calixarenes and Neoplasms

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for β-galactosides. The galectin-glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins' action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer.

Topics: Calixarenes; Clinical Trials as Topic; Galactose; Galectins; Humans; Mannans; Neoplasms; Pectins; Peptides; Polysaccharides; Thiogalactosides

Research on the therapeutic applications of calixarene derivatives is an emerging area of interest. The anticancer activity of various functionalized calixarenes has been reported by several research groups. Due to their superior geometric shape, calixarenes can accommodate drug molecules by forming inclusion complexes. Controlled release of anticancer drugs by calixarenes might help in targeted chemotherapy. This review summarizes the anticancer potential of the calixarenes and their drug loading properties. The potential use of calixarenes in chemoradiotherapy is also highlighted in brief.

Topics: Animals; Antineoplastic Agents; Calixarenes; Chemoradiotherapy; Delayed-Action Preparations; Humans; Neoplasms

Platinum-based anticancer drugs have been becoming one of the most effective drugs for clinical treatment of malignant tumors for its unique mechanism of action and broad range of anticancer spectrum. But, there are still several problems such as side effects, drug resistance/cross resistance and no-specific targeting, becoming obstacles to restrict its expanding of clinical application. In recent years, supramolecular chemistry drug delivery systems have been gradually concerned for their favorable safety and low toxicity. Supramolecular macrocycles-platinum complexes increased the water solubility, stability and safety of traditional platinum drugs, and have become hot focus of developing novel platinum-based anticancer drugs because of its potential targeting of tumor tissues/organs. This article concentrates in the research progress of the new drug delivery system between platinum-based anticancer drugs with three generations of macrocycles: crown ether, cyclodextrin, cucurbituril and calixarene.

Topics: Antineoplastic Agents; Calixarenes; Crown Compounds; Cyclodextrins; Drug Delivery Systems; Humans; Macrocyclic Compounds; Neoplasms; Platinum Compounds

Galectins belong to a family of carbohydrate-binding proteins with an affinity for β-galactosides. Galectin-1 is differentially expressed by various normal and pathologic tissues and displays a wide range of biological activities. In oncology, galectin-1 plays a pivotal role in tumor growth and in the multistep process of invasion, angiogenesis, and metastasis. Evidence indicates that galectin-1 exerts a variety of functions at different steps of tumor progression. Moreover, it has been demonstrated that galectin-1 cellular localization and galectin-1 binding partners depend on tumor localization and stage. Recently, galectin-1 overexpression has been extensively documented in several tumor types and/or in the stroma of cancer cells. Its expression is thought to reflect tumor aggressiveness in several tumor types. Galectin-1 has been identified as a promising drug target using synthetic and natural inhibitors. Preclinical data suggest that galectin-1 inhibition may lead to direct antiproliferative effects in cancer cells as well as antiangiogenic effects in tumors. We provide an up-to-date overview of available data on the role of galectin-1 in different molecular and biochemical pathways involved in human malignancies. One of the major challenges faced in targeting galectin-1 is the translation of current knowledge into the design and development of effective galectin-1 inhibitors in cancer therapy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Calixarenes; Galectin 1; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Peptides; Signal Transduction; Thiogalactosides; Up-Regulation

Extensive efforts have been devoted to the construction of functional supramolecular nanosystems for applications in catalysis, energy conversion, sensing and biomedicine. The applications of supramolecular nanosystems such as liposomes, micelles, inorganic nanoparticles, carbon materials for cancer diagnostics and therapeutics have been reviewed by other groups. Here, we will focus on the recent momentous advances in the implementation of typical supramolecular hosts (i.e., cyclodextrins, calixarenes, cucurbiturils and metallo-hosts) and their nanosystems in cancer diagnostics and therapeutics. We discuss the evolutive process of supramolecular nanosystems from the structural control and characterization to their diagnostic and therapeutic function exploitation and even the future potentials for clinical translation.

