Advertisement

Abstract

The history of heparin dates back to 1916 when Jay Maclean, a PhD student in Howell’s laboratory, isolated an anticoagulant substance instead of the expected procoagulant phospholipids (1, 2). Since this substance was extracted from liver it was named heparin, in 1918, by Howell and Holt. Several years of debate then followed about the chemical nature of heparin (3). While it was initially thought to be a phospholipid, the polysaccharidic nature of heparin was suspected in 1925 and confirmed in the following years. However, the high complexity of the compound and the paucity of the analytical tools then available resulted in a very intricate situation where several authors proposed conflicting hypotheses regarding the nature of the different monosaccharides present as well as their substituents. It was only in the late 1960’s that the currently accepted chemical structure of heparin could be established (for a review, see (4)).

Keywords

Chemical Synthesis Uronic Acid Glucuronic Acid Potent Analogue Methyl Glycoside 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

All

allyl

Ac

acetyl

Bn

benzyl

Me

methyl

Z

benzyloxycarbonyl

tBu

ter-butyl

MCA

monochloroacetyl

Lev

levulinoyl

Tf

trifluoromethylsulphonyl

Ph

phenyl

TBDMS

tert-butyldimethylsilyl

THP

tetrahydropyranlyl

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mclean, J.: The Thromboplastic Action of Cephalin. Am. J. Physiol. 41, 250 (1916).Google Scholar
  2. 2.
    Mclean, J.: The Discovery of Heparin. Circulation 19, 75 (1959). Eds. D.A. Lane and U. Lindhal.Google Scholar
  3. 3.
    Roden, L.: Highlights in the History of Heparin. In “Heparin”. (D.A. Lane and U. Lindahl, eds.), pp. 1–23. London: Edward Arnold. 1989.Google Scholar
  4. 4.
    Casu, B.: Structure and Biological Activity of Heparin. Adv. Carbohydr. Chem. Biochem. 43, 51 (1985).CrossRefGoogle Scholar
  5. 5.
    Lindahl, U., D.S. Feingold, and L. Roden: Biosynthesis of Heparin. Trends Biochem. Sci. 11, 221 (1986).CrossRefGoogle Scholar
  6. 6.
    Bjork, I., S.T. Olson, and J.D. Shore: Molecular Mechanisms of the Accelerating Effect of Heparin on the Reactions between Antithrombin and Clotting Proteinases. In “Heparin”. (D.A. Lane and U. Lindahl, eds.), pp. 229–255. London: Edward Arnold. 1989.Google Scholar
  7. 7.
    Verstraete, M.: Pharmacotherapeutic Aspects of Unfractioned and Low Molecular Weight Heparins. Drugs 40, 498 (1990).CrossRefGoogle Scholar
  8. 8.
    Jacques, L.B.: Heparins-Anionic Polyelectrolyte Drugs. Pharmacol. Rev. 31, 99 (1979).Google Scholar
  9. 9.
    Clowes, A.W. and M.J. Karnovsky: Suppression by Heparin of Smooth Muscle Cell Proliferation in Injured Arteries. Nature 265, 625 (1977).CrossRefGoogle Scholar
  10. 10.
    Folkman, J.: Regulation of Angiogenesis: A New Function of Heparin. Biochem. Pharmacol. 34, 905 (1985).CrossRefGoogle Scholar
  11. 11.
    Baba, M., R. Pauwels, J. Balzarini, J. Desmyter, and E. De Clercq: Antiviral Activity of Heparin and Dextran Sulphate against Human Immunodeficiency Virus (HIV) in Vitro. Ann. N.Y. Acad. Sci. 556, 419 (1989).CrossRefGoogle Scholar
  12. 12.
    Andersson, L.O., T.W. Barrowcliffe, E. Holmer, E.A. Johnson, and G.E.C. Sims: Anticoagulant Properties of Heparin Fractionated by Affinity Chromatography on matrix-bound Antithrombin III and by Gel Filtration. Thromb. Res. 9, 575 (1976).CrossRefGoogle Scholar
