Synthesis of MUC1 Peptide and Glycopeptide Dendrimers

Chun, Candy K. Y.; Payne, Richard J.

doi:10.1071/ch09282

Cited by 16 publications

(15 citation statements)

References 24 publications

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“…1 Synthesis of 2-azidoacetic acid 10. 32 Dry DMF (15 mL) was added to methyl bromoacetate (8 mL, 87 mmol, 1 equiv.) contained in a 100 mL round-bottom flask under an argon atmosphere.…”

Section: Procedures and Characterisation Datamentioning

confidence: 99%

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Water-soluble aryl-extended calix[4]pyrroles with unperturbed aromatic cavities: synthesis and binding studies

et al. 2015

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We report the synthesis of a novel, water-soluble aryl-extended calix[4]pyrrole receptor. The water-solubilising groups are placed at the lower rim of the receptor, leaving the binding pocket unperturbed and open for modification. Binding studies were performed with a series of pyridine N-oxides. These studies revealed the ability of the receptor to bind neutral and charged N-oxides in basified water with stability constants higher than 10(4) M(-1).

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“…1 Synthesis of 2-azidoacetic acid 10. 32 Dry DMF (15 mL) was added to methyl bromoacetate (8 mL, 87 mmol, 1 equiv.) contained in a 100 mL round-bottom flask under an argon atmosphere.…”

Section: Procedures and Characterisation Datamentioning

confidence: 99%

“…The 1 H NMR spectrum is in agreement with that previously reported in the literature. 32 Synthesis of calixpyrrole α,α,α,α-2 isomer. Degassed DMSO (0.9 mL) was added to α,α,α,α-calixpyrrole 3 (10 mg, 12 μmol, 1 equiv.)…”

Section: Procedures and Characterisation Datamentioning

confidence: 99%

Water-soluble aryl-extended calix[4]pyrroles with unperturbed aromatic cavities: synthesis and binding studies

et al. 2015

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“…Additionally, a multivalent display of the epitopes is predicted to be an important feature for a strong and sustained immunological response 29. Synthesis of MUC1 glycoproteins combining these two features would represent a much improved vaccine candidate 34. Given our interest in the development of glycopeptide‐based cancer vaccine candidates, we describe here our initial efforts in developing an efficient means for the preparation of defined glycopeptide oligomers bearing multiple copies of the hyperglycosylated MUC1 eicosapeptide VNTR region.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of MUC1 glycopeptide thioesters and ligation via direct aminolysis

2011

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MUC1 is a cell-surface, epithelial glycoprotein that forms an essential protective barrier of cells and serves to modulate intercellular communication. During cancer progression, the dysregulation of glycosyltransferases, which serve to elongate cell-surface glycans, leads to aberrant gIycosylation patterns on this glycoprotein. This results in the presentation of well-characterized, tumor-associated carbohydrate antigens (TACAs) which represent important biomarkers for a range of epithelial cancers. The synthesis of well-defined, multivalent MUC1 glycopeptide constructs bearing TACAs therefore represents a viable opportunity for the development of cancer vaccine candidates. We report herein the synthesis of a glycopeptide thioester, comprising the full eicosapeptide variable number tandem repeat (VNTR) region of MUC1, which was prepared bearing multiple copies of the cancer-associated TN antigen. The glycopeptide thioester was prepared on the solid-phase using two different methods on 2-chlorotrityl chloride and sulfamylbutyryl resins. The solid-phase assembly on 2-chlorotrityl chloride resin, followed by thioesterification in solution, afforded the desired thioester in 4% yield over 41 linear steps. Likewise, the glycopeptide thioester was successfully prepared on sulfamylbutyryl resin using an activation and thiol-release strategy in a 9% isolated yield. The resulting peptide thioester was successfully ligated to a deprotected MUC1 glycopeptide using the direct aminolysis ligation to afford a 5.8 kDa, 40 amino acid MUC1 glycopeptide bearing 10 copies of the T(N) antigen. This work represents an important step toward the immunological evaluation of multivalent MUC1 constructs.

