Synthesis and structure of cyclic phosphopeptides containing a phosphodiester linkage

Oijen, A. H. Van; Behrens, Stefan; Mierke, Dale F.; Kessler, Horst; Boom, Jacques H. van; Liskamp, Rob M. J.

doi:10.1021/jo00066a026

Cited by 6 publications

(6 citation statements)

References 3 publications

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“…Analytical high pressure liquid chromatography was performed on a Waters 2695 system (equipped with a 2996 diode array detector) at 220 nm as well as on a Merck‐Hitachi LaChrom D7000 system (equipped with L‐7400 UV‐Vis detector) at 220 nm, with an L‐7100 pump and L‐7200 autosampler. In all cases samples were analyzed on a Waters Atlantis™ dC,18 3 μm, 4.6 × 150 mm 2 column at 30°C or an XTerra™ RP8, 3.5 μm, 4.6 × 150 mm 2 column at 30°C or on a VYDAC 208TP™ Series C8, 5 μm, 4.6 × 250 mm 2 column at 30°C. The elution program on both systems used eluents A [0.1% trifluoroacetic acid (TFA) in triple distilled water (TDW)] and B [0.1% TFA in acetonitrile (ACN)], with a nonlinear option (system A) starting with 5% B at 30 min, 30% B at 35 min, 95% B at 40 min, and 5% B at 50 min.…”

Section: Methodsmentioning

confidence: 99%

“…Preparative high pressure liquid chromatography was performed on a Merck‐Hitachi 665A system (equipped with a Jasco Uvidec‐100‐v UV‐Vis detector set at 220 nm, a preparative L‐6200A intelligent pump, D‐2500 chromato integrator). All the compounds were purified on a Waters Atlantis™ dC,18 10 μm, 10 × 150 mm 2 column at 30°C or on a VYDAC 208TP™ Series C8, 10 μm, 22 × 250 mm 2 column at 30°C. Eluting compositions were A (0.1% TFA in TDW) and B (0.1% TFA in ACN), with a nonlinear option (system A) starting with 5% B at 30 min, 30% B at 35 min, 95% B at 40 min, and 5% B at 50 min.…”

Section: Methodsmentioning

confidence: 99%

“…No backbone cyclic and few cyclic phosphopeptides have been reported 14–19. The number of cyclic phosphopeptides is small because their synthesis is challenging.…”

Section: Introductionmentioning

confidence: 99%

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Design and synthesis of backbone cyclic phosphorylated peptides: The IκB model

Qvit¹,

Hatzubai²,

Shalev³

et al. 2008

Biopolymers

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Phosphopeptides have been used to study phosphorylation and dephosphorylation, which are key events in protein expression. Backbone cyclization has been shown to increase the stability and selectivity of peptides. Backbone cyclic peptides with conformational diversity have produced bioactive peptides with improved pharmaceutical properties, metabolic stability, and enhanced intestinal permeability. We demonstrate a successful methodology for incorporating phospho-amino acids into backbone cyclic peptides. The nuclear factor-kappa B (NF-kappaB) is a latent mammalian protein prototype of dimeric transcription factors that exists in all cell types and plays a pivotal role in a huge number of genes, such as those responsible for chronic and acute inflammatory diseases. To inhibit NF-kappaB, backbone cyclic phosphopeptides were designed and synthesized based on the conserved sequence of the Inhibitor kappa B (IkappaB). The peptides were screened for inhibiting IkappaB ubiquitylation. The best compound showed 90% inhibition at a concentration of 3 microM, and its solution structure showed similarity to a related beta-catenin protein. This general methodology can be use for synthesizing cyclic phosphorylated, as well as backbone cyclic phosphorylated peptides for various biological targets.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Design and synthesis of backbone cyclic phosphorylated peptides: The IκB model

Qvit¹,

Hatzubai²,

Shalev³

et al. 2008

Biopolymers

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“…van Oijen et al183, 184 synthesized a cyclic phosphopeptide in which the side chains of Thr and Ser in the tripeptide, Boc–Thr–Gly–Ser–NHMe were joined in a phosphodiester linkage—Scheme ).This peptide was synthesized to model potential intramolecular phosphodiester Ser–Thr linkages as proposed in azobacter flavodoxin. In this synthesis the starting tripeptide ( 80 ) was treated at 50 m M with the 2 equivalents of P III reagent, 4‐chlorobenzyl bis( N,N ‐diisopropylamino) phosporamidite ( 81 ) in the presence of 2 equivalents of tetrazole, by slow addition over 20 h, resulting in the cyclic phosphite, 82 .…”

Section: The Synthesis Of Cyclic Phosphopeptidesmentioning

confidence: 99%

The synthesis of phosphopeptides

et al. 2001

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Phosphorylation and dephosphorylation are key events in protein expression and regulation and in signal transduction. Phosphopeptides are very useful reagents for the study of these processes, and have been used to great advantage in the study of phosphatase substrate specificity, SH2 domain ligand specificity, and protein–protein interactions. Furthermore, the advent of cell‐permeable peptide carriers, such as those from the antennapedia homeodomain and the HIV TAT transcription factor, has allowed the study of intracellular events, thus underscoring the utility of these reagents. In this paper we review methods for the synthesis of phosphopeptides with the emphasis on the preparation of phosphoamino acid building blocks. © 2001 John Wiley & Sons, Inc. Biopolymers (Pept Sci) 60: 3–31, 2001

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“…Cyclic phosphopeptides, like other cyclic peptides, offer improved metabolic stability, bioavailability, and selectivity compared with their linear variants. Nevertheless, only a small number of cyclic phosphopeptides have been reported in the literature (8,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Microwave‐assisted Synthesis of Cyclic Phosphopeptide on Solid Support

Qvit

2014

Chem Biol Drug Des

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Phosphopeptides are important tools for studying intracellular signal transduction events in vitro and in vivo and are also potential drugs due to their direct competition with phosphoprotein recognition elements. Cyclization has been demonstrated to improve peptide selectivity, metabolic stability, and bioavailability. However, cyclic phosphopeptide synthesis may not be straightforward due to the sterically hindered phosphorylated side-chain amino acid derivatives. One option to overcome this hurdle is to use microwave-assisted synthesis, which has been shown to increase efficiency and reduce synthesis time. Herein, a detailed protocol is provided for synthesizing cyclic phosphopeptides using automated microwave. The overall synthesis duration was reduced and yields increased compared with a manual conventional method. This method provides a general, fast and facile way to synthesize cyclic peptides, demonstrating the synthesis of cyclic phosphorylated peptides which are known to be among the most challenging to produce.

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Synthesis and structure of cyclic phosphopeptides containing a phosphodiester linkage

Cited by 6 publications

References 3 publications

Design and synthesis of backbone cyclic phosphorylated peptides: The IκB model

Design and synthesis of backbone cyclic phosphorylated peptides: The IκB model

The synthesis of phosphopeptides

Microwave‐assisted Synthesis of Cyclic Phosphopeptide on Solid Support

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