C‐Disaccharides as Probes for Carbohydrate Recognition – Investigation of the Conformational Requirements for Binding of Disaccharide Mimetics of Sialyl Lewis X

A set of C-disaccharide analogs was designed to probe the recognition of a known O-disaccharide mimetic of sialyl Lewis X, to P-selectin. The synthesis of the C-glycosides centered on the de novo construction of the galactose residue via an oxocarbenium ion/enol ether cyclization. Conformational analysis was performed by a combination of NMR spectroscopy and molecular mechanics (MM) and molecular dynamics (MD) calculations. The inhibition of P-selectin binding was evaluated in a P-selectin Biacore assay. At 12 mM, the O-glycoside showed 48 % inhibition of binding, while the C-glycoside analogs exhibited between 25–31 % inhibition. This data is discussed within the context of the active conformation of sLex and the conformational behavior of these ligands. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

[1]  M. Postema,et al.  Synthesis of Stable Carbohydrate Mimetics as Potential Glycotherapeutics , 2005 .

[2]  Bert E Thomas,et al.  Quinic acid derivatives as sialyl Lewis(x)-mimicking selectin inhibitors: design, synthesis, and crystal structure in complex with E-selectin. , 2005, Journal of medicinal chemistry.

[3]  J. Angulo,et al.  The conformational behaviour of α,β-trehalose-like disaccharides and their C-glycosyl, imino-C-glycosyl and carbagalactose analogues depends on the chemical nature of the modification: an NMR investigation , 2005 .

[4]  S. R. Chhabra,et al.  Recent progress in the design of selectin inhibitors. , 2003, Mini reviews in medicinal chemistry.

[5]  G. Thoma,et al.  Simplified sialyl Lewisx analogues with improved E-selectin inhibition , 2003 .

[6]  N. Kaila,et al.  Design and synthesis of sialyl Lewisx mimics as E‐ and P‐selectin inhibitors , 2002, Medicinal research reviews.

[7]  J. Lowe,et al.  Synthesis and biological evaluation of a new sialyl Lewis X mimetic derived from lactose. , 2002, The Journal of organic chemistry.

[8]  S. Hanessian,et al.  Synthesis of a potent antagonist of E-selectin. , 2002, The Journal of organic chemistry.

[9]  W. Jahnke,et al.  A Readily Available, Highly Potent E-Selectin Antagonist. , 2001, Angewandte Chemie.

[10]  W. Jahnke,et al.  Preorganization of the Bioactive Conformation of Sialyl Lewis(X) Analogues Correlates with Their Affinity to E-Selectin. , 2001, Angewandte Chemie.

[11]  N. Powell,et al.  Studies on the total synthesis of formamicin: synthesis of the C(1)-C(11) fragment. , 2001, Organic letters.

[12]  W. Somers,et al.  Insights into the Molecular Basis of Leukocyte Tethering and Rolling Revealed by Structures of P- and E-Selectin Bound to SLeX and PSGL-1 , 2000, Cell.

[13]  Osamu Kanie,et al.  Synthesis of 1,1-linked galactosyl mannosides carrying a thiazine ring as mimetics of sialyl Lewis X antigen: investigation of the effect of carboxyl group orientation on P-selectin inhibition. , 2000, The Journal of organic chemistry.

[14]  D. R. Mootoo,et al.  Synthesis of the C-glycoside analogue of a novel sialyl Lewis X mimetic. , 2000, The Journal of organic chemistry.

[15]  Jesús Jiménez-Barbero,et al.  Conformational Differences Between O‐ and C‐Glycosides: The α‐O‐Man‐(1→1)‐β‐Gal/α‐C‐Man‐(1→1)‐β‐Gal Case‐ A Decisive Demonstration of the Importance of the exo‐Anomeric Effect on the Conformation of Glycosides , 2000 .

