Studies on Selectin Blockers. 2. Novel Selectin Blocker as Potential Therapeutics for Inflammatory Disorders

Abstract

As a part of our studies of selectin blockers, we prepared 1-(2-tetradecylhexadecyl)-3'-O-sulfo Le(X) 1 and 1-(2-tetradecylhexadecyl) sLe(X) 2 and examined their inhibitory activities against natural ligand (sLe(X)) binding to E-, P-, and L-selectins. Compounds 1 and 2 were 2 times more potent than the sLe(X) tetrasaccharide toward E-selectin binding and up to 4 times more potent than sLe(X) toward P- and L-selectin binding. Interestingly, compound 1 provided dose-dependent protective effects against an immunoglobulin E-mediated skin reaction in mouse ears. This protective effect was associated with diminished tissue accumulation of neutrophils in the ear (as assessed by myeloperoxidase). These findings indicate that the modification of sLe(X) or 3'-O-sulfo Le(X) with a "branched anchor", a 2-tetradecylhexadecyl group, is useful in the design of a more potent selectin blocker, which has broad inhibitory activities toward all selectins.

Anti-metastatic Effect of the Sialyl Lewis-X Analog GSC-150 on the Human Colon Carcinoma Derived Cell Line KM12-HX in the Mouse.

“…4) In the present study, the inhibitory effect of GSC-150 on cancer cell distribution was observed at a lower dose (0.03 mg/mouse, Fig. 3A).…”

“…3B), which was comparable with that for the inhibition by GSC-150 (0.28 mM) of specific binding of sLeX to E-selectin. 4) Considering that few KM12-HX cells were attached to non-activated HUVECs (data not shown), the inhibitory effect of GSC-150 shown in Fig. 3B seems to be directed against the cell adhesion molecules expressed on TNF-a-activated HUVECs.…”

“…LPS is also known to induce the expression of many adhesion molecules. 11,12) GSC-150 has an affinity for not only Eselectin but also L-selectin and P-selectin, 4) and, therefore, GSC-150 may possibly inhibit cell adhesion molecules other than E-selectin. The molecular mechanism of the antimetastatic effect of GSC-150 needs to be clarified by further investigations.…”

“…3,4) GSC-150, 4) an analog of sialyl Lewis-X (sLeX) (Fig. 1), was developed as a selectin-blocker and suppressed inflammation caused by Ovalbumin in BALB/c mice.…”

“…1), was developed as a selectin-blocker and suppressed inflammation caused by Ovalbumin in BALB/c mice. 4) Carbohydrate antigens, including sLeX, are expressed on the cancer cell surface and play an important role in metastasis. Various human cancer cells that express sLeX antigens adhere very tightly to cytokine-activated endothelial cells.…”