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“…[21] After full assembly of the desired scaffold, carbohydrate ligands are introduced by CuAAC, a method also commonly used in the SPS of other glycoconjugates such as glycopeptides. [27][28][29][30][31][32] As exemplary carbohydrate building blocks, azide-derivatives of acetylated mannose (Man) (7), N-acetylglucosamine (GlcNAc) (8), and lactose (Lac) (9) were selected for this work. Mannose is a monosaccharide widely used for conjugation, while lactose represents a disaccharide and N-acetylglucosamine the class of acetyl protected amino sugars.…”

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Recovery, Purification, and Reusability of Building Blocks for Solid Phase Synthesis

Shamout

Fischer

Snyder

et al. 2019

Macromol. Rapid Commun.

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reagents and protecting group strategies, solid phase approaches regularly rely on the use of a high excess of building blocks and reagents in every addition step. Repetitive coupling of the same building block achieves full conversion; however, this comes at the cost of excess nonconjugated building blocks which end up in the waste. For example, for the standard Fmoc peptide synthesis of a decamer, amino acids are used in 5-10 equivalents (eq.) per coupling and double couplings are performed, resulting in 40-180 eq. of amino acids that will end up in the solvent waste. While many building blocks for the synthesis of peptides and oligonucleotides are commercially available at low cost, other building blocks are rare or commercially more expensive. Examples of such building blocks include non-natural amino acids, 13 C-and 15 N-labeled amino acids, and glycan donors. [5,[8][9][10][11][12] For building blocks that have to be synthesized prior to SPS, for example, glycosylated building blocks or building blocks that are used in the SPS of synthetic polymers, the use of excess building blocks is a major limitation in terms of cost, time, and labor. [13] Within the last decade, polymer chemists have successfully developed advanced strategies to introduce monomer sequence-control into synthetic polymers giving access to materials with new properties and applications such as drug delivery and data storage. [14][15][16][17] Indeed, several of these strategies rely on the use of solid phase synthesis and the assembly of tailor-made building blocks. [18] For example, Lutz et al. reported a SPS strategy for monodisperse and sequenceencoded poly(alkoxyamine amides) that allow for the storing of information in single polymer chains. [19,20] In the previous work, we have introduced the SPS of glycooligoamides as mimetics of oligosaccharides and their use in antibacterial treatment. [21,22] Although macromolecules synthesized via SPS can be expected to be high value products to enter the market in smaller quantities compared to commodity polymers, finding ways to produce such materials at low cost and with resource efficiency might further strengthen their applicability.Here we present the recovery, purification, and reusability of building blocks used in the solid phase assembly of glycooligoamides. The process relies on simple and well-established methods such as precipitation and recrystallization, and does not require any special equipment or expertise. It can be integrated into a standard peptide synthesizer for automated synthesis and is suitable for chemically different building blocks, as demonstrated here for tailor-made dimer building blocks, Solid phase synthesis (SPS) is well established for the synthesis of biomacro molecules such as peptides, oligonucelotides, and oligosaccharides, and today is also used for the synthesis of synthetic macromolecules and poly mers. The key feature of this approach is the stepwise assembly of building blocks on solid support, enabling monodispersity and monomer sequence control. Howe...

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Synthesis of MUC1 Peptide and Glycopeptide Dendrimers

Cited by 16 publications

References 24 publications

Water-soluble aryl-extended calix[4]pyrroles with unperturbed aromatic cavities: synthesis and binding studies

Water-soluble aryl-extended calix[4]pyrroles with unperturbed aromatic cavities: synthesis and binding studies

Synthesis of MUC1 glycopeptide thioesters and ligation via direct aminolysis

Recovery, Purification, and Reusability of Building Blocks for Solid Phase Synthesis

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