| Research Abstract |
The role of the oligosaccharide attached to protein has often been described in connection with immunogenicity, cell adhesion, cancer metastasis and viral infection. However, the detail of the function remains uncertain due to the low availability of homogeneous samples from natural sources. Since preparation of a glycoprotein with single glycoform is so far difficult by means of recombinant technology, chemical synthesis may be a potent alternative to solve the problem of inaccessibility of the homogeneous samples. To this end, we have studied the syntheses of the part structures of such biologically important glycoproteins as leukosialin and emmprin. In order to facilitate the construction of N-and O-linked oligosaccharides, the sugar hydroxyl groups were protected as a benzyl ether. Two independent synthetic routes to the core 2 O-linked tetrasaccharides were investigated. Employment of trichloroacetamido group was particularly effective to stereoselectively produce a β-(1→6)-GlcNAc
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linkage. Having prepared the glycosylated amino acid building blocks, the solid-phase syntheses of glycopeptides were performed. The synthesized core 2 glycopeptide was efficiently deprotected under a "low-acidity TfOH" condition. Further elaboration of the glycopeptide by enzymatic sialylation was successful to quantitatively produce a disialo-hexasaccharide-linked peptide. The first Ig domain of emmprin, a cancer metastasis-related glycoprotein produced by cancer cells, carrys an N-linked oligosaccharide. Mono-, di-, and pentasaccharide-linked glycopeptides corresponding to the domain were synthesized by a combination of solid-phase synthesis of the segments and their coupling by the thioester method. Bioassay with the first two synthetic glycopeptides revealed that the disaccharide-linked glycopeptide stimulated the MMP 2 production by fibroblasts.
Solid-phase strategy is essential for the synthesis of such large glycopeptides. We have developed a silyl ether-type linker that can orthogonally be cleaved by fluoridolysis. Using the linker, a novel synthesis of glycopeptide thioester was achieved. Less
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