| 1. |
- Gustafsson, Tomas, et al.
(author)
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A total synthesis of hydroxylysine in protected form and investigations of the reductive opening of p-methoxybenzylidene acetals
- 2004
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In: Journal of Organic Chemistry. - Easton, Pa. : American Chemical Society. - 0022-3263 .- 1520-6904. ; 69:25, s. 8694-8701
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Journal article (peer-reviewed)abstract
- A synthesis of (2S,5R)-5-hydoxylysine, based on (R)-malic acid and Williams glycine template as chiral precursors, has been developed. This afforded hydroxylysine, suitably protected for direct use in peptide synthesis, in 32% yield over the 13-step sequence. Regioselective reductive opening of a p-methoxybenzylidene acetal and alkylation of the Williams glycine template were key steps in the synthetic sequence. Surprisingly, the regioselectivity in opening of the p-methoxybenzylidene acetal was reversed as compared to what was expected. It was found that this was due to chelation of the trialkylsilyl choride, used as an electrophile in the reductive opening, to an adjacent azide functionality. It was also discovered that an equivalent amount of trialkylsilyl hydride was formed in the reaction, a finding that led to additional mechanistic insight into reductive openings of p-methoxybenzylidene acetals with sodium cyanoborohydride as reducing agent.
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| 2. |
- Mogemark, Mickael, et al.
(author)
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Monitoring Solid-Phase Glycoside Synthesis with 19F NMR Spectroscopy
- 2001
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In: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 3:10, s. 1463-1466
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Journal article (peer-reviewed)abstract
- A simple and efficient method for monitoring and optimizing carbohydrate synthesis on polymeric support by using 19F NMR spectroscopy is described. The method relies on the use of fluorinated variants of protective groups that are in common use in oligosaccharide synthesis.
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| 3. |
- Vijayalekshmi, S., et al.
(author)
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A surface exposed O-linked galactose residue destabilises the structure of a folded helix-loop-helix dimer
- 2003
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In: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 1, s. 2455-60
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Journal article (peer-reviewed)abstract
- A 42-residue glycopeptide Tn-15 and the corresponding reference polypeptide Thr-15 were designed and synthesized to provide a model system for the study of how glycosylation affects the stability of a molten globule-like protein. Tn-15 and Thr-15 fold into hairpin helix-loop-helix motifs that dimerise to form four-helix bundles and the only difference between the sequences is that Tn-15 carries an O-linked N-acetylgalactosamine residue at the side chain of threonine-15 whereas the sequence Thr-15 is unglycosylated. An analysis of the mean residue ellipticities at 222 nm of the two polypeptides and of the a-H chemical shift deviations from random coil values showed that glycosylation reduced the helical content of the polypeptides and increased the dissociation constant of the helix-loop-helix dimer to form monomers. The pH dependencies of the helical content of Tn-15 and Thr-15 differed as that of Thr-15 was largely unaffected by pH in the range from pH 4 to pH 10, whereas Tn-15 lost almost half of the helical content at pH 4 upon raising the pH to 10. No single amino acid residue was found to ionize in a way that could explain the observed pH dependence of Tn-15. The temperature dependence of the mean residue ellipticity of Tn-15 revealed a surprising decrease in helicity at 278 K in comparison with that at 293 K, reminiscent of cold denaturation, that was not observed for the reference four-helix bundle Thr-15.
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| 4. |
- Saitton, Stina, 1972, et al.
(author)
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A synthetic approach to 2,3,4-substituted pyridines useful as scaffolds for tripeptidomimetics
- 2004
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In: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 60:29, s. 6113-6120
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Journal article (peer-reviewed)abstract
- The synthesis of 2,3,4-substituted pyridine derivatives useful as scaffolds in the development of peptidomimetics is described. The use of a variety of electrophiles in a halogen-dance reaction to produce 3-alkyl-2-fluoro-4-iodo-pyridine derivatives as 'functionalized scaffolds' and the possibility to differentiate between the reactivities of the two halogen handles have been explored. Coupling of amino acid derivatives in the 4-position of the pyridine was found to proceed efficiently by conversion of iodo-pyridine to a Grignard derivative, which was allowed to react with a protected amino aldehyde. Substitution of fluorine in the 2-position of the pyridine was found to be facile with alkoxide nucleophiles, whereas amines were much less reactive. (C) 2004 Elsevier Ltd. All rights reserved.
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| 5. |
- Saitton, Stina, 1972, et al.
(author)
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Design, synthesis and evaluation of a PLG tripeptidomimetic based on a pyridine scaffold.
- 2004
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In: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:26, s. 6595-602
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Journal article (peer-reviewed)abstract
- A 2,3,4-substituted pyridine derivative has been identified as a potential tripeptidomimetic scaffold. The design of the scaffold was based on conformational and electrostatic comparisons with a natural tripeptide. The scaffold has been used in the synthesis of a Pro-Leu-Gly-NH2 (PLG) mimetic. The different substituents in the 2-, 3-, and 4-positions of the pyridine ring were introduced via an aromatic nucleophilic substitution reaction, a "halogen-dancing" reaction, and a Grignard coupling of a Boc-protected amino aldehyde, respectively. The synthetic route involves eight steps and provides the mimetic in 20% overall yield. The pyridine based PLG-mimetic was evaluated for its ability to enhance the maximum response of the dopamine agonist N-propylapomorphine (NPA) at human D2 receptors using a cell based assay (the R-SAT assay). The dose-response curve of the mimetic was found to exhibit a down-turn phase, similar to that of PLG. In addition, the mimetic was more potent than PLG to enhance the NPA response; the maximum response was found to be 146% at 10 nM concentration, as compared to 115% for PLG at the same concentration. Interestingly, conformational analysis by molecular modeling showed that the pyridine mimetic cannot adopt a type II beta-turn conformation that previously has been suggested to be the bioactive conformation of PLG.
