Abstract
The biological functions of a variety of proteins are regulated by heparan sulfate glycosaminoglycans. In order to facilitate the elucidation of the molecular basis of glycosaminoglycan-protein interactions we have developed syntheses of heparin-like oligosaccharides on polymer supports. A completely stereoselective strategy previously developed by us for the synthesis of these oligosaccharides in solution has been extended to the solid phase using an acceptor-bound approach. Both a soluble polymer support and a polyethylene glycol-grafted polystyrene resin have been used and different strategies for the attachment of the acceptor to the support have been explored. The attachment of fully protected disaccharide building blocks to a soluble support through the carboxylic group of the uronic acid unit by a succinic ester linkage, the use of trichloroacetimidates as glycosylating agents and of a functionalized Merryfield type resin for the capping process allowed for the construction of hexasaccharide and octasaccharide fragments containing the structural motif of the regular region of heparin. This strategy may facilitate the synthesis of glycosaminoglycan oligosaccharides by using the required building blocks in the glycosylation sequence. Published in 2003.
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References
Conrad HE, Heparin-Binding Proteins (Academic Press, San Diego, 1998).
Capila I, Lindhardt RJ, Heparin, Protein interactions, Angew Chem Int Ed 41, 390-412 (2002).
Casu B, Lindahl U, Structure and biological interactions of heparin and heparan sulfate, Adv Carbohydr Chem Biochem 57, 159-206 (2001).
Lindahl U, Kjellen L, The Biology of the Extracellular Matrix: Proteoglycans (Academic Press, New York, 1987).
Thunberg L, Bäckström G, Lindahl U, Further characterization of the antithrombin-binding sequence in heparin, Carbohydr Res 100, 393-410 (1982).
Faham S, Linhardt RJ, Rees DC, Diversity does make a difference: Fibroblast growth factor-heparin interactions, Curr Opin Struct Biol 8, 578-86 (1998).
Kreuger J, Salmivirta M, Sturiale L, Giménez-Gallego G, Lindhal U, Sequence analysis of heparan sulfate epitopes with graded affinities for fibroblast growth factors 1 and 2, J Biol Chem 276, 30744-52 (2001).
Faham S, Hileman SE, Fromm JR, Lindhardt RJ, Rees DC, Heparin structure and interactions with basic fibroblast growth factor, Science 271, 1116-20 (1996).
DiGabriele AD, Lax I, Chen DI, Svahn CM, Jaye M, Schlessinger J, Hendrickson WA, Structure of a heparin-linked biologically ac-tive dimer of fibroblast growth factor, Nature 393, 812-7 (1998).
Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova V, Yeh BK, Yayon A, Linhardt RJ, Mohammadi M, Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization, Mol Cell 6, 743-50 (2000).
Pellegrini L, Burke DF, Von Delft F, Mulloy B, Blundell TL, Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin, Nature 407, 1029-34 (2000).
de Paz JL, Angulo J, Lassaletta JM, Nieto PM, Redondo-Horcajo M, Lozano RM, Gimenez-Gallego G, Martin-Lomas M, The activation of fibroblast growth factors by heparin: Synthesis, structure, and biological activity of heparin-like oligosaccharides, Chem-Biochem 2, 673-85 (2001).
Ojeda R, Angulo J, Nieto PM, Martin-Lomas M, The activation of fibroblast growth factors by heparin: Synthesis and structural study of rationally modified heparin-like oligosaccharides, Can J Chem 80, 673-85 (2002).
Lucas R, Angulo J, Nieto PM, Martin-Lomas M, Synthesis and structural study of two new heparin-like hexasaccharides, Org Biomol Chem 1, 2253-66 (2003).
de Paz JL, Ojeda R, Reichardt N, Martin-Lomas M, Some key experimental features of a modular synthesis of heparin-like oligosaccharides, Eur J Org Chem 3308-24 (2003).
Angulo J, Nieto PM, Martin-Lomas M, A molecular dynamics description of the conformational flexibility of the L-iduronate ring in glycosaminoglycans, Chem Commun 2486-7 (2003).
Angulo J, Ojeda R, de Paz JL, Lucas R, Nieto PM, Lozano RM, Redondo-Horcajo M, Gimenez-Gallego G, Martin-Lomas M, The activation of fibroblast growth factors (FGFs) by glycosaminogly-cans: Influence of the sulfation pattern on the biological activity of FGF-1, ChemBioChem 5, 55-61 (2004).