  13. 13.
    Hook, M., I. Bjork, J. Hopwood, and U. Lindahl: Anticoagulant Activity of Heparin: Separation of High Activity and Low Activity Heparin Species by Affinity Chromatography on Immobilized Antithrombin. FEBS Lett. 66, 90 (1976).CrossRefGoogle Scholar
  14. 14.
    Lam, L.H., J.E. Silbert, and R.D. Rosenberg: The Separation of Active and Inactive Forms of Heparin. Biochem. Biophys. Res. Commun. 69, 570 (1976).CrossRefGoogle Scholar
  15. 15.
    Choay, J., J.C. Lormeau, M. Petitou, P. Sinay, and J. Fareed: Structural Studies on a Biologically Active Hexasaccharide Obtained from Heparin. Ann. N.Y. Acad. Sci. 370, 644 (1981).CrossRefGoogle Scholar
  16. 16.
    Thunberg, L., G. Backstrom, and U. Lindahl: Further Characterization of the Antithrombin-binding Sequence in Heparin. Carbohydr. Res. 100, 393 (1982).CrossRefGoogle Scholar
  17. 17.
    Lindahl, U., G. Backstrom, L. Thunberg, and I.G. Leder: Evidence for a 3-O-sulphated D-glucosamine Residue in the Antithrombin-binding Sequence of Heparin. Proc. Natl. Acad. Sci. USA 77, 6551 (1980).CrossRefGoogle Scholar
  18. 18.
    Klemer, A., and U. Kraska: Synthese von Athyl-2-Amino-2-Desoxy-4-O-(β-D-Glucuronopyranosyl)-a, β-D-Glucopyranosid. Tetrahedron Lett. 13, 431 (1972).CrossRefGoogle Scholar
  19. 19.
    Kiss, J., and P. Taschner: Synthesis of Heparin Saccharides. VI. Synthesis and Reactivity of some 4-O-(α-D-Hexopyranosyl)-α-D-Glucopyranosiduronate Derivatives. J. Carbohydr. Nucl. Nuc. 4, 101 (1977).Google Scholar
  20. 20.
    Kiss, J., and P.C. Wyss: Synthesis of Heparin Saccharides. Stereospecific Synthesis of Derivatives of 2-Amino-2-Deoxy-4-O-(a-D-Glucopyranuronosyl)-D-Glucose. Tetrahedron Lett. 13, 3055 (1972).CrossRefGoogle Scholar
  21. 21.
    Kiss, J., and P.C. Wyss: Synthesis of Heparin Saccharides. II. Synthesis and Stereochemical Aspects of Anomeric Methyl (Benzyl 2,3-di-O-Benzyl-L-Idopyranosid) Uronates. Carbohydr. Res. 27, 282 (1973).CrossRefGoogle Scholar
  22. 22.
    Kiss, J., and P.C. Wyss: Synthesis of Heparin Saccharides. V. Anomeric O-Benzyl Derivatives of L-Idopyranosyluronic Acid. Tetrahedron 32, 1399 (1976).CrossRefGoogle Scholar
  23. 23.
    Wyss, P.C., and J. Kiss: Synthesis of Heparin Saccharides. III. Synthesis of Derivatives of D-Glucosamine as Starting Materials for Disaccharides. Helv. Chim. Acta 58, 1833 (1975).CrossRefGoogle Scholar
  24. 24.
    Wyss, P.C., J. Kiss, and W. Arnold: Synthesis of Heparin Saccharides. IV. Synthesis of Disaccharides Possessing the Structure of a Repeating Unit of Heparin. Helv. Chim. Acta 58, 1847 (1975).CrossRefGoogle Scholar
  25. 25.
    Paulsen, H.: Advances in Selective Chemical Syntheses of Complex Oligosaccharides. Angew. Chem. Int. Ed. Engl. 21, 155 (1982).CrossRefGoogle Scholar
  26. 26.
    Schmidt, R.R.: New Methods for the Synthesis of Glycosides and Oligosaccharides-Are There Alternatives to the Koenigs-Knorr Method? Angew. Chem. Int. Ed. Engl. 25, 212 (1986).CrossRefGoogle Scholar
  27. 27.
    Wessel, H.P., Alkylating γ-Lactone-Opening: a short Synthesis of benzyl 3-O-Benzyl-1,2-O-Isopropylidene-α-D-Glucofuranuronate. J. Carbohydr. Chem. 8, 443–455 (1989).CrossRefGoogle Scholar
  28. 28.
    Sinay, P., J.C. Jacquinet, M. Petitou, P. Duchaussoy, I. Lederman, J. Choay, and G. Torri: Total Synthesis of a Heparin Pentasaccharide Fragment having High Affinity for Antithrombin III. Carbohydr. Res. 132, C5 (1984).Google Scholar
