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1.
Sci Rep ; 8(1): 11075, 2018 07 23.
Article in English | MEDLINE | ID: mdl-30038406

ABSTRACT

meso-(p-acetamidophenyl)-calix[4]pyrrole 3 was found to exhibit remarkable cytotoxicity towards A549 cancer cells. A comparative study including the isomer of 3 meso-(m-acetamidophenyl)-calix[4]pyrrole 5, as well as molecules containing 'fragments' of these structures, demonstrated that both the calix[4]pyrrole and the acetamidophenyl units are essential for high cytotoxicity. Although calix[4]pyrroles and other anion-complexing ionophores have recently been reported to induce apoptosis by perturbing cellular chloride concentrations, in our study an alternative mechanism has emerged, as proven by the isolation of covalent DNA adducts revealed by the 32P postlabelling technique. Preliminary pharmacokinetic studies indicate that 3 is able to cross the Blood-Brain-Barrier, therefore being a potential drug that could kill primary and brain metastatic cancer cells simultaneously.


Subject(s)
Antineoplastic Agents/pharmacology , Calixarenes/pharmacology , DNA Adducts/metabolism , Mutagens/toxicity , Porphyrins/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Calixarenes/chemistry , Calixarenes/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Porphyrins/chemistry , Porphyrins/pharmacokinetics , Tissue Distribution/drug effects
2.
Life Sci ; 168: 65-76, 2017 Jan 01.
Article in English | MEDLINE | ID: mdl-27863957

ABSTRACT

AIMS: p-tertbutylcalix[4]arene loaded nanoemulsion has been designed, characterized and evaluated for skin decontamination of radionuclides of interest in nuclear and radiological emergencies. Further, nanoemulsion was evaluated for Ex-vivo complexation, skin permeation, interaction and cytodermal toxicity. MATERIALS AND METHODS: Ex-vivo skin complexation studies were conducted using High-resolution sector field inductively coupled plasma mass spectroscopy (HR-SF-ICPMS). Skin studies at dermal and cyto-dermal level have been carried out using techniques such as florescence microscopy, Differential scanning calorimetry (DSC), Flow cytometry, Confocal microscopy, Prestoblue and Comet assay. KEY FINDINGS: HR-SF-ICPMS study confirmed >95% complexation of surrogate nuclides of thallium and Iodine applied on excised rat skin mounted over Franz diffusion cell. Temporal analysis of aliquots obtained from Franz diffusion cell using UV-Vis absorption spectroscopy indicated that only 3.37% of formulation permeates through the skin. Skin penetration study of rhodamine 123 nanoemulsion carried out using florescence microscopy confirmed that formulation remains localised in epidermis of rat skin. DSC data confirmed skin compatibility of nanoemulsion, as no lipid extraction was observed from skin. In-vitro cell viability and cellular uptake assays performed on human skin fibroblasts prove no cellular uptake and cytotoxic effects. Comet assay, cell cycle arrest, and apoptosis-inducing mechanistic studies prove that prepared nanoemulsion is safe at cellular level. SIGNIFICANCE: Taken together, data indicate that p-tertbutylcalix[4]arene nanoemulsion is both effective and safe formulation to use on skin for radio-decontamination.


Subject(s)
Calixarenes/pharmacology , Calixarenes/pharmacokinetics , Decontamination , Skin Absorption , Skin/drug effects , Administration, Cutaneous , Animals , Calixarenes/administration & dosage , Calixarenes/toxicity , Cell Line , Decontamination/methods , Emulsions/administration & dosage , Emulsions/pharmacokinetics , Emulsions/toxicity , Female , Fibroblasts/drug effects , Humans , Iodine Isotopes/isolation & purification , Isotopes/isolation & purification , Male , Rats , Skin/cytology , Skin/metabolism , Thallium/isolation & purification
3.
Chem Commun (Camb) ; 51(45): 9374-6, 2015 Jun 07.
Article in English | MEDLINE | ID: mdl-25958962

ABSTRACT

The passage of Lucifer Yellow across the Caco-2 intestinal model membrane has been studied for the para-sulphonato-calix[n]arenes, the results show that para-sulphonato-calix[4]arene and para-sulphonato-calix[8]arene activate membrane passage when used simultaneously with a transport probe, Lucifer Yellow, whereas para-sulphonato-calix[6]arene has no effect.


Subject(s)
Calixarenes/chemistry , Calixarenes/pharmacology , Intestinal Mucosa/drug effects , Sulfonic Acids/chemistry , Biological Transport , Caco-2 Cells , Calixarenes/pharmacokinetics , Humans , Models, Biological , Molecular Structure , Sulfonic Acids/pharmacology
4.
Org Biomol Chem ; 13(11): 3298-307, 2015 Mar 21.
Article in English | MEDLINE | ID: mdl-25645306

ABSTRACT

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.


