Abstract
On the basis of the highly branched ovomucoid-type undecasaccharide that had been shown previously to be an endogenous ligand for CD69 leukocyte receptor, a systematic investigation of smaller oligosaccharide mimetics was performed based on linear and branched N-acetyl-d-hexosamine homooligomers prepared synthetically using hitherto unexplored reaction schemes. The systematic structure-activity studies revealed the tetrasaccharide GlcNAcbeta1-3(GlcNAcbeta1-4)(GlcNAcbeta1-6)GlcNAc (compound 52) and its alpha-benzyl derivative 49 as the best ligand for CD69 with IC(50) as high as 10(-9) M. This compound thus approaches the affinity of the classical high-affinity neoglycoprotein ligand GlcNAc(23)BSA. Compound 68, GlcNAc tetrasaccharide 52 dimerized through a hydrophilic flexible linker, turned out to be effective in activating CD69(+) lymphocytes. It also proved efficient in enhancing natural killing in vitro, decreasing the growth of tumors in vivo, and activating the CD69(+) tumor infiltrating lymphocytes examined ex vivo. This compound is thus a candidate for carbohydrate-based immunomodulators with promising antitumor potential.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Acetylglucosamine / analogs & derivatives*
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Acetylglucosamine / chemical synthesis
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Acetylglucosamine / chemistry
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Acetylglucosamine / pharmacology
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Animals
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Antigens, CD / metabolism*
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Antigens, Differentiation, T-Lymphocyte / metabolism*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Carbohydrate Sequence
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Cell Line, Tumor
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Dimerization
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Drug Screening Assays, Antitumor
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Female
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Humans
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Immunologic Factors / chemical synthesis
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Immunologic Factors / chemistry
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Immunologic Factors / pharmacology*
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In Vitro Techniques
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Killer Cells, Natural / drug effects*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lectins, C-Type / metabolism*
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Ligands
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Lymphocyte Activation
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Melanoma, Experimental / immunology
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Melanoma, Experimental / pathology
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Molecular Mimicry
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Molecular Sequence Data
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NK Cell Lectin-Like Receptor Subfamily B / metabolism
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Oligosaccharides / chemical synthesis
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Oligosaccharides / chemistry
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Oligosaccharides / pharmacology*
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Rats
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Recombinant Proteins / chemistry
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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Antineoplastic Agents
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CD69 antigen
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Immunologic Factors
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Lectins, C-Type
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Ligands
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NK Cell Lectin-Like Receptor Subfamily B
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Oligosaccharides
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Recombinant Proteins
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Acetylglucosamine