Synthesis and conformational analysis of 18-membered Aib-containing cyclohexapeptides

The alpha-aminoisobutyric (Aib) residue has generally been considered to be a strongly helicogenic residue as evidenced by its ability to promote helical folding in synthetic and natural sequences. Crystal structures of several peptide natural products, peptaibols, have revealed predominantly helical conformations, despite the presence of multiple helix-breaking Pro or Hyp residues. Survey of synthetic Aib-containing peptides shows a preponderance of 3(10)-, alpha-, and mixed 3(10)/alpha-helical structures. This review highlights the examples of Aib residues observed in nonhelical conformations, which fall 'primarily' into the polyproline II (P(II)) and fully extended regions of conformational space. The achiral Aib residue can adopt both left (alpha(L))- and right (alpha(R))-handed helical conformations. In sequences containing chiral amino acids, helix termination can occur by means of chiral reversal at an Aib residue, resulting in formation of a Schellman motif. Examples of Aib residues in unusual conformations are illustrated by surveying a database of Aib-containing crystal structures.

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“…This overview has attempted to highlight the circumstances in which Aib residues have been observed in unusual conformations. [104] …”

Section: Conformational Distributions In Peptide Crystalmentioning

confidence: 99%

Aib Residues in Peptaibiotics and Synthetic Sequences: Analysis of Nonhelical Conformations

Aravinda

Shamala

Balaram

2008

Chemistry & Biodiversity

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“…13 ) Specific examples of cyclo-b-peptides -(bhXaa) n À: n ¼ 2 [18 -20] [24]. Typical activation for peptide coupling, such as HATU, can also be used to induce cyclization [37]. 15 ) In a recent work, there is the statement that it is known that the cyclization rate of a linear peptide sequence is somewhat unpredictable and may well be sequence-dependent [35a], with reference to Freidinger, one of the masters of peptide chemistry [38].…”

Section: Receptors Hsst 1-5 Were Determined By Competition With [ 125mentioning

confidence: 99%

New Open‐Chain and Cyclic Tetrapeptides, Consisting of α‐, β²‐, and β³‐Amino‐Acid Residues, as Somatostatin Mimics – A Survey

Seebàch

Dubost

Mathad

et al. 2008

Helvetica Chimica Acta

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Dedicated to Prof. Elias J. Corey on the occasion of his 80th birthday Cyclo-b-tetrapeptides are known to adopt a conformation with an intramolecular transannular hydrogen bond in solution. Analysis of this structure reveals that incorporation of a b 2 -amino-acid residue should lead to mimics of a-peptidic b-turns (cf. A, B, C). It is also known that short-chain mixed b/a-peptides with appropriate side chains can be used to mimic interactions between a-peptidic hairpin turns and G protein-coupled receptors. Based on these facts, we have now prepared a number of cyclic and open-chain tetrapeptides, 7 -20, consisting of a-, b 2 -, and b 3 -amino-acid residues, which bear the side chains of Trp and Lys, and possess backbone configurations such that they should be capable of mimicking somatostatin in its affinity for the human SRIF receptors (hsst 1-5 ). All peptides were prepared by solid-phase coupling by the Fmoc strategy. For the cyclic peptides, the three-dimensional orthogonal methodology (Scheme 3) was employed with best success. The new compounds were characterized by high-resolution mass spectrometry, NMR and CD spectroscopy, and, in five cases, by a full NMRsolution-structure determination (in MeOH or H 2 O; Fig. 4). The affinities of the new compounds for the Fig. 1. Molecular formulae of somatostatin (SRIF-14) and Sandostatin , and X-ray crystal structure of Sandostatin [11] 16 ) One of the first to recognize the quasi-high-dilution effect with polymer-bound reagents and intermediates was Patchornik [39]. 17 ) Cf. the use of a simple thioester linkage [45]. 18 ) For some representative examples, see [31] [46]. 19 ) Besides the somatostatin-mimicking cyclopeptides described herein, we have also synthesized RGD-mimicking cyclopeptides, and, in all cases, the yields obtained with the safety catch method were disappointingly low. Scheme 2. Cyclopeptide Head-to-Tail Synthesis by the Kenner -Ellman Safety Catch Methodology [43].The 4-sulfamoyl-butyryl AM resin is commercially available. For activation of the acyl-sulfonamide group, the sulfamoyl N-atom is alkylated (R' ¼ Me, CH 2 CN). In the cyclization step, the peptide is removed from the resin, with the side-chain functional-group protection still in place [44]. This method was applied to the synthesis of the cyclo-b-tetrapeptide 7.Helvetica Chimica Acta -Vol. 91 (2008) 20 ) In the spectrum of 18, this second Cotton effect is at 220 nm! Fig. 2. Normalized CD spectra of cyclic tetrapeptides 10 -14 recorded in MeOH (0.2 mm). The CD spectra of compounds 7 -9 have not been recorded. Fig. 4. NMR Solution structures of the cyclic tetrapeptides 7, 9, and 14 , and of the open-chain tetrapeptides 16 and 17. Low-energy structures derived from SA annealing calculations are shown.

