Synthesis and biological evaluation of a potent E-selectin antagonist

Journal of Medicinal Chemistry

Volumn 42, Issue 23, 1999, Pages 4909-4913

  Thoma, Gebhard ^a   Kinzy, Willy ^a   Bruns, Christian ^a   Patton, John T ^b   Magnani, John L ^b   Bänteli, Rolf ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

^b GlycoTech Corporation   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE 1; ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE ANTAGONIST; SIALIC ACID DERIVATIVE; THIOGLYCOLIC ACID; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG BINDING; DRUG SYNTHESIS; ENDOTHELIUM CELL; LEUKOCYTE; LIGAND BINDING; MOLECULAR INTERACTION; MOUSE; NONHUMAN; PERITONITIS;

ACUTE DISEASE; ANIMALS; CARBOHYDRATE SEQUENCE; E-SELECTIN; LIGANDS; MICE; MOLECULAR MIMICRY; MOLECULAR SEQUENCE DATA; OLIGOSACCHARIDES; PERITONITIS; STRUCTURE-ACTIVITY RELATIONSHIP; THIOGLYCOLATES;

EID: 0032700539     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990422n     Document Type: Article

References (20)

1. Lobb, R. R. In Adhesion. Its Role in Inflammatory Disease; Harlan, J. M., Liu, D. Y., Eds.; W. H. Freeman: New York, 1992; Chapters 1-18, p 1.
2. (b) Paulson, J. C. In Adhesion. Its Role in Inflammatory Disease; Harlan, J. M., Liu, D. Y., Eds.; W. H. Freeman: New York, 1992; Chapter 2, p 19-35.
3. Mousa, S. A. Recent advances in cell adhesion molecule (CAM) research and development: Targeting CAMs for therapeutic and diagnostic applications. Drugs Future 1996, 21, 283-289.
4. Spertini, O.; Luscinskas, F. W.; Gimbrone, M. A.; Tedder, T. F. Monocyte attachment to activated human vascular endothelium in vitro is mediated by leukocyte adhesion molecule-1 (L-selectin) under nonstatic conditions. J. Exp. Med. 1992, 175, 1789-1792.
5. Kansas, G. S. Selectins and their ligands: current concepts and controversies. Blood 1996, 88, 3259-3287.
6. The efforts of the various research groups involved have been recently been summarized in an excellent review. Simanek, E. E.; McGarvey, G. J.; Jablonowski, J. A.; Wong, C.-H. Selectin-Carbohydrate Interactions: From Natural Ligands to Designed Mimics. Chem. Rev. 1998, 98, 833-862.
7. Kolb, H. C.; Ernst, B. Development of tools for the design of selectin antagonists. Chem. Eur. J. 1997, 1571-1578.
8. (b) Jahnke, W.; Kolb, H. C.; Blommers, M. J. J.; Magnani, J. L.; Ernst, B. Comparison of the bioactive conformations of sialyl Lewisx and a potent sialyl Lewisx mimic. Angew. Chem., Intl. Ed. 1997, 36, 2603-2607.
9. (c) Kolb, H. C.; Ernst, B. Recent progress in the glycodrug area. Pure Appl. Chem. 1997, 69, 1879-1884.
10. x. Toepfer, A.; Kretzschmar, G.; Schuth, S.; Sonnentag, M. Malonic acid derivatives as sialyl Lewis X mimetics. Bioorg. Med. Chem. Lett. 1997, 7, 1317-1322.
11. Hydrogenation in methanol gave less satisfactory results, most probably due to partial decomposition of the sensitive starting material.
12. Contour, M. O.; Defaye, J.; Little, M.; Wong, E. Stereoselective thioglycoside synthesis. Part XI. Zirconium(IV) chloride-catalyzed synthesis of 1,2-trans-1-thioglycopyranosides. Carbohydr. Res. 1989, 193, 283-287.
13. Very surprisingly, under identical reaction conditions but using galactosyl donors with an ether linkage in the 3-position and ester protecting groups in the 2-, 4-, and 6-position we isolated 10-15% of the corresponding α-anomer in addition to the desired β-linked product (∼60%). The formation of the side product could not be suppressed when NIS/TfOH was replaced by DMTST.
14. Yamazaki, F.; Kitajima, T.; Nukada, T.; Ito, T.; Ogawa, T. Synthetic studies on cell surface glycans. 66. Synthesis of an appropriately protected core glycotetraoside, a key intermediate for the synthesis of "bisected" complex-type glycans of a glycoprotein. Carbohydr. Res. 1990, 201, 15-30.
15. David, S.; Hanessian, S. Regioselective manipulation of hydroxyl groups via organotin derivatives. Tetrahedron 1986, 41, 643-663.
16. It has been reported that compounds contaminated with trace amounts of polyanions released from ion exchange resins can give false positive test results in selectin assays. To exclude such an effect, a batch of the free carboxylic acid of compound 2 has been prepared without applying ion exchange resin. The biological results in our assays were identical for both compounds. Kretzschmar, G.; Toepfer, A.; Huels, C.; Krause, M. Pitfalls in the preparation and biological evaluation of sialyl Lewisx mimetics as potential selectin antagonists. Tetrahedron 1997, 53, 2485-2494.
17. Thoma, G.; Magnani, J. L.; Oehrlein, R.; Ernst, B.; Schwarzenbach, F.; Duthaler, R. O. Synthesis of Oligosaccharide-Polylysine Conjugates: A Well Characterized Sialyl Lewisa Polymer for ELISA. J. Am. Chem. Soc. 1997, 119, 7414-15.
18. Thoma, G.; Duthaler, R. O.; Ernst, B.; Magnani, J. L.; Patton, J. T. Preparation of multivalent polymers as agents for preparing biologically active compounds. PCT Int. Appl., WO 97/19105, 1997.
19. (b) Thoma, G.; Patton, J. T.; Magnani, J. L.; Ernst, B.; Oehrlein, R.; Duthaler, R. O. Versatile functionalization of polylysine: synthesis, characterization, and use of neoglycoconjugates. J. Am. Chem. Soc. 1999, 121, 5919-5929.
20. This model of acute inflammation has been described earlier. Bosse, R.; Vestweber, D. Only simultaneous blocking of the L- and P-selectin completely inhibits neutrophil migration into mouse peritoneum. Eur. J. Immunol. 1994, 24, 3019-3024. We demonstrated that the model is dependent on E-selectin by using an anti-mouse E-sel mAb (10E9.6; 10 μg/animal) which showed a marked inhibitory effect.