  29. 29.
    Petitou, M., P. Duchaussoy, I. Lederman, J. Choay, P. Sinay, J.C. Jacquinet, and G. Torri: Synthesis of Heparin Fragments. A Chemical Synthesis of the Pentasaccharide O-(2-Deoxy-2-Sulfamido-6-O-Sulfo-α-D-Glucopyranosyl)-(l→4)-O-(β-D-Glucopyranosyluronic Acid)-(1→4)-O-(2-Deoxy-2-Sulfamido-3,6-di-O-Sulfo-α-D-Glucopyranosyl)-(1→4)-O-(2-O-Sulfo-α-L-Idopyranosyluronic Acid)-(1→4)-2-Deoxy-2-Sulfamido-6-O-sulfo-D-Glucopyranose Decasodium Salt, a Heparin Fragment Having High Affinity for Antithrombin III. Carbohydr. Res. 147, 221 (1986).Google Scholar
  30. 30.
    Zissis, E., and H.G. Fletcher Jr.: Benzyl 2,3,4-Tri-O-Benzyl-β-D-Glucopyranosiduronic Acid and some Related Compounds. Carbohydr. Res. 12, 361 (1970).CrossRefGoogle Scholar
  31. 31.
    Mehltretter, C.L.: D-Glucuronic acid: α-D-Glucofuranurono-6,3-Lactone by Catalytic Air Oxidation of 1,2-O-Isopropylidene-α-D-Glucofuranose. Meth. Carbohydr. Chem. vol II, 29 (1963).Google Scholar
  32. 32.
    Nakahara, Y, and T. Ogawa: Synthesis of Methyl (Allyl 2,3-di-O-Benzyl-β-D-Galactopyranosid) Uronate and Methyl (2,3-di-O-Benzyl-α- and β-D-Galactopyranosyl Fluoride)Uronate. Carbohydr. Res. 173, 306 (1988).CrossRefGoogle Scholar
  33. 33.
    Nakahara, Y., and T. Ogawa: Stereoselective Total Synthesis of Dodecagalacturonic Acid, a Phytoalexin Elicitor of Soybean. Carbohydr. Res. 205, 147 (1990).CrossRefGoogle Scholar
  34. 34.
    Van Boeckel, C.A.A., T. Beetz, J.N. Vos, A.J.M. de Jong, S.F. van Aelst, R.H. van den Bosch, J.M.R. Mertens, and van der Vlugt, F.A.: Synthesis of a Pentasaccharide Corresponding to the Antithrombin III Binding Fragment of Heparin. J. Carbohydr. Chem. 4, 293 (1985).CrossRefGoogle Scholar
  35. 35.
    Meyer, A.S., and T. Reichstein: L-Idose aus D-Glucose, sowie ein neuer Weg zur L-Idomethylose. Helv. Chem. Acta 29, 152 (1946).CrossRefGoogle Scholar
  36. 36.
    Perchemlides, P., T. Osawa, E.A. Davidson, and R.W. Jeanloz: Synthesis of α-L-Idopyranosyl, (α-L-Idopyranosyluronic Acid), α-D-Mannopyranosyl, and (α-D-Mannopyranosyluronic Acid) Phosphates. Carbohydr. Res. 3, 463 (1967).CrossRefGoogle Scholar
  37. 37.
    Dax, K., I. Macher, and H. Weidmann: Reaktionen der D-glucuronsäure. 8.Mitt. Synthese von Derivaten der L-Idofuranose und des D-Mannofuranurono-6,3-Lactons aus D-Glucofuranurono-6,3-Lacton. J. Carbohydr. Nue. Nue. 1, 323 (1974).Google Scholar
  38. 38.
    Blanc-Muesser, M., J. Defaye, D. Horton, and J.H. Tsai: L-Idose and L-Iduronic Acid. Meth. Carbohydr. Chem. 8, 177 (1980).Google Scholar
  39. 39.
    Bagget, N., and A.K. Samra: Re-Examination of the Acid Hydrolysis of 5,6-Anhydro-1,2-O-Isopropylidene-β-L-Idofuranose. Carbohydr. Res. 127, 149 (1984).CrossRefGoogle Scholar
  40. 40.
    Lehmann, J.: Reaktionen Enolischer Zuckerderivate. Teil 1. Hydroborierung enolischer Zuckerderivate, ein Weg zur Darstellung schwer zugänglicher Hexosen und zur spezifischen Markierung mit Tritum. Carbohydr. Res. 2, 1 (1966).CrossRefGoogle Scholar
  41. 41.
    Nassr, M.A.M., M. Petitou, J. Choay, and P. Sinay: Synthèse de Disaccharides Contenant le L-Idopyrannose à l’Extrémité non-Réductrice. Xèmes Journées sur la Chimie et la Biochimie des Glucides, Paris, 5–7 juillet 1982.Google Scholar
  42. 42.
