Synthesis of Constrained Head‐to‐Tail Cyclic Tetrapeptides by an Imine‐Induced Ring‐Closing/Contraction Strategy

Wong, Chi‐Ming; Lam, Hiu Yung; Song, Tao; Chen, Guanhua; Li, Xuechen

doi:10.1002/anie.201304773

Cited by 86 publications

(99 citation statements)

References 42 publications

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“…We elected two peptides: NH 2 -AEGSQAKFG X - SE as the C-terminal peptide where X represents different amino acids, and NH 2 -SPKALTFG-CO 2 H as the model peptide containing Ser at the N-terminus. The necessary peptide SAL esters (X = A, G, T, S, V, L, I, P, F, Y, D, E, N, Q, H, and K) were prepared by Boc-SPPS (Wong et al, 2013b), while the peptide SAL esters (X = W, C, M, and R) were synthesized via Fmoc-SPPS (Zhang et al, 2013) due to the incompatibility of ozonolysis (M, C, and W) and TFMSA deprotection of the tosyl group of Arg. The ligation of two unprotected peptide segments was performed as follows: two peptide segments were dissolved in pyridine acetate buffer (1:1, mole: mole) at the concentration of 1 mM at room temperature.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the SAL linker synthesized previously (Wong et al, 2013b), the standard Boc-SPPS protocol was employed. A solution of 20% piperidine in DMF (10 mL) was added to the loaded resin (0.5 mmol/g) and the mixture was gently agitated for 1 h to remove the acetyl group.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, STL-mediated peptide cyclization has been used to synthesize daptomycin and other cyclic peptides of various sizes (Lam et al, 2013; Wong et al, 2013a,b; Zhao et al, 2013). More recently, STL has been used in the form of expression protein ligation, producing a RNase-peptiod conjugate (Levine et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

Wong

Lam

et al. 2014

Front. Chem.

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Serine/Threonine ligation (STL) has emerged as an alternative tool for protein chemical synthesis, bioconjugations as well as macrocyclization of peptides of various sizes. Owning to the high abundance of Ser/Thr residues in natural peptides and proteins, STL is expected to find a wide range of applications in chemical biology research. Herein, we have fully investigated the compatibility of the STL strategy for X-Ser/Thr ligation sites, where X is any of the 20 naturally occurring amino acids. Our studies have shown that 17 amino acids are suitable for ligation, while Asp, Glu, and Lys are not compatible. Among the working 17 C-terminal amino acids, the retarded reaction resulted from the bulky β-branched amino acid (Thr, Val, and Ile) is not seen under the current ligation condition. We have also investigated the chemoselectivity involving the amino group of the internal lysine which may compete with the N-terminal Ser/Thr for reaction with the C-terminal salicylaldehyde (SAL) ester aldehyde group. The result suggested that the free internal amino group does not adversely slow down the ligation rate.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

Wong

Lam

et al. 2014

Front. Chem.

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“…Thus, cyclic tri - 1–4 A and tetra -peptides B 5–11 are notoriously difficult to prepare because they are constrained in 9- and 12-membered ring conformations. Analogs of cyclic tetrapeptides, like the 12-membered ring system C , may be more easily prepared but another problem arises: cis/trans amide bond equilibria introduces conformational heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Xin

Burgess

2016

Org. Biomol. Chem.

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Each amino acid in a peptide contributes three atom units to main-chains, hence natural cyclic peptides can be 9, 12, 15, …. ie 3n membered-rings, where n is the number of amino acids. Cyclic peptides that are 9 or 12-membered ring compounds tend to be hard to prepare because of strain, while their one amino acid homologs (15-membered cyclic pentapeptides) are not conformationally homogeneous unless constrained by strategically placed proline or D-amino acid residues. We hypothesized that replacing one genetically encoded amino acid in a cyclic tetrapeptide with a rigid β-amino acid would render peptidomimetic designs that rest at a useful crossroads between synthetic accessibility and conformational rigidity. Thus this research explored non-proline containing 13-membered ring peptides 1 featuring one anthranilic acid (Anth) residue. Twelve cyclic peptides of this type were prepared, and in doing so the viability of both solution- and solid-phase methods was demonstrated. The library produced contained a complete set of four diastereoisomers of the sequence 1aaf (ie cyclo-AlaAlaPheAnth). Without exception, these four diastereoisomers each adopted one predominant conformation in solution; basically these conformations feature amide N-H vectors puckering above and below the equatorial plane, and approximately oriented their N-H atoms towards the polar axis. Moreover, the shapes of these conformers varied in a logical and predictable way (NOE, temperature coefficient, D/H exchange, circular dichroism). Comparisons were made of the side-chain orientations presented by compounds 1aaa in solution with ideal secondary structures and protein-protein interaction interfaces. Various 1aaa stereoisomers in solution present side-chains in similar orientations to regular and inverse γ-turns, and to the most common β-turns (types I and II). Consistent with this, compounds 1aaa have a tendency to mimic various turns and bends at protein-protein interfaces. Finally, proteolytic- and hydrolytic stabilities of the compounds at different pHs indicate they are robust relative to related linear peptides, and rates of permeability through an artificial membrane indicate their structures are conducive to cell permeability.

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“…其十二元环骨架具有较大张力, 直接环化反应难以发生. 能够在不引入转角诱导因素(如 D-氨基酸和脯氨酸等)及辅助基团的情况下实现其构建的合成方法极为罕见 [8] . 2012 年, 刘磊课题组在本刊发表了通过多肽酰肼化学连接反应合成环状四肽分子的研究(图 2) [9] .…”

Section: 良好的发展前景作为链状体系的拓展当多肽酰基叠氮中间体的unclassified

Synthesis of Highly-strained Cyclic Tetrapeptides via Peptide Hydrazide Based Ligation

Liu¹,

Li²

2014

Acta Chim. Sinica

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A series of highly-strained cyclic tetrapeptides were efficiently synthesized via peptide hydrazide based ligation, reported by Liu et al. Upon mild oxidative activation, the peptide hydrazide was transformed into a highly active peptide azide intermediate and then in situ converted into a peptide 4-mercaptophenylacetic acid (MPAA) thiol ester, which underwent native chemical ligation (NCL)-mediated cyclization to afford the desired cyclic tetrapeptides. After radical desulfurization, the product with alanine residue at the ligation site can be obtained.

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Synthesis of Constrained Head‐to‐Tail Cyclic Tetrapeptides by an Imine‐Induced Ring‐Closing/Contraction Strategy

Cited by 86 publications

References 42 publications

Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Synthesis of Highly-strained Cyclic Tetrapeptides via Peptide Hydrazide Based Ligation

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