Topics: Animals; Calixarenes; Cyclodextrins; Humans; Macrocyclic Compounds; Nanostructures; Nanotechnology; Neoplasms

An L-arginine-functionalized pillar[5]arene-based supramolecular photosensitizer LAP5⊃NBSPD was constructed by host-guest interactions, which could self-assemble into nano-micelles to achieve effective delivery and selective release of LAP5 and NBS in cancer cells.

Topics: Arginine; Calixarenes; Humans; Micelles; Neoplasms; Photosensitizing Agents; Quaternary Ammonium Compounds

Tumor selectivity is yet a challenge in chemotherapy-based cancer treatment. A series of calixarenes derivatized at the lower rim with 3-phenyl-1H-pyrazole units with variable upper-rim substituent and conformations of macrocyclic core, alkyl chain length between heterocycle and core, as well as phenolic monomer (5-(4-tert-butylphenyloxy)methoxy-3-phenyl-1H-pyrazole) have been synthesized and characterized in a range of therapeutically relevant cellular models (M-HeLa, MCF7, A-549, PC3, Chang liver, and Wi38) from different target organs/systems. Specific cytotoxicity for M-HeLa cells has been observed in tert-butylcalix[4]arene pyrazoles in 1,3-alternate (compound 7b) and partial cone (compound 7c) conformations with low mutagenicity and haemotoxicity and in vivo toxicity in mice. Compounds 7b,c have induced mitochondrial pathway of apoptosis of M-HeLa cells through caspase-9 activation preceded by the cell cycle arrest at G0/G1 phase. A concomitant overexpression of DNA damage markers in pyrazole-treated M-HeLa cells suggests that calixarene pyrazoles target DNA, which was supported by the presence of interactions between calixarenes and ctDNA at the air-water interface.

Topics: Animals; Calixarenes; HeLa Cells; Humans; Mice; Neoplasms; Porifera; Pyrazoles

Despite the tremendous breakthrough of immunotherapy, the low response rate and resistance of immune checkpoint inhibitors (ICIs) toward solid tumors occur frequently. A highly hypoxic tumor microenvironment (TME) provides tumor cells with high concentrations of HIF-1α and polyamines to evade immune cell destruction. Reprogramming of an immunogenic TME has exhibited a brilliant future to boost immunotherapeutic performances. Herein, a supramolecular nanomedicine (

Topics: Animals; Calixarenes; Cell Line, Tumor; Gastropoda; Immunotherapy; Neoplasms; Tumor Microenvironment

Nitric oxide (NO)-mediated gas therapy (GT) and alkyl radical (R•) therapy (ART) are emerging cancer therapy modes, and multi-mode therapy has been recognized as an attractive strategy for enhancing anti-cancer efficacy. In this work, a thermal-responsive R• initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIBI)-loaded glycol-targeting NO nanogenerator was constructed by first the covalent conjugation of thermal-responsive NO donor of S-nitrosothiols (RSNO) on the surface of mesoporous silica-coated gold nanorods (AuNRs@MSN), then the coating of a supramolecular complex of amino pillar[5]arene (NP5) and galactose derivative (G), and finally the loading of AIBI. The glycol-targeting NO nanogenerator demonstrated specific targeting ability to HepG2 cells owing to the recognition between galactose residues and asialoglycoprotein receptors (ASGPR). Specially, upon 808 nm near-infrared (NIR) irradiation, the AIBI-loaded NO nanogenerator generated hyperthermia to achieve photothermal therapy (PTT), and further GT and ART resulted from the thermal responsiveness of RSNO and AIBI, respectively. In vitro experiments revealed that the AIBI-loaded glyco-targeting NO nanogenerator had good biocompatibility and exhibited effective inhibition to the proliferation of HepG2 cells. This work provides a novel way to supramolecular hybrid drug delivery systems for triple-mode targeting therapy of PTT/GT/ART.