    Ichikawa, Y., and H. Kuzuhara: Synthesis of 1,6-Anhydro-2,3-di-O-Benzoyl-4-O-(methyl-2,3,4-tri-O-Benzoyl-α-L-Idopyranosyluronate)-β-D-Glucopyranose from Cellobiose. Carbohydr. Res 115, 117 (1983).CrossRefGoogle Scholar
  43. 43.
    Bagget, N., and A. Smithson: Synthesis of L-Iduronic Acid Derivatives by Epimerisation of Anancomeric D-Glucuronic Acid Analogues. Carbohydr. Res. 108, 59 (1982).CrossRefGoogle Scholar
  44. 44.
    Chiba, T., and P. Sinay: Application of a Radical Reaction to the Synthesis of L-Iduronic acid Derivatives from D-Glucuronic Acid Analogues. Carbohydr. Res. 151, 379 (1986).CrossRefGoogle Scholar
  45. 45.
    Chida, N., E. Yamada, and S. Ogawa: Synthesis of Methyl (Methyl D- and L-Idopyranosid) uronates from Myo-Inositol. J. Carbohydr. Chem. 7, 555 (1988).CrossRefGoogle Scholar
  46. 46.
    Ichikawa, Y., R. Monden, and H. Kuzuhara: Synthesis of a Heparin Pentasaccharide Fragment with a High Affinity for Antithrombin III Employing Cellobiose as a Key Starting Material. Tetrahedron Lett. 27, 611 (1986).CrossRefGoogle Scholar
  47. 47.
    Ichikawa, Y., A. Manaka, and H. Kuzuhara: Discrimination between the 2,3- and the 2′,3′-Hydroxyl Groups of Maltose and Cellobiose through their Specific Protection. Carbohydr. Res. 138, 55 (1985).CrossRefGoogle Scholar
  48. 48.
    Ichikawa, Y., R. Ichikawa, and H. Kuzuhara: Synthesis from Cellobiose, of a Trisaccharide Closely Related to the GlcNAc → GlcA → GlcN Segment of the Antithrombin-binding Sequence of Heparin. Carbohydr. Res. 141, 273 (1985).CrossRefGoogle Scholar
  49. 49.
    Ichikawa, Y., R. Monden, and H. Kuzuhara: Synthesis of Methyl Glycoside Derivatives of Tri- and Penta-saccharides Related to the Antithrombin III-binding Sequence of Heparin, employing Cellobiose as a Key Starting Material. Carbohydr. Res. 172, 37 (1988).CrossRefGoogle Scholar
  50. 50.
    Shing, T.K.M., and A.S. Perlin: Synthesis of Benzyl 2-Azido-2-Deoxy-4-O-β-D-Glucopyranosyl-α-D-Glucopyranoside and 1,6-Anhydro-2-Azido-2-Deoxy-4-O-β-D-Glucopyranosyl-β-D-Glucopyranose. Carbohydr. Res. 130, 65 (1984).CrossRefGoogle Scholar
  51. 51.
    Glushka, J.N., D.N. Gupta, and A.S. Perlin: The Conversion of Maltose into Disaccharides having 2-Amino-2-Deoxy-α-D-Glucose and L-Idose as Constituent Sugars, for the Synthesis of Model Compounds Related to Heparin. Carbohydr. Res. 124, C12 (1983).CrossRefGoogle Scholar
  52. 52.
    Glushka, J.N., and A.S. Perlin: Formation of Disaccharides related to Heparin and Heparan Sulphate by Chemical Modification of Maltose. Carbohydr. Res. 205, 305 (1990).CrossRefGoogle Scholar
  53. 53.
    Ueno, Y., K. Hori, R. Yamauchi, M. Kiso, A. Hasegawa, and K. Kato: Reaction of Maltose with 2,2-Dimethoxypropane. Carbohydr. Res. 89, 271 (1981).CrossRefGoogle Scholar
  54. 54.
    Petitou, M., P. Duchaussoy, I. Lederman, J. Choay, J.C. Jacquinet, P. Sinay, and G. Torri: Synthesis of Heparin Fragments: A Methyl α-Pentaoside with High Affinity for Antithrombin III. Carbohydr. Res. 167, 67 (1987).CrossRefGoogle Scholar
  55. 55.
    Petitou, M., G. Jaurand, M. Derrien, P. Duchaussoy, and J. Choay: A New Highly Potent, Heparin-like Pentasaccharide Fragment Containing a Glucose Residue instead of a Glucosamine. BioMed. Chem. Lett. 1, 95 (1991).CrossRefGoogle Scholar
  56. 56.
