopeptides containing b-amino acids has focused a great deal of current interest on the conformational properties of peptides constructed from higher homologues (u) of a-amino acids. This review examines the nature of intramolecularly hydrogen-bonded conformations of hybrid peptides formed by amino acid residues, with a varying number of backbone atoms. The b-turn, a ubiquitous structural feature formed by two residue (aa) segments in proteins and peptides, is stabilized by a 10-atom (C 10 ) intramolecular 4/1 hydrogen bond. Hybrid turns may be classified by comparison with their aa counterparts. The available crystallographic information on hydrogen-bonded hybrid turns is surveyed in this review. Several recent examples demonstrate that individual u-amino acid residues and hybrid dipeptide segments may be incorporated into the regular structures of a-peptides. Examples of both peptide helices and hairpins are presented. The present review explores the relationships between folded conformations in hybrid sequences and their counterparts in all a-residue sequences. The use of stereochemically constrained u-residues promises to expand the range of peptide design strategies to include u-amino acids. This approach is exemplified by well-folded structures like the C 12 (ag) and C 14 (gg) helices formed in short peptides containing multiply substituted g-residues. The achiral g-residue gabapentin is a readily accessible building block in the design of peptides containing g-amino acids. The construction of globular polypeptide structures using diverse hybrid sequences appears to be a realistic possibility.

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Section: Reverse Turnsmentioning

confidence: 99%

Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of α-amino acids

Chatterjee

Roy

Balaram

2007

J. R. Soc. Interface.

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“…[10] Interestingly, only one example of an intramolecularly hydrogen-bonded b-turn analogue was observed in the peptide Piv-Pro-b 3,3 Ac 6 c-NHMe [Piv = pivaloyl (tert-butyl carbonyl)]. [11] We describe herein conformational studies of the model sequences Boc-Xxx-b 2,2 Ac 6 c-NHMe (Xxx = Leu (1), Phe (2)) and Notably, the tripeptide exhibits an unusual C 10 intramolecular hydrogen bond with reversed polarity of the type NÀH i ···O = C i + 1 .…”

Section: Introductionmentioning

confidence: 99%

β‐Turn Analogues in Model αβ‐Hybrid Peptides: Structural Characterization of Peptides Containing β^2,2Ac₆c and β^3,3Ac₆c Residues

Basuroy

Appavu

Raghothama

et al. 2012

Chemistry An Asian Journal

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The effect of gem-dialkyl substituents on the backbone conformations of β-amino acid residues in peptides has been investigated by using four model peptides: Boc-Xxx-β(2,2)Ac(6)c(1-aminomethylcyclohexanecarboxylic acid)-NHMe (Xxx = Leu (1), Phe (2); Boc = tert-butyloxycarbonyl) and Boc-Xxx-β(3,3)Ac(6)c(1-aminocyclohexaneacetic acid)-NHMe (Xxx = Leu (3), Phe (4)). Tetrasubstituted carbon atoms restrict the ranges of stereochemically allowed conformations about flanking single bonds. The crystal structure of Boc-Leu-β(2,2)Ac(6)c-NHMe (1) established a C(11) hydrogen-bonded turn in the αβ-hybrid sequence. The observed torsion angles (α(ϕ≈-60°, ψ≈-30°), β(ϕ≈-90°, θ≈60°, ψ≈-90°)) corresponded to a C(11) helical turn, which was a backbone-expanded analogue of the type III β turn in αα sequences. The crystal structure of the peptide Boc-Phe-β(3,3)Ac(6)c-NHMe (4) established a C(11) hydrogen-bonded turn with distinctly different backbone torsion angles (α(ϕ≈-60°, ψ≈120°), β(ϕ≈60°, θ≈60°, ψ≈-60°)), which corresponded to a backbone-expanded analogue of the type II β turn observed in αα sequences. In peptide 4, the two molecules in the asymmetric unit adopted backbone torsion angles of opposite signs. In one of the molecules, the Phe residue adopted an unfavorable backbone conformation, with the energetic penalty being offset by a favorable aromatic interaction between proximal molecules in the crystal. NMR spectroscopy studies provided evidence for the maintenance of folded structures in solution in these αβ-hybrid sequences.

