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J Med Chem ; 53(10): 4050-65, 2010 May 27.
Article in English | MEDLINE | ID: mdl-20433142

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.


Subject(s)
Acetylglucosamine/analogs & derivatives , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Antineoplastic Agents/pharmacology , Immunologic Factors/pharmacology , Killer Cells, Natural/drug effects , Lectins, C-Type/metabolism , Oligosaccharides/pharmacology , Acetylglucosamine/chemical synthesis , Acetylglucosamine/chemistry , Acetylglucosamine/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carbohydrate Sequence , Cell Line, Tumor , Dimerization , Drug Screening Assays, Antitumor , Female , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/chemistry , In Vitro Techniques , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Ligands , Lymphocyte Activation , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Mimicry , Molecular Sequence Data , NK Cell Lectin-Like Receptor Subfamily B/metabolism , Oligosaccharides/chemical synthesis , Oligosaccharides/chemistry , Rats , Recombinant Proteins/chemistry
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