Topics: Calixarenes; Cell Line, Tumor; Gold; Hyperthermia, Induced; Nanotubes; Neoplasms; Nitric Oxide; Phototherapy; Quaternary Ammonium Compounds

Combination therapy based on molecular drugs and therapeutic genes provides an effective strategy for malignant tumor treatment. However, effective gene and drug combinations for cancer treatment are limited by the widespread antagonism between therapeutic genes and molecular drugs. Herein, a calixarene-embedded nanoparticle (CENP) is developed to co-deliver molecular drugs and therapeutic genes without compromising their biological functions, thereby achieving interference-free gene-drug combination cancer therapy. CENP is composed of a cationic polyplex core and an acid-responsive polymer shell, allowing CENP loading and delivering therapeutic genes with improved circulation stability and enhanced tumor accumulation. Moreover, the introduction of carboxylated azocalix[4]arene, which is a hypoxia-responsive calixarene derivatives, in the polyplex core endows CENP with the capability to load molecular drugs through the host-guest complexation as well as inhibit the interference between the drugs and genes by encapsulating the drugs into its cavity. By loading doxorubicin and a plasmid DNA-based CRISPR interference system that targets miR-21, CENP exhibits the significantly enhanced anti-tumor effects in mice. Considering the wide variety of calixarene derivatives, CENP can be adapted to deliver almost any combination of drugs and genes, providing the potential as a universal platform for the development of interference-free gene-drug combination cancer therapy.

Topics: Animals; Calixarenes; Cell Line, Tumor; Combined Modality Therapy; Doxorubicin; Mice; Nanoparticles; Neoplasms

An orthogonal strategy was utilized for synthesizing a novel water-soluble pillar[5]arene (

Topics: Animals; Benzylidene Compounds; Calixarenes; Camptothecin; Cell Line, Tumor; Drug Carriers; Drug Design; Drug Liberation; Female; Fluorescent Dyes; Fluorometry; Humans; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Prodrugs; Quaternary Ammonium Compounds; Solubility; Water

Host-guest complexation between calix[5]arene and aggregation-induced emission luminogen (AIEgen) can significantly turn off both the energy dissipation pathways of intersystem crossing and thermal deactivation, enabling the absorbed excitation energy to mostly focus on fluorescence emission. The co-assembly of calix[5]arene amphiphiles and AIEgens affords highly emissive supramolecular AIE nanodots thanks to their interaction severely restricting the intramolecular motion of AIEgens, which also show negligible generation of cytotoxic reactive oxygen species. In vivo studies with a peritoneal carcinomatosis-bearing mouse model indicate that such supramolecular AIE dots have rather low in vivo side toxicity and can serve as a superior fluorescent bioprobe for ultrasensitive fluorescence image-guided cancer surgery.

Topics: Animals; Calixarenes; Carcinoma; Fluorescent Dyes; Mice; Nanostructures; Neoplasms; Optical Imaging; Surgery, Computer-Assisted

Functional antitumor vaccine constructs are the basis for active tumor immunotherapy, which is useful in the treatment of many types of cancers. MUC1 is one key glycoprotein for targeting and designing new strategies for multicomponent vaccines. Two self-adjuvant tetravalent vaccine candidates were prepared by clustering four or eight PDTRP MUC1 core epitope sequences on calixarene scaffolds. In this work, the different activities of two molecules with calix[4]arene and calix[8]arene skeleton are rationalized. Quantum mechanics, docking, and molecular dynamics structural optimization were first carried out followed by metadynamics to calculate the energy profiles. Further insights were obtained by complementarity studies of molecular fields. The molecular modeling results are in strong agreement with the experimental

Topics: Calixarenes; Humans; Molecular Dynamics Simulation; Mucin-1; Neoplasms; Static Electricity; Vaccines

A charge-reversal amphiphilic pillar[5]arene, P5NH-DCA, bearing 10 charge-reversal headgroups is reported. It targets the cell membrane of cancer cells and selectively destroys the cancer cells by disrupting the membrane. In the acidic tumor microenvironment, the headgroup charge of P5NH-DCA reversed from negative to positive owing to hydrolysis of the acid-labile amide group. The hydrolyzed product bearing multiple positive charges can bind to the cell membrane and then disrupt the membrane of cancer cells with high efficiency. However, under the neutral microenvironment of healthy cells, the negatively charged P5NH-DCA remains stable and the cytotoxicity is considerably reduced. The strategy killing the cancer cells by membrane disruption may represent a new route of cancer chemotherapy.