[16]  A. Imberty,et al.  Synthesis and Conformational Analysis of a Conformationally Constrained Trisaccharide, and Complexation Properties with Concanavalin A , 1999 .

[17]  Richard D. Cummings,et al.  Affinity and Kinetic Analysis of P-selectin Binding to P-selectin Glycoprotein Ligand-1* , 1998, The Journal of Biological Chemistry.

[18]  H. Togo,et al.  C-Glycosidation Technology With Free Radical Reactions , 1998 .

[19]  A. Otter,et al.  Thermodynamic and Conformational Implications of Glycosidic Rotamers Preorganized for Binding , 1998 .

[20]  J. A. Jablonowski,et al.  Selectin-Carbohydrate Interactions: From Natural Ligands to Designed Mimics , 1998 .

[21]  B. Ernst,et al.  DEVELOPMENT OF TOOLS FOR THE DESIGN OF SELECTIN ANTAGONISTS , 1997 .

[22]  F. D’Andrea,et al.  Efficient Differentiation of the Hydroxyl Groups of 3,4-O-Isopropylidene-D-Galactopyranosides by Lipase Catalyzed Esterification and De - Esterification , 1997 .

[23]  T. Gallagher,et al.  Nucleophilic C-glycosyl donors for C-glycoside synthesis , 1997 .

[24]  G. Kretzschmar,et al.  PIPERIDINE CARBOXYLIC ACID DERIVATIVES AS SIALYL LEWIS X MIMETICS , 1997 .

[25]  John S. Philo,et al.  Conformation of sLex Tetrasaccharide, Free in Solution and Bound to E-, P-, and L-Selectin†,‡ , 1997 .

[26]  G. Kretzschmar,et al.  Pitfalls in the synthesis and biological evaluation of sialyl-LewisX mimetics as potential selectin antagonists , 1997 .

[27]  I. Ollmann,et al.  Rational Design and Synthesis of a 1,1-Linked Disaccharide That Is 5 Times as Active as Sialyl Lewis X in Binding to E-Selectin , 1996 .

[28]  E. Bartnik,et al.  Synthesis of novel mimetics of the sialyl Lewis X determinant , 1995 .

[29]  Thomas Peters,et al.  Determination of the Bioactive Conformation of the Carbohydrate Ligand in the E‐Selectin/Sialyl LewisX Complex , 1995 .

[30]  K. Kopple,et al.  The soluble form of E-selectin is an asymmetric monomer. Expression, purification, and characterization of the recombinant protein. , 1994, The Journal of biological chemistry.

[31]  R. Cooke,et al.  The conformation of the sialyl Lewis X ligand changes upon binding to E-selectin. , 1994, Biochemistry.

[32]  T. Springer.  Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm , 1994, Cell.

[33]  W. C. Still,et al.  Semianalytical treatment of solvation for molecular mechanics and dynamics , 1990 .

[34]  G. Chang,et al.  Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics , 1990 .

[35]  Rodger P. McEver,et al.  Rapid neutrophil adhesion to activated endothelium mediated by GMP-140 , 1990, Nature.

[36]  Norman L. Allinger,et al.  Molecular mechanics. The MM3 force field for hydrocarbons. 1 , 1989 .

[37]  R. Linhardt,et al.  Recent advances in the synthesis of C-oligosaccharides. , 2005, Current topics in medicinal chemistry.

[38]  F. Cañada,et al.  The conformation of C-glycosyl compounds. , 2000, Advances in carbohydrate chemistry and biochemistry.

[39]  S. Mousa.  RECENT ADVANCES IN CELL ADHESION MOLECULE (CAM) RESEARCH AND DEVELOPMENT :TARGETING CAMS FOR THERAPEUTIC AND DIAGNOSTIC APPLICATIONS , 1996 .

[40]  F. D. Leeuw,et al.  The relationship between proton-proton NMR coupling constants and substituent electronegativities—I : An empirical generalization of the karplus equation , 1980 .