E-selectin inhibitors

Zanini D, Roy R, Park WKC, Foxall C, Srivastava OP (1996) 3 -Sulfo-LewisX-Glc den-drimers as potent l- and E-selectin inhibitors. Proceedings of the XVIIIth International Carbohydrate Symposium, Milan, Italy, July 21-26, p 543... 

The n-3 PUFAs are reported to reduce expression of endothelial adhesion molecules VCAM-1, E-selectin, and ICAM-1, therefore influencing leukocyte-endothelial cell interactions and leukocyte migration across the endothelium. 105,106 Oxidized EPA has been shown to be a more potent inhibitor of leukocyte-endothelial interaction, in vitro and in vivo, than EPA.107 Since EFAs regulate intercellular adhesion, it has been speculated that the skin changes that are observed in EFA deficiency, may be due, at least in part, to damaged cell adhesion.108 n-3 PUFAs and GLA supplementation enhance E-cadherin expression in cancer cells and this possibly reduces the invasiveness of these cells.109... 

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. 

Ichikawa Y, Wong C-H (1994) Topochemistry and inhibition of selectin-mediated cell adhesion Chemical-enzymatic synthesis of inhibitors related to E-selectin recognition. In Bock K, Clausen H (eds) Complex carbohydrates in drug research. Structural and functional aspects. Munksgaard, Copenhagen, p 118... 

Rao, B N N, Anderson, M B, Musser, J H, Gilbert, J H, Schaefer, M E, Eoxah, C, Brandley, B K, Sialyl Lewis mimics derived from a pharmacophore search are selectin inhibitors with antiinflammatory activity, J. Biol. Chem., 269, 19663-19666, 1994. 

Pabna-Vargas, J M, Toledo-Pereyra, L, Dean, R E, Harkema, JM, Dixon, R A E, Kogan, T P, Small-molecule selectin inhibitor protects against bver inflammatory response after ischemia and reperfusion, J. Am. Coll. Surg., 185, 365-372, 1997. 

Dasgupta, F, Musser, J H, Levy, D E, and Tang, P C, Preparation of Eucose-Containing Siahc Acids as Selectin Inhibitors, U.S. Patent 5658880, 1997. 

Several groups have prepared glycopeptide constructs as inhibitors of specific selectins. Spren-gard et al. have synthesized iV-linked trivalent sialyl Lewis (sLe ) cyclic glycopeptides as inhibitors of E-selectin (O Fig. 16) [195]. Cyclic heptapeptides were prepared, followed by peptide coupling to sLe formulated as the glycosyl amine. The trivalent constructs were found to be two to three times as effective as monovalent sLe in the inhibition of HL-60 cells binding to immobilized E-selectin. 

Several groups have employed polyamino acid backbones as templates for the display of multiple carbohydrate residues [164,165]. For example, potent E-selectin antagonists have been generated from poly lysine [166,167] These materials are highly effective inhibitors of leukocyte rolling. Multivalent polylysine displays have also been used to inhibit Shiga-like toxin binding [168]. 

The synthesis of a collection of sulfated or sialylated oligosaccharides has confirmed that sulfates are the best inhibitors. The most active is the sulfated pentasaccharide 17.31 which is, until the present, the best ligand known of E-selectin, giving 50% inhibition at the very low concentration of 5 x 10 M (Lubineau et al. 1994). 

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