    Walenga, J.M., J. Fareed, M. Petitou, M. Samama, J.C. Lormeau, and J. Choay: Intravenous Antithrombotic Activity of a Synthetic Heparin Pentasaccharide in a Human Serum Induced Stasis Thrombosis Model. Thromb. Res. 43, 243 (1986).CrossRefGoogle Scholar
  57. 57.
    Walenga, J.M., M. Petitou, J.C. Lormeau, M. Samama, J. Fareed, and J. Choay: Antithrombotic Activity of a Synthetic Heparin Pentasaccharide in a Rabbit Stasis Thrombosis Model using Different Thrombogenic Challenges. Thromb. Res. 46, 187 (1987).CrossRefGoogle Scholar
  58. 58.
    Hobbelen, P.M.J., T.G. van Dinther, G.M.T. Vogel, C.A.A. van Boeckel, H.C.T. Moelker, D.G. Meuleman: Pharmacological Profile of the Chemically Synthesized Antithrombin III Binding Fragment of Heparin (pentasaccharide) in Rats. Thromb. Haemost. 63, 265–270 (1990).Google Scholar
  59. 59.
    Meuleman, D.G., P.M.J. Hobbelen, T.G. van Dinther, G.M.T. Vogel, C.A.A. van Boeckel, and H.C.T. Moelker: Anti-factor Xa Activity and Antithrombotic Activity in Rats of Structural Analogues of the Minimum Antithrombin III binding Sequence: Discovery of Compounds with A Longer Duration of Action than of the Natural Pentasaccharide. Semin. Thromb. Hemostasis 17, 112 (1991).Google Scholar
  60. 60.
    Loganathan, D., H.M. Wang, L.M. Mallis, and R.J. Linhardt: Structural Variation in the Antithrombin III Binding Site Region and its Occurrence in Heparin from Different Sources. Biochemistry 29, 4362 (1990).CrossRefGoogle Scholar
  61. 61.
    Duchaussoy, P., P.S. Lei, M. Petitou, P. Sinay, J.C. Lormeau, and J. Choay: The First Total Synthesis of the Antithrombin III Binding Site of Porcine Mucosa Heparin. BioMed. Chem. Lett 1, 99 (1991).CrossRefGoogle Scholar
  62. 62.
    Lindahl, U., G. Backstrom, and L. Thunberg: The Antithrombin-Binding Sequence in Heparin. Identification of an essential 6-O-Sulfate Group. J. Biol. Chem. 258, 9826 (1983).Google Scholar
  63. 63.
    Atha, D.H., J.C. Lormeau, M. Petitou, R.D. Rosenberg, and J. Choay: Contribution of Monosaccharide Residues in Heparin Binding to Antithrombin III. Biochemistry 24, 6723 (1985).CrossRefGoogle Scholar
  64. 64.
    Riesenfeld, J., L. Thunberg, M. Hook, and U. Lindahl: The Antithrombin-Binding Sequence of Heparin. Location of Essential N-Sulfate Groups. J. Biol. Chem. 256, 2389 (1981).Google Scholar
  65. 65.
    Petitou, M.: Synthetic Heparin Fragments: New and Efficient Tools for the Study of Heparin and its Interactions. Nouv. Rev. Fr. Hematol. 26, 221 (1984).Google Scholar
  66. 66.
    Choay, J.: Biologic Studies on Chemically Synthesized Pentasaccharide and Tetrasaccharide Fragments. Semin. Thromb. Hemostasis 11, 81 (1985).CrossRefGoogle Scholar
  67. 67.
    Petitou, M., P. Duchaussoy, L. Lederman, J. Choay, and P. Sinay: Binding of Heparin to Atithrombin III: a Chemical Proof of the Critical Role played by a 3-Sulfated-2-Amino-2-Deoxy-D-Glucose Residue. Carbohydr. Res. 179, 163 (1988).CrossRefGoogle Scholar
  68. 68.
    Atha, D.H., J.-C. Lormeau, M. Petitou, R.D. Rosenberg, and J. Choay: Contribution of 3-O- and 6-O-Sulfated Glucosamine Residues in the Heparin Induced Conformational Change in Antithrombin III, Biochemistry 26, 6454 (1987).CrossRefGoogle Scholar
  69. 69.
    Beetz, T., and C.A.A. van Boeckel: Synthesis of an Antithrombin Binding Heparin-like Pentasaccharide lacking 6-O-Sulfate at its Reducing End. Tetrahedron Lett. 27, 5889 (1986).CrossRefGoogle Scholar
  70. 70.
