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SyntheticN-Acetyl-<scp>d</scp>-glucosamine Based Fully Branched Tetrasaccharide, a Mimetic of the Endogenous Ligand for CD69, Activates CD69+Killer Lymphocytes upon Dimerization via a Hydrophilic Flexible Linker
- Source :
- Journal of Medicinal Chemistry. 53:4050-4065
- Publication Year :
- 2010
- Publisher :
- American Chemical Society (ACS), 2010.
-
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.
- Subjects :
- Antigens, Differentiation, T-Lymphocyte
Models, Molecular
Stereochemistry
Molecular Sequence Data
Melanoma, Experimental
Oligosaccharides
Antineoplastic Agents
In Vitro Techniques
Ligands
Lymphocyte Activation
Acetylglucosamine
Mice
Antigens, CD
In vivo
Cell Line, Tumor
Drug Discovery
Animals
Humans
Immunologic Factors
Tetrasaccharide
Lectins, C-Type
Receptor
chemistry.chemical_classification
Chemistry
Molecular Mimicry
Oligosaccharide
Ligand (biochemistry)
Recombinant Proteins
In vitro
Rats
Killer Cells, Natural
Mice, Inbred C57BL
Carbohydrate Sequence
Molecular Medicine
Female
Drug Screening Assays, Antitumor
Dimerization
Linker
Ex vivo
NK Cell Lectin-Like Receptor Subfamily B
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 53
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....941f93a6e9d308d5066e1275bd9aa273