Selectins synthesis

ICAM-1, VCAM-1 and E-selectin synthesis was successfully blocked in vitro using these types of molecules [113]. In vivo, the systemic administration of ICAM-1 antisense oligonucleotide prevented and reversed murine colitis without serious side-effects [114]. In a place-bo-controUed trial of the human analogue, the antisense oligonucleotide was effective and well tolerated [115]. 

DeFrees, S., Kosch, W., Way, W., Paulson, J., Sabesan, S., Halcomb, R., etal. (1995) Ligand recognition by E-selectin Synthesis, inhibitory activity and conformational analysis of bivalent sialyl Lewis x analogs. J. Am. Chem. Soc., 117, 66-79. 

Flgure10.23 Sialyl Lewis -related selectin inhibitorandfluorogenicscreening compound for transketolase prepared using enzymatic aldolization, and multienzymatic oxidation-aldolization strategy for the synthesis of bicyclic higher carbon sugars. 

A similar approach was used in the synthesis of the sialyl Lewis X mimetics of type 85 (Scheme 13.22).66 Protein crystallization,67 conformational studies of sLex in solution68 and in bound form to E- and P-selectin69 as well as the study of structure-function relationships70,71 gave information about the functional groups of the sLex-epitope essential for the binding to the selectins. Synthesized mimetics must contain the three essential hydroxyl functions of the fucose. Sialic acid, galactose, and... 

Parallel synthesis of 62 different fucosylated tripeptides resulted in two ligands with submicromolar affinity for the P-selectin however, the desired activity for the E-selectin was not observed.98 For the E-selectin selectivity, it was necessary to incorporate a hydroxyl group that mimics the 4-hydroxyl of the central Gal in SLex in addition to a Fuc-residue and a carboxylate to obtain ligands with > 10-fold increased activity over that of the SLex tetrasaccharide.81 One of the best ligands was obtained from Thr(a-Fuc)-OEt, which was first /V-acylated with a hydroxyl amino acid and then elongated with a di-acid to furnish the acid mimic of the sialic acid carboxylate (Fig. 14.4). This approach was further developed as a solid-phase method where the molecule was linked to a solid support through the invariable fucosyl moiety.99... 

S. Hanessian and H. Prabhanjan, Design and synthesis of glycomimetic protolypes-a model sialyl Lewis ligand for E-selectin, Synlett p. 868 (1994). 

W. Stahl, U. Sprengard, G. Kretzschmar, and H. Kunz, Synthesis of deoxy sialyl Lewis analogues, potential selectin antagonists, Angew. Chem. Int. Ed. Engl. 33 2096 (1994). 

Lex-antigenic trisaccharide (a-L-Fuc(l-3)-[p-D-Gal-(l-4)-p-D-GlcNAc]) and its sialylated structure (SLex) are terminal components of a nnmber of glycoconjugates on cell surfaces [31]. SLex serves as a ligand for the endothelial leukocyte molecule-1 (E-selectin) [32], which mediates the initial stages of adhesion of leukocytes to activated endothelial cells, and pays a critical role during inflammatory responses [33]. Lex-based carbohydrates have shown promise in therapeutic investigations related to the inflammatory process. As a result, extensive efforts have been directed toward the synthesis of SLex and related molecules [34 also see Chap. 15],... 

After infection and immune cell activation, endothelial cells are variously activated to bind peripheral blood leucocytes. Bacterial toxins such as lipopolysaccharide (LPS), inflammatory cytokines such as tumour necrosis factors a and (5 (TNFa and TNFP) and interleukin-1 (5 (IL-ip) increase the synthesis of cell surface E- and P-selectins in endothelial cells. Histamine and thrombin increase PM P-selectins in endothelial cells and platelets. L-selectins are constitutively expressed in monocytes and lymphocytes. The selectins are involved in the initial adhesion of leucocytes with endothelial cells via selectin-selectin receptor interactions, for example, monocyte L-selectin-endothelial L-selectin ligand binding and T-lymphocyte-endothelial selectin-integrin interactions. This initial phase of leucocyte-endothelial adhesion enables an early stage of leucocyte rolling through successive formation and breakage of adhesive interactions. 

Halcomb RL, Huang HM, Wong CH. Solution- and solid-phase synthesis of inhibitors of H. pylori attachment and E-Selectin-mediated leukocyte adhesion. J. Am. Chem. Soc. 1994 116 11315-11322. 

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