    Petitou, M., J.C. Lormeau, and J. Choay: Interaction of Heparin and Antithrombin III. The Role of O-Sulfate Groups. Eur. J. Biochem. 88, 637 (1988).CrossRefGoogle Scholar
  71. 71.
    Petitou, M., P. Duchaussoy, and J. Choay: p-Anisyl Ethers in Carbohydrate Chemistry: Selective Protection of the Primary Alcohol Function. Tetrahedron Lett. 1389, (1988).Google Scholar
  72. 72.
    van Boeckel, C.A.A., et al.: unpublished results.Google Scholar
  73. 73.
    Agarwal, A., and I. Danishefsky: Requirement of free Carboxyl Groups for the Anticoagulant Activity of Heparin, Thromb. Res. 42, 673 (1986).CrossRefGoogle Scholar
  74. 74.
    van Boeckel, C.A.A., H. Lucas, S.F. van Aelst, M.W.P. van den Nieuwenhof, G.N. Wagenaars, and J.-R. Mellema: Synthesis and Conformational Analysis of an Analogue of the Antithrombin-binding Region of Heparin: the Role of the Carboxylate Function of α-L-Idopyranuronate. Reel. Trav. Chim. Pays-Bas 106, 581 (1987).CrossRefGoogle Scholar
  75. 75.
    van Aelst, S.F., and C.A.A. van Boeckel: Synthesis of an Analogue of the Antithrombin Binding Region of Heparin containing α-L-Idopyranose; Reel. Trav. Chim. Pays-Bas 106, 593 (1987).CrossRefGoogle Scholar
  76. 76.
    Vos, J., et al.: unpublished results.Google Scholar
  77. 77.
    Petitou, M., et al.: unpublished results.Google Scholar
  78. 78.
    van Boeckel, C.A.A., T., Beetz, and S.F. van Aelst: Synthesis of a potent Antithrombin activating Pentasaccharide: A new Heparin-like Fragment Containing two 3-O-Sulphated Glucosamines. Tetrahedron Lett. 803 (1988).Google Scholar
  79. 79.
    van Boeckel, C.A.A., S.F. van Aelst, T. Beetz, D.G. Meuleman, Th.G. van Dinther, and H.C.T. Moelker: Structure-Activity Relationships of Synthetic Heparin Fragments: Discovery of a very Potent AT-III Activating Pentasaccharide. Ann. N.Y. Acad. Sci. 556, 489, 1989.CrossRefGoogle Scholar
  80. 80.
    Visser, A., M.T. Buiting, T.G. van Dinther, C.A.A. van Boeckel, P.D.J. Grootenhuis, and D.G. Meuleman: The AT-III Binding Affinities of a Series of Synthetic Pentasaccharide Analogues. Thromb. Haemost. 65, 1296 (1991).Google Scholar
  81. 81.
    Barzu, T., M. Petitou, G. Jaurand, J.C. Lormeau, and J. Choay: Binding to Antithrombin III of the synthetic Oligosaccharides derived from the High Affinity Pentasaccharide Sequence of Heparin. Thromb. Haemost. 65, 934 (1991).Google Scholar
  82. 82.
    Petitou, M., J.C. Lormeau, and J. Choay: A New Synthetic Pentasaccharide with Increased Anti-Factor Xa Activity: Possible Role for Anionic Clusters in the Interaction of Heparin and Antithrombin III. Semin. Thromb. Hemostasis 17,143, (1991).Google Scholar
  83. 83.
    Basten, J., G. Jaurand, et al.: unpublished results.Google Scholar
  84. 84.
    Basten, J., et al.: unpublished results.Google Scholar
  85. 85.
    Kat-Vanden Nieuwenhof, M.W.P., J.E.M. Basten, M. Lucas, and C.A.A. van Boeckel: Synthesis of some very potent Antithrombin III activating Heparin-Like Fragments. Fifth European Symposium on Carbohydrates, Eurocarb V, Prague, 21–25 August 1989. Abstr. A-39.Google Scholar
  86. 86.
    Petitou, M., G. Jaurand, M. Derrien, P. Duchaussoy, and J. Choay: Synthesis of selectively oversulfated Heparin-Like Pentasaccharides with high anti-factor Xa Activity. Fifth European Symposium on Carbohydrates, Eurocarb V, Prague, 21–25 August 1989. Abstr. A-68.Google Scholar
  87. 87.