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“…4 Seebach et al 5 have recently shown that a,a-disubstitution in b-peptides leads to the formation of very stable peptide secondary structures. In this context, especially remarkable folding properties were observed in b-peptides bearing a cyclic a,a-disubstitution pattern ( Figure 1).…”

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confidence: 99%

Synthesis of α,α-Disubstituted β-Amino Esters and Peptide Derivatives

Alonso¹,

Pozo²,

González³

2002

Synlett

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The synthesis of a,a-disubstituted b-amino esters and peptide derivatives from readily available 4-spiro-b-lactams 1 is described. The geminally disubstituted b-amino esters are obtained from the N-Boc spiro b-lactams 2 by treatment with potassium cyanide in methanol. Alternatively, the use of spiro b-lactams 2 as acylating agents of the amino group of C-protected amino acids, allowed its direct incorporation into a peptidic chain.b-Amino acids have attracted a great deal of interest during the last few years due to their presence in a wide number of natural products (e.g., the side chain of the anticancer agent, taxol). On the other hand, and perhaps even more interesting, recent results show that synthetic b-peptides (b-amino acids oligomers) present some interesting features. They form much more stable secondary structures than do their parents a-peptides, 1 and some of them exhibit biological activity acting as inhibitors of cholesterol and fat absorption 2 or as antibiotics. 3Among the available methods for the synthesis of b-amino acids (a-or b-monosubstituted), just a few are suitable for the preparation of a,a-and b,b-disubstituted ones. 4 Seebach et al. 5 have recently shown that a,a-disubstitution in b-peptides leads to the formation of very stable peptide secondary structures. In this context, especially remarkable folding properties were observed in b-peptides bearing a cyclic a,a-disubstitution pattern ( Figure 1). These cyclic a,a-disubstituted b-peptides adopt unprecedented peptide secondary structures not only in the a-amino acid field, but also in realm of b-peptides. 6 Figure 1In this paper we describe the synthesis of cyclic a,a-disubstituted b-amino esters and peptide derivatives employing 4-spiro b-lactams 1 as starting materials (Scheme 1). 7 b-Lactams can be viewed as cyclic b-amino acids, in which both the amino and the acid moieties are simultaneously protected, and therefore they are usually employed as precursors of b-amino acids. 8 It is interesting to point out that a few synthetic methodologies to prepare spiro b-lactams have been described so far, 9 and only in one case they were employed as precursors of cyclic a,adisubstituted b-amino acid derivatives (Figure 2). 10 Figure 2At this point, we thought that 4-spiro b-lactams 1, could be useful intermediates for the preparation of b-amino acids with a,a-cyclic disubstitution. These a,a-disubstituted cyclic b-amino acids present some new interesting structural features: a) their unsymmetrical (tetrahydrofuran ring) a,a-disubstitution (almost all previously described cyclic a,a-or b,b-disubstituted b-amino acids bear a cycloalkane ring); 6,11 b) the presence of an oxygen atom in the tetrahydrofuran ring, since oxygen could act as a hydrogen bond acceptor increasing the conformational bpeptide possibilities and their hydrogen bond interactions with peptide receptors.Although b-amino acids could be directly obtained from N-alkyl or N-aryl b-lactams by treatment with HCl (6 N) at 100 ºC, we previously transformed the b-lactams 1 to the N-B...

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Preparation and Structure ofβ-Peptides Consisting of Geminally Disubstitutedβ2,2- andβ3,3-Amino Acids: A Turn Motif forβ-Peptides

Cited by 120 publications

References 28 publications

Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of α-amino acids

Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of α-amino acids

β‐Turn Analogues in Model αβ‐Hybrid Peptides: Structural Characterization of Peptides Containing β^2,2Ac₆c and β^3,3Ac₆c Residues

Synthesis of α,α-Disubstituted β-Amino Esters and Peptide Derivatives

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Preparation and Structure ofβ-Peptides Consisting of Geminally Disubstitutedβ2,2- andβ3,3-Amino Acids: A Turn Motif forβ-Peptides

Cited by 120 publications

References 28 publications

Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of α-amino acids

Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of α-amino acids

β‐Turn Analogues in Model αβ‐Hybrid Peptides: Structural Characterization of Peptides Containing β2,2Ac6c and β3,3Ac6c Residues

Synthesis of α,α-Disubstituted β-Amino Esters and Peptide Derivatives

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β‐Turn Analogues in Model αβ‐Hybrid Peptides: Structural Characterization of Peptides Containing β^2,2Ac₆c and β^3,3Ac₆c Residues