Backbone Amide Linker Strategy for the Synthesis of 1,4‐Triazole‐Containing Cyclic Tetra‐ and Pentapeptides

Springer, Jasper; Cuba, Kimberly R. de; Calvet-Vitale, Sandrine; Geenevasen, Jan A. J.; Hermkens, Pedro H. H.; Hiemstra, Henk; Maarseveen, Jan H. van

doi:10.1002/ejoc.200800143

Cited by 31 publications

(15 citation statements)

References 38 publications

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“…Applications in various fields of the CuI-catalyzed azide-alkyne reaction have been reviewed [39][40][41][42][43][44]. Only very recently a few studies on conformational constraints by triazole intramolecular cyclization have been reported, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…'Click' chemistry-cyclized peptide (7) As for the β-amino acid-containing linear peptides, modelling studies were performed prior to the syntheses to select the sequence to be cyclized. Fmoc-Pra being commercially available, was chosen for introducing the alkyne component of the Huisgen reaction [39][40][41], the azido partner coming from either an N-terminal α-azido acid, readily accessible by known procedures [42][43][44] or from 3-azido-alanine, both enantiomers being commercially available (Fig. 2).…”

Section: Cyclic Peptidesmentioning

confidence: 99%

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β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

Larregola

Lequin

Karoyan

et al. 2011

Journal of Peptide Science

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The increasing interest in click chemistry and its use to stabilize turn structures led us to compare the propensity for β-turn stabilization of different analogs designed as mimics of the β-turn structure found in tendamistat. The β-turn conformation of linear β-amino acid-containing peptides and triazole-cyclized analogs were compared to 'conventional' lactam- and disulfide-bridged hexapeptide analogs. Their 3D structures and their propensity to fold in β-turns in solution, and for those not structured in solution in the presence of α-amylase, were analyzed by NMR spectroscopy and by restrained molecular dynamics with energy minimization. The linear tetrapeptide Ac-Ser-Trp-Arg-Tyr-NH(2) and both the amide bond-cyclized, c[Pro-Ser-Trp-Arg-Tyr-D-Ala] and the disulfide-bridged, Ac-c[Cys-Ser-Trp-Arg-Tyr-Cys]-NH(2) hexapeptides adopt dominantly in solution a β-turn conformation closely related to the one observed in tendamistat. On the contrary, the β-amino acid-containing peptides such as Ac-(R)-β(3) -hSer-(S)-Trp-(S)-β(3) -hArg-(S)-β(3) -hTyr-NH(2) , and the triazole cyclic peptide, c[Lys-Ser-Trp-Arg-Tyr-βtA]-NH(2) , both specifically designed to mimic this β-turn, do not adopt stable structures in solution and do not show any characteristics of β-turn conformation. However, these unstructured peptides specifically interact in the active site of α-amylase, as shown by TrNOESY and saturation transfer difference NMR experiments performed in the presence of the enzyme, and are displaced by acarbose, a specific α-amylase inhibitor. Thus, in contrast to amide-cyclized or disulfide-bridged hexapeptides, β-amino acid-containing peptides and click-cyclized peptides may not be regarded as β-turn stabilizers, but can be considered as potential β-turn inducers.

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Section: Discussionmentioning

confidence: 99%

Section: Cyclic Peptidesmentioning

confidence: 99%

β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

Larregola

Lequin

Karoyan

et al. 2011

Journal of Peptide Science

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“…This methodology could not be extended to the solid-phase synthesis of cyclic peptidomimetics. [52] However, in this case, CuAAC in solution again gave the cyclised peptidomimetics in good yield, including an example that mimics the natural product Segetalin B. A detailed NMR study of this peptidomimetic and the parent Segetalin B, suggests that both adopt a type-II β-turn.…”

Section: Head-to-tail Cyclisationmentioning

confidence: 96%

1,2,3‐Triazoles in Peptidomimetic Chemistry

2011

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The ability to synthesise small peptidomimetics that mimic the secondary structure of proteins is an ever expanding area of research directed at sourcing new medicinal agents and biological probes. A significant current challenge is to mimic protein epitopes under physiological conditions using small peptidomimetics that are easy to prepare. The copper‐ and ruthenium‐catalysed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3‐triazoles being good peptide bond mimics. The ability to prepare both 1,4‐ and 1,5‐substituted 1,2,3‐triazoles under these chemically benign conditions provides both “linear” and “bent” peptidomimetics. Examples of the use of 1,2,3‐triazoles to define the geometry and properties of a peptidomimetic abound. This review highlights such successes but also describes a number of failures in order to guide and inspire future efforts of chemists in this area.

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“…Similarly, many cyclic peptides, such as gramicidin S, include proline residues. Work by van Maarseveen and co-workers further corroborates that through more aggressive chemistries such as Cu I -catalyzed cycloaddition, the challenging synthesis of cyclo-[Pro-Val-Gly-ψ(triazole)-Tyr] , a triazole analog of cyclo-[Pro-Val-ProTyr], can readily be achieved in solution phase chemistry [34].…”

Section: Introductionmentioning

confidence: 75%

Disfavoring Macrocycle b Fragments by Constraining Torsional Freedom: The “Twisted” Case of QWFGLM b₆

Tirado

Rutters

Chen

et al. 2012

J. Am. Soc. Mass Spectrom.

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While recent studies have shown that for some peptides, such as oligoglycines and Leu-enkephalin, mid-sized b fragment ions exist as a mixture of oxazolone and macrocycle structures, other primary structure motifs, such as QWFGLM, are shown to exclusively give rise to macrocycle structures. The aim of this study was to determine if certain amino acid residues are capable of suppressing macrocycle formation in the corresponding b fragment. The residues proline and 4-aminomethylbenzoic acid (4AMBz) were chosen because of their intrinsic rigidity, in the expectation that limited torsional flexibility may impede "head-to-tail" macrocycle formation. The presence of oxazolone versus macrocycle b 6 fragment structures was validated by infrared multiple photon dissociation (IRMPD) spectroscopy, using the free electron laser FELIX. It is confirmed that proline disfavors macrocycle formation in the cases of QPWFGLM b 7 and in QPFGLM b 6 . The 4AMBz substitution experiments show that merely QWFG(4AMBz)M b 6 , with 4AMBz in the fifth position, exhibits a weak oxazolone band. This effect is likely ascribed to a stabilization of the oxazolone structure, due to an extended oxazolone ring-phenyl π-electron system, not due to the rigidity of the 4AMBz residue. These results show that some primary structures have an intrinsic propensity to form macrocycle structures, which is difficult to disrupt, even using residues with limited torsional flexibility.

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Backbone Amide Linker Strategy for the Synthesis of 1,4‐Triazole‐Containing Cyclic Tetra‐ and Pentapeptides

Cited by 31 publications

References 38 publications

β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

1,2,3‐Triazoles in Peptidomimetic Chemistry

Disfavoring Macrocycle b Fragments by Constraining Torsional Freedom: The “Twisted” Case of QWFGLM b₆

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Backbone Amide Linker Strategy for the Synthesis of 1,4‐Triazole‐Containing Cyclic Tetra‐ and Pentapeptides

Cited by 31 publications

References 38 publications

β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

1,2,3‐Triazoles in Peptidomimetic Chemistry

Disfavoring Macrocycle b Fragments by Constraining Torsional Freedom: The “Twisted” Case of QWFGLM b6

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Product

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Disfavoring Macrocycle b Fragments by Constraining Torsional Freedom: The “Twisted” Case of QWFGLM b₆