Topics: Animals; Antineoplastic Agents; Calixarenes; Cell Line, Tumor; Cell Membrane; Cell Survival; Humans; Hydrogen-Ion Concentration; Mice; Mice, Nude; Microscopy, Confocal; Neoplasms

The synthesis of conjugates of flutamide with resorcinarene-PAMAM-dendrimers as well as alkyl and ethyl phenyl chains in the lower part of the macrocycle as a nucleus and diethylenetriamines in the dendritic branches gives the opportunity to obtain conjugates in one step of synthesis with 16 and 64 flutamide moieties in the structure.. The in vitro anticancer studies showed that the conjugates of flutamide are more active than the free flutamide and the flutamide derivatives, thus diminishing the amount of flutamide used. The resorcinarenedendrimer- flutamide conjugates with a high drug payload improve the activity of the drug.. This is important in delivering a sufficient amount of flutamide and suggests that the dendrimer facilitates more of the drug being introduced into cells. It was also observed that the new conjugates are less toxic than the anti-androgens.

Topics: Antineoplastic Agents; Apoptosis; Calixarenes; Cell Line, Tumor; Cell Proliferation; Dendrimers; Drug Carriers; Flutamide; Humans; Models, Molecular; Neoplasms; Phenylalanine

A fluorescent 2,7-dimethoxy-substituted calix[4]carbazole (1) is facilely synthesized. The spectral behaviors of both the guest-induced switchable conformation of 1 and its abilities serving as the stabilizer and molecular carrier of curcumin are investigated. UV-vis, fluorescence and NMR spectral results show that upon binding to curcumin, the 1,3-alternate conformation of 1 is converted to be the cone one. The relative high association constant (6.4×10

Topics: Antineoplastic Agents; Calixarenes; Carbazoles; Cell Proliferation; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Stability; Fluorescent Dyes; Humans; Neoplasms; Tumor Cells, Cultured

A new bimodal fluorescent cationic calix[4]arene (L

Topics: Calixarenes; Humans; Luminescent Proteins; Neoplasms; Phenols; Plasmids; Red Fluorescent Protein; Transfection; Water

A modular p-phosphonated calix[4]arene vesicle (PCV) loaded with paclitaxel (PTX) and conjugated with folic acid as a cancer targeting ligand has been prepared using a thin film-sonication method. It has a pH-responsive capacity to trigger the release of the encapsulated PTX payload under mildly acidic conditions. PTX-loaded PCV conjugated with alkyne-modified PEG-folic acid ligands prepared via click ligation (fP-PCVPTX) has enhanced potency against folate receptor (FR)-positive SKOV-3 ovarian tumour cells over FR-negative A549 lung tumour cells. Moreover, fP-PCVPTX is also four times more potent than the non-targeting PCVPTX platform towards SKOV-3 cells. Overall, as a delivery platform the PCVs have the potential to enhance efficacy of anticancer drugs by targeting a chemotherapeutic payload specifically to tumours and triggering the release of the encapsulated drug in the vicinity of cancer cells.