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| 6. |
- Wellner, Eric, et al.
(author)
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Synthesis of a C-glycoside analogue of β-D-galactosyl hydroxynorvaline and its use in immunological studies
- 2000
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In: ChemBioChem (Print). - : John Wiley & Sons. - 1439-4227 .- 1439-7633. ; 1:4, s. 272-280
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Journal article (peer-reviewed)abstract
- A C-linked isostere of β-d-galactosylated hydroxynorvaline has been prepared in eight steps from per-O-benzylated galactopyranolactone. Addition of a homoallylic Grignard reagent to the lactone, reduction of the resulting hemiacetal with triethylsilane, and a Wittig reaction with Garner's aldehyde were key steps in this synthesis. The C-linked building block was then incorporated at position 264 into the fragment CII(256–270) from type II collagen by solid-phase synthesis using a combination of the tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) protective group strategies. Deprotection of the benzylated C-linked galactosyl moiety was achieved simultaneously with cleavage of the glycopeptide from the solid phase by using triethylsilyl trifluoromethanesulfonate in TFA. Helper T-cell hybridomas obtained in a mouse model for rheumatoid arthritis responded to the C-linked glycopeptide when presented by class II MHC molecules. However, 10- to 20-fold higher concentrations were required as compared to when O-linked β-d-galactosylated hydroxynorvaline or hydroxylysine (Hyl) were present at position 264 of CII(256–270). Thus, replacement of a single oxygen atom by a methylene group in the carbohydrate moiety of a glycopeptide antigen had a substantial influence on the T-cell response. This reveals that T cells are able to recognize the carbohydrate moiety of glycopeptide antigens with high specificity. Finally, the results suggest that structural modifications of β-d-Gal-Hyl264in CII(256–270) may give altered peptide ligands that can be used for induction of tolerance in autoimmune rheumatoid arthritis.
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| 7. |
- Holm, B, et al.
(author)
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Role of the galactosyl moiety of collagen glycopeptides for T-cell stimulation in a model for rheumatoid arthritis
- 2003
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In: Bioorganic & Medicinal Chemistry. - 0968-0896. ; 11:18, s. 3981-3987
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Journal article (peer-reviewed)abstract
- Two protected derivatives of beta-D-galactopyranosyl-5-hydroxy-L-lysine, in which HO-4 of galactose has been O-methylated or replaced by fluorine, have been prepared. The building blocks were incorporated at position 264 of the peptide fragment CII259-273 from type II collagen by solid-phase synthesis. The ability of these two glycopeptides, and two CII259-273 glycopeptides in which HO-4 of galactose was either unmodified or deoxygenated, to elicit responses from T-cell hybridomas obtained in a mouse model for rheumatoid arthritis was then determined. The hybridomas were all highly sensitive towards modifications at C-4 of the beta-D-galactosyl residue of CII259-273, highlighting the role of HO-4 as an important contact point for the T-cell receptor. Most likely, this glycopeptide hydroxyl group is involved in hydrogen bonding with the T-cell receptor. (C) 2003 Elsevier Ltd. All rights reserved.
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| 8. |
- Blomberg, David, et al.
(author)
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Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin
- 2004
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In: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 69:10, s. 3500-3508
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Journal article (peer-reviewed)abstract
- A β-turn mimetic in which the four amino acids of a β-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular COi − HNi+3 hydrogen bond that is often found in β-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a β-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a β-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on 1H NMR data showed that the β-turn mimetic was flexible, but that it resembled a type-II β-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.
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| 9. |
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| 10. |
- George, Shaji K, et al.
(author)
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Chemoenzymatic synthesis of derivatives of a T-cell-stimulating peptide which carry tumor-associated carbohydrate antigens
- 2001
-
In: Journal of the Chemical Society-Perkin Transactions 1. - : Royal Society of Chemistry (RSC). - 1472-7781 .- 1364-5463. ; , s. 880-5
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Journal article (peer-reviewed)abstract
- The Tn (GalNAc-Ser/Thr), T [Gal(13)GalNAc-Ser/Thr], sialyl-Tn [Neu5Ac(26)GalNAc-Ser/Thr] and 2,3-sialyl-T [Neu5Ac(23)Gal(13)GalNAc-Ser/Thr] antigens are examples of tumor-associated carbohydrate antigens expressed by epithelial cancers. We now describe the preparation of 2-bromoethyl glycosides corresponding to the Tn and T antigens in one and five chemical steps (51 and 15% total yield), respectively, starting from N-acetylgalactosamine. The 2-bromoethyl Tn and T glycosides were used to alkylate a homocysteine residue incorporated in a peptide that is able to bind to class I MHC molecules on antigen-presenting cells. The two neoglycopeptides were then converted into glycopeptides which carry the sialyl-Tn and 2,3-sialyl-T antigens by using recombinant sialyltransferases. Interestingly, the sialyltransferases were able to sialylate the Tn and T carbohydrate moieties even though they were linked to the peptide backbone via a spacer instead of being attached to serine or threonine. The four glycopeptides will be used in studies directed towards inducing a carbohydrate-specific T cell response against the Tn, T, sialyl-Tn, and 2,3-sialyl-T antigens.
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