Seeberger PH, Haase WC, Solid-Phase oligosaccharides synthesis and combinatorial carbohydrate libraries, Chem Rev 100, 4349-93 (2000).
Plante OJ, Palmacci ER, Seeberger PH, Automated solid-phase synthesis of oligosaccharides, Science 291, 1523-7 (2001).
Palmacci ER, Plante OJ, Seeberger PH, Oligosaccharide synthesis in solution and on solid support with glycosyl phosphates, Eur J Org Chem 595-606 (2002).
La Ferla B, Lay L, Guerrini M, Poletti L, Panza L, Russo G, Synthesis of disaccharidic sub-units of a new series of heparin related oligosaccharides, Tetrahedron 55, 9867-80 (1999).
Haller M, Boons GJ, Towards a modular approach for heparin synthesis, J Chem Soc Perkin Trans 1, 814-22 (2001).
Haller M, Boons GJ,Selectively protected disaccharide building blocks for modular synthesis of heparin fragments, Eur J Org Chem 2033-8 (2002).
Orgueira HA, Bartolozzi A, Schell P, Litjens REJN, Palmacci ER, Seeberger PH, Modular synthesis of heparin oligosaccharides, Chem Eur J 9, 140-69 (2003).
Ojeda R, de Paz JL, Martin-Lomas M, Synthesis of heparin-like oligosaccharides on a soluble polymer support, Chem Commun 2486-7 (2003).
For a reviews see Tamura J, Recent advances in the synthetic studies of glycosaminoglycans, Trend Glycosci Glycotechnol 13, 65-88 (2001).
For a review see van Boeckel CAA, Petitou M, The unique antithrombin III binding domain of heparin: A lead to new synthetic antithrombotics, Angew Chem Int Ed 32, 1671-90 (1993).
Dreef-Tromp CM, Willems HAM, Westerduin P, van Veelen P, van Boeckel CAA, Polymer-supported solution synthesis of heparan-sulphate like oligomers, Biorg Med Chem Lett 7, 1175-80 (1997).
Schmidt RR, Kinzy, Anomeric-oxygen activation for glycoside synthesis: The trichloroacetimidate method, Adv Carbohydr Chem Biochem 50, 21-123 (1994).
Excoffier G, Gagnaire D, Utille JP, Selective cleavage of anomeric acetyl groups of acetylated glycosyl residues by hydrazine, Carbohydr Res 39, 368-73 (1975).
Douglas SP, Whitfield DM, Krepinsky JJ, Polymer-supported so-lution synthesis of oligosaccharides, J AmChem Soc 113, 5095-7 (1991).
Jaquinet JC, Petitou M, Duchaussoy P, Lederman I, Choay J, Torri G, Sinaÿ P, Synthesis of heparan fragments-a chemical synthesis of the trisaccharide O-(2-deoxy-2-sulfamido-3,6-di-O-sulfo-alpha-D-glucopyranosyl)-(1 → 4)-O-(2-O-sulfo-alpha-L-idopyranosyluronic acid)-(1 → 4)-2-deoxy-2-sulfamido-6-O-sulfo-D-glucopyranose heptasodium salt, Carbohydr Res 130, 221-41 (1984).
Ojeda R, de Paz JL, Martin-Lomas H, Lassaletta JM, A new route to L-iduronate building-blocks for the synthesis of heparin-like oligosaccharides, Synlett 8, 1316-8 (1999).
Lubineau A, Gavard O, Alais J, Bonnaffe D, New accesses to L-iduronyl synthons, Tetrahedron Lett 41, 307-11 (2000).
Baumhof P, Mazitschek R, Giannis A, Amild and effective method for the transesterification of carboxylic acid esters, Angew Chem Int Ed 40, 3672-4 (2001).
Ando H, Manabe S, Nakahara Y, Ito Y, Solid-phase capture-release strategy applied to oligosaccharide synthesis on a soluble polymer support, Angew Chem Int Ed 40, 4725-8 (2001).
A. Kirshing, H. Monenschain, R. Wittenberg, The "resin-capture-release" hybrid technique: a merger between solid-and solution-phase synthesis, Chem Eur J 6, 4445-50, (2000).
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Ojeda, R., Terentí, O., de Paz, JL. et al. Synthesis of heparin-like oligosaccharides on polymer supports. Glycoconj J 21, 179–195 (2004). https://doi.org/10.1023/B:GLYC.0000045091.18392.a8
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DOI: https://doi.org/10.1023/B:GLYC.0000045091.18392.a8