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“…The therapeutic properties of cyclic peptides prompted us to explore them as potential lead compounds. A common strategy employed to improve yields in cyclization reactions involves the incorporation of amino acid residues such as proline, glycine, N-alkylated and D-amino acids, which induce turns in the conformations of peptides [13][14][15]. It is a general observation that the cyclization of linear peptides that do not contain turn structure-inducing residues is improbable or a very slow process.…”

Section: Introductionmentioning

confidence: 99%

Modeling of peptides containing D-amino acids: implications on cyclization

Yongye

Giulianotti

et al. 2009

J Comput Aided Mol Des

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Cyclic peptides are therapeutically attractive due to their high bioavailability, potential selectivity, and scaffold novelty. Furthermore, the presence of D-residues induces conformational preferences not followed by peptides consisting of naturally abundant L-residues. Therefore, comprehending how amino acids induce turns in peptides, subsequently facilitating cyclization, is significant in peptide design. Here, we performed 20-ns explicit-solvent molecular dynamics simulations for three diastereomeric peptides with stereochemistries: LLLLL, LLLDL, and LDLDL. Experimentally LLLLL and LDLDL readily cyclize, whereas LLLDL cyclizes in low yield. Simulations at 310 K produced conformations with inter-terminal hydrogen bonds that correlated qualitatively with the experimental cyclization trend. Energies obtained for representative structures from quantum chemical (B3LYP/PCM/cc-pVTZ//HF/6-31G*) calculations predicted pseudo-cyclic and extended conformations as the most stable for LLLLL and LLLDL, respectively, in agreement with the experimental data. In contrast, the most stable conformer predicted for peptide LDLDL was not a pseudo-cyclic structure. Moreover, D-residues preferred the experimentally less populated alpha(L) rotamers even when simulations were performed at a higher temperature and with strategically selected starting conformations. Energies calculated with molecular mechanics were consistent only with peptide LLLLL. Thus, the conformational preferences obtained for the all L: -amino acid peptide were in agreement with the experimental observations. Moreover, refinement of the force field is expected to provide far-reaching conformational sampling of peptides containing D-residues to further develop force field-based conformational-searching methods.

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Synthesis and conformational analysis of 18-membered Aib-containing cyclohexapeptides

Cited by 30 publications

References 36 publications

Aib Residues in Peptaibiotics and Synthetic Sequences: Analysis of Nonhelical Conformations

Aib Residues in Peptaibiotics and Synthetic Sequences: Analysis of Nonhelical Conformations

New Open‐Chain and Cyclic Tetrapeptides, Consisting of α‐, β²‐, and β³‐Amino‐Acid Residues, as Somatostatin Mimics – A Survey

Modeling of peptides containing D-amino acids: implications on cyclization

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Synthesis and conformational analysis of 18-membered Aib-containing cyclohexapeptides

Cited by 30 publications

References 36 publications

Aib Residues in Peptaibiotics and Synthetic Sequences: Analysis of Nonhelical Conformations

Aib Residues in Peptaibiotics and Synthetic Sequences: Analysis of Nonhelical Conformations

New Open‐Chain and Cyclic Tetrapeptides, Consisting of α‐, β2‐, and β3‐Amino‐Acid Residues, as Somatostatin Mimics – A Survey

Modeling of peptides containing D-amino acids: implications on cyclization

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New Open‐Chain and Cyclic Tetrapeptides, Consisting of α‐, β²‐, and β³‐Amino‐Acid Residues, as Somatostatin Mimics – A Survey