Synthetic N-Acetyl-d-glucosamine Based Fully Branched Tetrasaccharide, a Mimetic of the Endogenous Ligand for CD69, Activates CD69+ Killer Lymphocytes

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• 作者：Anna Kovalov ; Miroslav Ledvina ; David aman ; Daniel Zyka ; Monika Kubkov ; Luk dek ; Vladimr Sklen ; Petr Pompach ; Daniel Kavan ; Jan Bl ; Ondej Vank ; Zuzana Kubnkov ; Martina Libigerov ; Ljubina Ivanov ; Mria
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 27, 2010
• 年：2010
• 卷：53
• 期：10
• 页码：4050-4065
• 全文大小：1301K
• 年卷期：v.53,no.10(May 27, 2010)
• ISSN：1520-4804

文摘

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 GlcNAcβ1−3(GlcNAcβ1−4)(GlcNAcβ1−6)GlcNAc (compound 52) and its α-benzyl derivative 49 as the best ligand for CD69 with IC₅₀ as high as 10⁻⁹ M. This compound thus approaches the affinity of the classical high-affinity neoglycoprotein ligand GlcNAc₂₃BSA. 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.