    van Boeckel, C.A.A., G.N. Wagenaars, and J.R. Mellema: Conformational Analysis of a Biological Active Heparin-like Compound, which Contains an Open Chain Fragment. Reel. Trav. Chim. Pays-Bas 107, 649 (1988).CrossRefGoogle Scholar
  88. 88.
    Lucas, H., J.E.M. Basten, Th.G. van Dinther, D.G., Meuleman, S.F. van Aelst, and C.A.A. van Boeckel: Synthesis of Heparin-Like Pentamers Containing “Opened” Uronic Acid Moieties. Tetrahedron 46, 8207 (1990).CrossRefGoogle Scholar
  89. 89.
    Wessel, H.P., L. Labler, and T.B. Tschopp: Synthesis of an N-Acetylated Heparin Pentasaccharide and its Anticoagulant Activity in Comparison with the Heparin Pentasaccharide with High anti-Factor-Xa Activity. Helv. Chem. Acta 72, 1268 (1989).CrossRefGoogle Scholar
  90. 90.
    Kraaijeveld, N.A., and C.A.A. van Boeckel: Synthesis of Several Sulphated and Non-Sulphated Pentasaccharides, corresponding to the E. Coli K5 Glycosaminoglycan. Reel. Trav. Chem. Pays-Bas 108, 39 (1989).CrossRefGoogle Scholar
  91. 91.
    Vos, J.N., P. Westerduin, and C.A.A. van Boeckel: Synthesis of a 6-O-Phosphorylated Analogue of the Antithrombin III Binding Sequence of Heparin. BioMed. Chem. Lett. 1, 143 (1991).CrossRefGoogle Scholar
  92. 92.
    Kanyo, Z.F., and D.W. Christianson: Biological Recognition of Phosphate and Sulfate. J. Biol. Chem. 266, 4264 (1991).Google Scholar
  93. 93.
    Edge, A.S.B., and R.G. Spiro: Characterization of novel Sequences Containing 3-O-Sulfated Glucosamine in Glomerular Basement Membrane Heparan Sulfate and Localization of Sulfated Disaccharides to a Peripheral Domain. J. Biol. Chem. 265, 15874 (1990).Google Scholar
  94. 94.
    Nukada, T., H. Lucas, P. Konradsson, and C.A.A. van Boeckel,: Syntheses of larger Modified Oligosaccharides Containing “Opened Carbohydrate” Fragments. Synlett 365 (1991).Google Scholar
  95. 95.
    Lemieux, R.U., K.B. Hendriks, R.V. Stick, and K. James: Halide Ion Catalyzed Glycosidation Reactions. Synthesis of α-linked Disaccharides. J. Am. Chem. Soc. 97, 4056 (1975).CrossRefGoogle Scholar
  96. 96.
    Lucas, H., J. Basten, P. Konradsson, B. Olde Hanter, C.A.A. van Boeckel, G, Jaurand, P. Duchaussoy, M. Derrien, and M. Petitou: Syntheses and Structure-Activity Relationships of some new Potent Analogues of Heparin; Preparation of Alkylated “Non-Glycsoaminoglycans”. Presented at Eurocarb VI, Vlth European Symposium Carbohydrate Chemistry, Edinburgh Sept. 1991. Abstract B. 170.Google Scholar
  97. 97.
    Meuleman, D., et al.:, to be published.Google Scholar
  98. 98.
    Gatti, G., B. Casu, G.K. Hamer, and A.S. Perlin: Studies on the Conformation of Heparin by 1H- and 13C-NMR Spectroscopy. Macromolecules 12, 1001 (1979).CrossRefGoogle Scholar
  99. 99.
    Torri, G., B. Casu, G. Gatti, M. Petitou, J. Choay, J.C. Jacquinet, and P. Sinay: Mono- and Bidimensional 500 MHz 1H-NMR Spectra of a Synthetic Pentasaccharide Corresponding to the Binding Sequence of Heparin to Antithrombin III: Evidence for Conformational Peculiarity of the Sulphated Iduronate Residue. Biochem. Bio-phys. Res. Commun. 128, 134 (1985).CrossRefGoogle Scholar
  100. 100.
    Ragazzi, M., D.R. Ferro, and A. Provasoli: A Force-field Study of the Conformational Characteristics of the Iduronate Ring. J. Comput. Chem. 7, 105 (1986).CrossRefGoogle Scholar
  101. 101.