Topics: A549 Cells; Antineoplastic Agents; Calixarenes; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Folic Acid; Humans; Hydrogen-Ion Concentration; Nanostructures; Neoplasms; Paclitaxel

A novel fluorescently labeled folate conjugate in which four folic acid units are covalently conjugated with a 7-nitro-benzofurazan fluorophore by means of a calix[4]arene platform was synthesized by using a Cu-catalyzed azide-alkyne cycloaddition reaction (click chemistry). The synthesized construct (FA-C4-NBD) was characterized by mass spectrometry, NMR and fluorescence spectroscopy. Confocal fluorescence microscopy experiments were carried out to evaluate the cell penetration ability of FA-C4-NBD on normal and cancer cells. The cellular uptake of FA-C4-NBD proceeds via folate receptor-mediated endocytosis. FA-C4-NBD is internalized into HeLa cancer cells which express high levels of folate receptors, whereas the uptake into fibroblast NIH3T3 cells which have very low expression levels of folate receptors is negligible. The involvement of the folate receptor was corroborated by competition tests with free folic acid. Co-localization analysis with different organelle markers indicated that FA-C4-NBD is not eliminated by recycling towards the outside of the cell, but accumulates intracellularly in the endo-lysosomal system.

Topics: Animals; Calixarenes; Cell Line, Tumor; Drug Design; Fluorescent Dyes; Folic Acid; HeLa Cells; Humans; Mice; Molecular Structure; Neoplasms; NIH 3T3 Cells; Phenols

Galectin-1 (Gal1), a carbohydrate-binding protein is implicated in cancer cell proliferation, invasion and tumour angiogenesis. Several Gal1-targeting compounds have recently emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic β-sheet conformation. Our study contributes to the current understanding of the role of Gal1 in cancer progression, providing mechanistic insights into the anti-tumoural activity of a novel small molecule Gal1-inhibitor.. We evaluated in vitro OTX008 effects in a panel of human cancer cell lines. For in vivo studies, an ovarian xenograft model was employed to analyse the antitumour activity. Finally, combination studies were performed to analyse potential synergistic effects of OTX008.. In cultured cancer cells, OTX008 inhibited proliferation and invasion at micromolar concentrations. Antiproliferative effects correlated with Gal1 expression across a large panel of cell lines. Furthermore, cell lines expressing epithelial differentiation markers were more sensitive than mesenchymal cells to OTX008. In SQ20B and A2780-1A9 cells, OTX008 inhibited Gal1 expression and ERK1/2 and AKT-dependent survival pathways, and induced G2/M cell cycle arrest through CDK1. OTX008 enhanced the antiproliferative effects of Semaphorin-3A (Sema3A) in SQ20B cells and reversed invasion induced by exogenous Gal1. In vivo, OTX008 inhibited growth of A2780-1A9 xenografts. OTX008 treatment was associated with downregulation of Gal1 and Ki67 in treated tumours, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with several cytotoxic and targeted therapies, principally when OTX008 was administered first.. This study provides insights into the role of Gal1 in cancer progression as well as OTX008 mechanism of action, and supports its further development as an anticancer agent.

Topics: Animals; Apoptosis; Calixarenes; Cell Growth Processes; Cell Line, Tumor; Down-Regulation; Drug Screening Assays, Antitumor; Female; Galectin 1; HT29 Cells; Humans; MCF-7 Cells; Mice; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Xenograft Model Antitumor Assays

MUC1 protein overexpressed in human epithelial carcinoma is a target in development of novel anticancer vaccines. Multiple units of immunodominant B-cell epitope PDTRP MUC1 core sequence were conjugated to calix[4,8]arene platforms containing TLR2 ligand, to produce two novel anticancer self-adjuvant vaccine candidates. The immunogenicity of the synthetic constructs was investigated by immunization of mice in vivo. ELISA assay evidenced that the vaccine candidates stimulate anti MUC1 IgG antibody production (major for the octavalent construct) and no additive effect but a multivalency effect was observed when compared to an analogous monovalent. Octa- and tetravalent constructs lacking in PDTRP peptide moieties did not show anti MUC1 IgG antibody production in mice. The antibodies induced by the synthesized constructs are able to recognize the MUC1 structures present on MCF7 tumor cells. The results display that calixarenes are convenient platforms for building multicomponent self-adjuvant vaccine constructs promising as immunotherapeutic anticancer agents.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Calixarenes; Cancer Vaccines; Cell Line, Tumor; Female; Humans; Immunodominant Epitopes; Immunoglobulin G; Mice; Mice, Inbred BALB C; Mucin-1; Neoplasms; Oligopeptides; Toll-Like Receptor 2

