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Synthesis and application of N-[1-(4-(4-fluorophenyl)-2,6-dioxocyclohexylidene)ethyl] (Fde)-protected amino acids for optimization of solid-phase peptide synthesis using gel-phase (19)F NMR spectroscopy.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
2009 (English)In: Journal of Peptide Science, ISSN 1075-2617, Vol. 15, no 4, 264-71 p.Article in journal (Refereed) Published
Abstract [en]

N-[1-(4-(4-fluorophenyl)-2,6-dioxocyclohexylidene)ethyl] (Fde) protected amino acids have been prepared and applied in solid-phase peptide synthesis monitored by gel-phase (19)F NMR spectroscopy. The Fde protective group could be cleaved with 2% hydrazine or 5% hydroxylamine solution in DMF as determined with gel-phase (19)F NMR spectroscopy. The dipeptide Ac-L-Val-L-Val-NH(2) 12 was constructed using Fde-L-Val-OH and no noticeable racemization took place during the amino acid coupling with N,N'-diisopropylcarbodiimide and 1-hydroxy-7-azabenzotriazole or Fde deblocking. To extend the scope of Fde protection, the hydrophobic nonapeptide LLLLTVLTV from the signal sequence of mucin MUC1 was successfully prepared using Fde-L-Leu-OH at diagnostic positions. Copyright (c) 2009 European Peptide Society and John Wiley & Sons, Ltd.

Place, publisher, year, edition, pages
European Peptide Society and John Wiley & Sons, Ltd. , 2009. Vol. 15, no 4, 264-71 p.
Keyword [en]
solid-phase peptide synthesis, gel-phase 19F NMR spectroscopy, fluorinated -amino protective group, difficult peptide
URN: urn:nbn:se:umu:diva-18745DOI: 10.1002/psc.1110PubMedID: 19235188OAI: diva2:174681
Available from: 2009-02-24 Created: 2009-02-24 Last updated: 2010-01-21
In thesis
1. Antigens derived from the mucin MUC1: Solution and solid-phase synthesis of saccharides, peptides and glycopeptides
Open this publication in new window or tab >>Antigens derived from the mucin MUC1: Solution and solid-phase synthesis of saccharides, peptides and glycopeptides
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mucin is a term used to describe a large family of heavily glycosylated proteins which are present on the surfaces of secretory epithelial cells and are overexpressed by many carcinomas. Membrane-bound mucin MUC1 is of special interest. Its backbone consists of repeating units of twenty amino acids with five potential glycosylation sites. These sites are expanded to structures like the T (Galβ(1->3)GalNA-Ser/Thr) and Tn (GalNA-Ser/Thr) antigens by the action of various glycosyltransferases. In different types of carcinomas these epitopes are being terminated by sialic acid residues to form among others: 2,3-sialyl-T and sialyl-Tn structures due to the elevated levels of different sialyltransferases.

Solid-phase synthesis of the selected antigens derived from the mucin MUC1 has been developed and optimized. A chemoenzymatic approach has been used to effectively prepare 2,3-sialyl-T and 2,6-sialyl-Tn glycopeptides. The formation of intramolecular sialic acid lactones in presence of acetic acid was investigated. The stability of lactones formed from 2,3-sialyl-T towards water was studied using NMR spectroscopy and it appeared that 1''->2' lactone displayed remarkable strength to hydrolysis and it was suggested as a candidate for cancer vaccine.

Gel-phase 19F NMR spectroscopy is known to be a very good tool to characterize resin-bound products using fluorinated protecting groups and linker molecules. The hydrophobic peptide LLLLTVLTV, which is a fragment from the MUC1 signal sequence, was prepared using solid-phase synthesis according to a modified Fmoc protocol with more active coupling reagent, stronger base, and the isopropylidene dipeptide Fmoc-Leu-Thr-(ΨMe,Mepro)-OH. Gel-phase 19F NMR spectroscopy was used to evaluate peptide chain aggregation and coupling and deprotection efficiency.

A carbamate linker strategy proved to be effective in solid-phase synthesis of serine-based neoglycolipids with terminal amino functionality. Neoglycolipids were covalently bound to secondary amines in microtiter plates using squaric acid ester methodology. These arrays have potential to study the interactions between carbohydrates and e.g. proteins and microbes.

The new fluorinated α-amino protective group [1-(4-(4-fluorophenyl)-2,6-dioxocyclohexylidene)ethyl] Fde was developed. This group is cleaved with hydrazine in DMF solution. By using amino acids protected with this group, it was possible to quantify the efficiency of peptide coupling using gel-phase 19F NMR spectroscopy.

Place, publisher, year, edition, pages
Umeå: Kemi, 2008. 76 p.
Lactones, glycopeptides, signal peptide, neoglycolipid arrays, solid-phase synthesis, MUC1, gel-phase 19F NMR spectroscopy, fluorinated alpha-amino protective group
National Category
Organic Chemistry
urn:nbn:se:umu:diva-1630 (URN)978-91-7264-557-8 (ISBN)
Public defence
2008-05-24, KB3B1, Stora Hörsalen, KBC, Linneaus v., Umeå, 10:00 (English)
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2010-01-21Bibliographically approved

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