    van Boeckel, C.A.A., S.F. van Aelst, G.N. Wagenaars, J.R. Mellema, H. Paulsen, J. Peters, A. Pollex, and V. Sinnwell: Conformational Analysis of Synthetic Heparin-like Oligosaccharides Containing α-L-Idopyranosyluronic Acid. Reel. Trav. Chim. Pays-Bas 106, 19 (1987).CrossRefGoogle Scholar
  102. 102.
    Ferro, D.R., A. Provasoli, M. Ragazzi, B. Casu, G. Gatti, G. Torri, V. Bossennec, B. Perly, P. Sinay, M. Petitou, and J. Choay: Conformer Populations of L-Iduronate Acid Residue in Glycosaminoglycan Sequences. Carbohydr. Res. 195, 157 (1990)CrossRefGoogle Scholar
  103. 103.
    Ferro, D.R., A. Provasoli, M. Ragazzi, B. Casu, G. Gatti, J.C. Jacquinet, P. Sinay, M. Petitou, and J. Choay: Evidence for Conformational Equilibrium of the Sulphated L-Iduronate Residue in Heparin and in Synthetic Heparin Mono- and Oligosaccharides: MNR and Force-field Studies. J. Am. Chem. Soc. 108, 6773 (1986).CrossRefGoogle Scholar
  104. 104.
    Sanderson, P.N., T.N. Huckerby, and I.A. Nieduszynski: Conformational Equilibrium of Unsulphated Iduronate in Heparan Sulphate Tetrasaccharides. Glycoconjugate J. 2, 109 (1985).CrossRefGoogle Scholar
  105. 105.
    Paulsen, H., A. Pollex, V. Sinnwell, and C.A.A. van Boeckel: Konformationsanalyse von Heparin-analogen Di- und Trisacchariden mit α-L-Idopyranose-Einheiten. Liebigs Ann. Chem. 411 (1988).Google Scholar
  106. 106.
    Meyer, B., and R. Stuike-Prill: Syntheses of Benzyl 6-O-Sulfo-β-D-Glucopyranoside Salts and their 6-S-Deuterated Analogues. Conformational Preferences of their (Sulfonyloxy)methyl Group. J. Org. Chem. 55, 902 (1990).CrossRefGoogle Scholar
  107. 107.
    Nishida, Y., H. Hori, H. Ohrui, and H. Meguro: 1HNMR Analyses of Rotameric Distribution of C5-C6 Bonds of Glucopyranoses in Solution. J. Carbohydr. Chem. 7, 239 (1988).CrossRefGoogle Scholar
  108. 108.
    Ragazzi, M., D.R. Ferro, B. Perly, P. Sinay, M. Petitou, and J. Choay: Conformation of the Pentasaccharide Corresponding to the Binding Site of Heparin for Antithrombin III. Carbohydr. Res. 195, 169 (1990).CrossRefGoogle Scholar
  109. 109.
    Grootenhuis, P.D.J., and C.A.A. van Boeckel: Constructing a Molecular Model of the Interaction between Antithrombin III and a Potent Heparin Analogue. J. Am. Chem. Soc. 113, 2743 (1991).CrossRefGoogle Scholar
  110. 110.
    Jaurand, G., J. Basten, I. Lederman, C.A.A. van Boeckel, M. Petitou: Biologically Active Heparin-Like Fragments with a “Non-Glycosamino” glycan Structure. Part 1: A Pentasaccharide Containing a 3-O-Methyl Iduronic Acid Unit. BioMed. Chem. Lett. 2, 897 (1992).CrossRefGoogle Scholar
  111. 111.
    Basten, J., G. Jaurand, B. Olde-Hanter, M. Petitou, C.A.A. van Boeckel: Biologically Active Heparin-like Fragments with a “Non-Glycosamino”glycan Structure. Part 2: A Tetra-O-Methylated Pentasaccharide with High Affinity for Antithrombin III. BioMed. Chem. Lett. 2, 901 (1992).CrossRefGoogle Scholar
  112. 112.
    Basten, J., G. Jaurand, B. Olde-Hanter, P. Duchaussoy, M. Petitou, C.A.A. van Boeckel: Biologically Active Heparin-like Fragments with a “Non-Glycosamino”glycan Structure. Part 3: O-Alkylated-O-Sulphated Pentasaccharides. BioMed. Chem. Lett. 2, 905 (1992).CrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1992

Authors and Affiliations

  • M. Petitou
    • 1
  • C. A. A. van Boeckel
    • 2
  1. 1.Sanofi RechercheGentillyFrance
  2. 2.Organon Scientific Development GroupOssThe Netherlands

Personalised recommendations