Sialyl-Lewis inhibition

Selectins mediate contact by binding to carbohydrate-containing receptors on leucocytes through their N-terminal lectin domain. Sialyl-Lewis X (Neu5Aca2-3-Gaipi-4(Fucal-3)Glc-NAc) and derivatives thereof were shown to bind to the selectins and subsequently inhibit ischaemia-induced leucocyte infiltration in the liver [76-78]. A similar compound prevented antigen-induced late bronchial responses and airway hyper-responsiveness in allergic sheep [79]. 

Carbohydrate-mediated cell adhesion is an important event which can be initiated by tissue injury or infection and is involved in metastasis. One such adhesion process is the interaction between the glycoprotein E-selectin and oligosaccharides on the surface of neutrophils (white blood cells). The ligand that E-selectin recognizes is the tetrasaccharide sialyl Lewis X (SLe ). Since SLe competes with white blood cells for binding to E-selectin, thus inhibiting the adhesion process, it may useful as an anti-inflammatoiy and anticancer agent. 

Rolling of cells (neutrophils) initiated by cell adhesion was studied in a Y-channel. Inhibition by various anti-cell-adhesion molecules (anti-E-selectin, anti-P-selectin, sialyl Lewis X, Furoidan) was studied. Comparison can easily be made for cells with rolling and without rolling (control) in the two arms of the Y-channel [881],... 

Lin, C-C, ShimazaM, M, Heck, M-P, Aoki, S, Wang, R, Kimura, T, Ritzen, H, Takayama, S, Wu, S-H, Weitz-Schmidt, G, Wong, C-H, Synthesis of sialyl Lewis X mimetics and related structures using the glycosyl phosphite methodology and evaluation of E-selectin inhibition, J. Am. Chem. Soc., 118, 6826-6840, 1996. 

Tsai, C-Y, Huang, X, Wong, C-H, Design and synthesis of cyclic sialyl Lewis X mimetics a remarkable enhancement of inhibition by pre-organizing all essential functional groups. Tetrahedron Lett., 41, 9499-9503, 2000. 

Fukuda, M N, Ohyama, C, Lowitz, K, Matsuo, O, Pasqualini, R, Ruoslahti, E, Fukuda, M, A peptide mimic of E-selectin ligand inhibits sialyl Lewis -dependent lung colonization of tumor cells. Cancer Res., 60, 450-456, 2000. 

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. 

With the aid of monoclonal antibodies, sialylated carbohydrate structures, notably sialyl Lea and sialyl Lex, were discovered to function as receptors for the selectins [43]. Sialyl Lex is usually located on leukocytes, but also highly expressed on a variety of different cancer cells [45]. The same holds true for sialyl Lea, which serves as a tumor marker on gastrointestinal and pancreatic cancers [46]. Owing to the function of sialyl Lewis structures in the extravasation of cancer cells from the bloodstream and promoting metastatic spread to other tissues, a clear correlation of expression of sialyl Lea and sialyl Lex on tumors with enhanced progression and metastasis was observed. Since it is assumed that these tumor-associated carbohydrate markers enhance extravasation and metastasis by interactions with selectins, experiments were performed where selectin expression was inhibited. Long-term studies showed that cancer... 

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