Preferred conformation of peptides based on cycloaliphatic C?,?-disubstituted glycines: 1-amino-cycloundecane-1-carboxylic acid (Ac11c)

Abstract

Two complete series of N‐protected oligopeptide esters to the pentamer level from 1‐amino‐cycloundecane‐1‐carboxylic acid (Ac11c), an α‐amino acid conformationally constrained through a medium‐ring Cαi↔Cαi cyclization, and either the L‐Ala or Aib residue, along with the N‐protected Ac11c monomer and homo‐dimer alkylamides, have been synthesized by solution methods and fully characterized. The preferred conformation of these model peptides has been assessed in deuterochloroform solution by FT‐IR absorption and 1H‐NMR techniques. Furthermore, the molecular structures of one derivative (Z‐Ac11c‐OH) and two peptides (the tripeptide ester Z‐Aib‐Ac11c‐Aib‐OtBu and the pentapeptide ester Z‐Ac11c‐(Aib)2‐Ac11c‐Aib‐OtBu) have been determined in the crystal state by X‐ray diffraction. The experimental results support the view that β‐bends and 310‐helices are preferentially adopted by peptides rich in Ac11c, the second largest cycloaliphatic Cα,α‐disubstituted glycine known. This investigation has allowed the authors to approach the completion of a detailed conformational analysis of the whole 1‐amino‐cycloalkane‐1‐carboxylic acid (Acnc, with n=3–12) series, which represents the prerequisite for their recent proposal of the ‘Acnc scan’ concept. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.

Control of peptide conformation by the Thorpe-Ingold effect (C?-tetrasubstitution)

“…Interestingly, the largely preferred conformations (regular type III/III′ β‐bends and 3 10 /α‐helices) and the typical value for the τ bond angle (110°–111°) theoretically and experimentally found for the 1‐amino‐1‐cycloalkanecarboxylic acids Ac n c ( n = 4–12) (Figure 8) with the cyclic moieties larger than that of Ac 3 c, closely parallel those of the prototype Aib (Table I). 24–27, 73, 74, 99–108 The effect of the side‐chain conformational changes produced by cyclization upon the preferred peptide backbone structure is evident from a comparison of the results of the Ac 5 c, Ac 7 c, and Ac 9 c residues with those of the corresponding open‐chain analogs Deg, Dp n g, and Dbg with the same number of side‐chain carbon atoms. Results of x‐ray diffraction analyses of the structural preferences of the cycloalkyl moieties of the Ac n c ( n = 4–12) residues have been described and discussed in comparison with those of related cycloalkanes 109, 110.…”

“…The two concepts differ in the sense that the classical type of scan involves the incorporation of the same residue (e.g. Ala) at different positions of the peptide chain, whereas the Ac n c scan 106 involves the incorporation of different residues at the same position of the peptide chain. Both types of scan strictly require that the amino acid replacements would not alter the overall conformation (helical for the Ac n c‐bound peptides) of the set of compounds under investigation.…”

Non-Canonical Amino Acids as Building Blocks for Peptidomimetics: Structure, Function, and Applications

“…Previous experimental and modelling findings indicate that Ac n c cycles with more than 3 atoms (n = 4–12) explore, mostly, the main chain geometry similar to Aib ( φ , ψ ≈ ±60°, ±30°) which is typical of α-helix or 3 10 -helix SS [ 76 , 83 , 84 , 85 , 86 , 87 , 88 ]. The residues Ac 5 c (1-aminocyclopentane-1-carboxylic acid) and Ac 6 c (1-aminocyclohexane-1-carboxylic acid) have been found to yield γ-turn conformations in small peptides [ 78 , 89 , 90 , 91 ].…”

Crystal structure of a tripeptide containing aminocyclododecane carboxylic acid: a supramolecular twisted parallel β-sheet in crystals

“…Incorporation of C α,α ‐dialkylated amino acids such as α‐aminoisobutyric acid and its analogues in polypeptide sequences has enabled the structural characterization of major secondary structural elements of proteins in medium sized peptides and has provided information which are useful in designing higher levels of protein structures . Extensive studies on C α,α ‐dialkylated amino acid residues with both linear and cycloalkyl side chains have revealed that they favor helical or β‐turn conformations . 1‐Amino‐cycloalkane‐1‐carboxylic acid, Ac n c, (where n is the number of atoms in the cycloalkane side chain) with ring sizes (n) varying from 3 to 12 had been incorporated in synthetic peptides and been structurally characterized .…”

“…Extensive studies on C α,α ‐dialkylated amino acid residues with both linear and cycloalkyl side chains have revealed that they favor helical or β‐turn conformations . 1‐Amino‐cycloalkane‐1‐carboxylic acid, Ac n c, (where n is the number of atoms in the cycloalkane side chain) with ring sizes (n) varying from 3 to 12 had been incorporated in synthetic peptides and been structurally characterized . They exhibit similar backbone conformational preferences as the linear side chain counterparts, and provide large hydrophobic surfaces for molecular aggregation, facilitating crystal formation.…”