N-acetyl-D-glucosamine substituted calix[4]arenes as stimulators of NK cell-mediated antitumor immune response.
A series of calixarenes substituted with 2-acetamido-2-deoxy-beta-D-glucopyranose linked by a thiourea spacer was prepared and tested for binding activity to heterogeneously expressed activation receptors of the rat natural killer cells NKR-P1, and the receptor CD69 (human NK cells, macrophages). In the case of NKR-P1, the binding affinity of beta-D-GlcNAc-substituted calixarenes carrying two or four sugar units was in a good agreement with the inhibitory potencies of the linear chitooligomers (chitobiose to chitotetraose) reported previously. The influence of GlcNAc substitution of the calixarene skeleton on binding affinity for CD69 receptor was more profound and the 5,11,17,23-tetrakis[N-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-thioureido]-25,26,27,28-tetrapropoxycalix[4]arene (cone) (1) proved to be the best CD69 ligand identified to date. Lower GlcNAc substitution led to dramatic decrease of the binding activity (by about 1.5 order of magnitude per one GlcNAc unit). The immunostimulating activity results with the newly synthesized GlcNAc tetramers on calixarene scaffolds exhibited stimulation of natural cytotoxicity of human PBMC in concentrations 10(-4) and 10(-8)M. These calix-sugar compounds were superior to the previously tested PAMAM-GlcNAc(8)5.
Krenek
Karel
K
Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídenská 1083, 142 20 Praha 4, Czech Republic.
Kuldová
Markéta
M
Hulíková
Katarína
K
Stibor
Ivan
I
Lhoták
Pavel
P
Dudic
Miroslav
M
Budka
Jan
J
Pelantová
Helena
H
Bezouska
Karel
K
Fiserová
Anna
A
Kren
Vladimír
V
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D047250:Calixarenes / Q000737:chemistry; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000627:therapeutic use; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000970:Antineoplastic Agents; D006001:Glycoconjugates; D047250:Calixarenes; D000117:Acetylglucosamine