Mononuclear 5-(4-pyridyl)-10,15,20-triphenylporphyrin and 5-(3-pyridyl)-10,15,20-triphenylporphyrin as well as tetranuclear 5,10,15,20-tetra(4-pyridyl)porphyrin (tetra-4-pp) and 5,10,15,20-tetra(3-pyridyl)porphyrin) (tetra-3-pp) arene ruthenium(II) derivatives (arene is C(6)H(5)Me or p-Pr(i)C(6)H(4)Me) were prepared and evaluated as potential dual photosensitizers and chemotherapeutics in human Me300 melanoma cells. In the absence of light, all tetranuclear complexes were cytotoxic (IC(50) < or = 20 microM), while the mononuclear derivatives were not (IC(50) > or = 100 microM). Kinetic studies of tritiated thymidine and tritiated leucine incorporations in cells exposed to a low concentration (5 microM) of tetranuclear p-cymene derivatives demonstrated a rapid inhibition of DNA synthesis, while protein synthesis was inhibited only later, suggesting arene ruthenium-DNA interactions as the initial cytotoxic process. All complexes exhibited phototoxicities toward melanoma cells when exposed to laser light of 652 nm. At low concentration (5 microM), LD(50) of the mononuclear derivatives was between 5 and 10 J/cm(2), while for the tetranuclear derivatives LD(50) was approximately 2.5 J/cm(2) for the [Ru(4)(eta(6)-arene)(4)(tetra-4-pp)Cl(8)] complexes and less than 0.5 J/cm(2) for the [Ru(4)(eta(6)-arene)(4)(tetra-3-pp)Cl(8)] complexes. Examination of cells under a fluorescence microscope revealed the [Ru(4)(eta(6)-arene)(4)(tetra-4-pp)Cl(8)] complexes as cytoplasmic aggregates, whereas the [Ru(4)(eta(6)-arene)(4)(tetra-3-pp)Cl(8)] complexes were homogenously dispersed in the cytoplasm. Thus, these complexes present a dual synergistic effect with good properties of both the arene ruthenium chemotherapeutics and the porphyrin photosensitizer.

Topics: Antineoplastic Agents; Calixarenes; Cell Proliferation; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Screening Assays, Antitumor; Humans; Light; Metalloporphyrins; Molecular Structure; Neoplasms; Photosensitizing Agents; Ruthenium; Time Factors; Tumor Cells, Cultured

A novel anticancer vaccine candidate built on a nonpeptidic scaffold has been synthesized. Four S-Tn tumor-associated glycomimetic antigens have been clustered onto a calix[4]arene scaffold bearing an immunoadjuvant moiety (P3CS). The immunogenicity of the synthetic construct has been investigated by immunization of mice in vivo. ELISA assay has evidenced that the tetravalent construct stimulates a higher production of anti-Tn antigen IgG antibodies when compared to an analogous monovalent compound. This result is ascribable to an antigen cluster effect and makes the reported vaccine candidate a good mimic of the natural motifs present on the mucine surface.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Calixarenes; Cancer Vaccines; Chromatography, Thin Layer; Dipeptides; Enzyme-Linked Immunosorbent Assay; Female; Immunoglobulin G; Immunotherapy; Indicators and Reagents; Lipoproteins; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Molecular Mimicry; Neoplasms; Phenols; Spectrometry, Mass, Electrospray Ionization

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.

Topics: Acetylglucosamine; Antineoplastic Agents; Calixarenes; Glycoconjugates; Humans; Killer Cells, Natural; Kinetics; Leukocytes, Mononuclear; Lymphocyte Activation; Models, Molecular; Molecular Conformation; Neoplasms; T-Lymphocytes