Subject(s)
Calixarenes/pharmacokinetics , Drug Design , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacokinetics , Folic Acid/pharmacokinetics , Neoplasms/pathology , Phenols/pharmacokinetics , Animals , Calixarenes/chemistry , Cell Line, Tumor , Fluorescent Dyes/chemistry , Folic Acid/chemistry , HeLa Cells , Humans , Mice , Molecular Structure , NIH 3T3 Cells , Phenols/chemistry
5.
Chem Commun (Camb) ; 50(56): 7440-3, 2014 Jul 18.
Article in English | MEDLINE | ID: mdl-24875493

ABSTRACT

Stable core-shell nanospheres self-assemble in water from heterodimers combining a hydrophobic calix[4]arene moiety and a hydrophilic ß-cyclodextrin head; their potential to encapsulate and provide sustained release of the anticancer drug docetaxel and undergo surface post-modification with glycoligands targeting the macrophage mannose receptor is discussed.


Subject(s)
Calixarenes/chemistry , Cyclodextrins/chemistry , Drug Carriers/chemistry , Drug Delivery Systems , Nanospheres/chemistry , Calixarenes/pharmacokinetics , Cyclodextrins/pharmacokinetics , Drug Carriers/pharmacokinetics , Drug Delivery Systems/trends , Humans , Hydrophobic and Hydrophilic Interactions , Ligands , Nanospheres/metabolism
6.
Cancer Chemother Pharmacol ; 72(4): 879-87, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23978989

ABSTRACT

PURPOSE: OTX008 is a galectin-1-targeting compound, currently undergoing a phase I clinical trial. This study aimed at investigating OTX008 pharmacokinetics (PK) and antineoplastic activity. METHODS: Pharmacokinetics and activity of OTX008 were analyzed in the human ovarian carcinoma A2780-1A9 and glioblastoma U87MG xenografted in nude mice. In vitro, OTX008 was tested on tumor and endothelial cells. RESULTS: After 5 mg/kg i.v., OTX008 achieved plasma Cmax of 14.39 µg/mL, distributed rapidly, and was eliminated with a half-life of 31.4 h. Tumor OTX008 Cmax (1.65 µg/g, 1.76 µM), achieved at 0.5 h, remained high at 24 h (0.516 µg/g, 0.55 µM) with AUC of 15.76 µg/g*h. OTX008 accumulated in the tumor after repeated administrations achieving a concentration of 2.3 µM, compatible with the concentrations active in vitro. OTX008 (5 mg/kg i.v., every other day for 3 weeks) inhibited the in vivo growth of A2780-1A9, whereas U87MG was not sensitive. In vitro, OTX008 affected endothelial cell proliferation, motility, invasiveness, and cord formation. Tumor cell proliferation was also inhibited, with differences in sensitivity among cell lines (IC50 from 1 to 190 µM). OTX008 potentiated the activity of the tyrosine kinase inhibitor sunitinib on A2780-1A9 in vivo and in vitro, where the combination showed synergistic (endothelial cells) and additive (A2780-1A9) antiproliferative activity, indicating that the combination targets both the tumor and vascular compartments. CONCLUSIONS: OTX008-alone or in combination with sunitinib-has a favorable PK and antineoplastic activity on selected tumor models through the effects on both endothelial and tumor cells.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Calixarenes/pharmacology , Galectin 1/metabolism , Glioblastoma/drug therapy , Ovarian Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Area Under Curve , Calixarenes/administration & dosage , Calixarenes/pharmacokinetics , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Synergism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Female , Glioblastoma/pathology , Half-Life , Humans , Indoles/administration & dosage , Inhibitory Concentration 50 , Mice , Mice, Nude , Molecular Targeted Therapy , Ovarian Neoplasms/pathology , Pyrroles/administration & dosage , Sunitinib , Tissue Distribution , Xenograft Model Antitumor Assays
7.
Nat Commun ; 4: 1721, 2013.
Article in English | MEDLINE | ID: mdl-23591888

ABSTRACT

Cell-penetrating peptides are widely used as molecular transporters for the internalization inside cells of various cargo, including proteins and nucleic acids. A special role is played by arginine-rich peptides and oligoarginines covalently linked or simply mixed with the cargo. Here we report cell-penetrating agents in which arginine units are clustered on a macrocyclic scaffold. Instead of using long peptides, four single arginine units were covalently attached to either the upper or lower rim of a calix[4]arene, kept in the cone conformation building a 'parallel' cyclic array. These new macrocyclic carriers show high efficiency in DNA delivery and transfection in a variety of cell lines.


Subject(s)
Arginine/metabolism , Calixarenes/metabolism , DNA/administration & dosage , Macrocyclic Compounds/metabolism , Phenols/metabolism , Animals , Calixarenes/pharmacokinetics , Humans , Macrocyclic Compounds/pharmacokinetics , Phenols/pharmacokinetics , Transfection
8.
Cytometry A ; 79(2): 126-36, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21265006

ABSTRACT

The uptake of a fluorescently labeled cationic calix[4] (NBDCalAm) in live, nonfixed cells has been investigated. The compound is taken into the cells rapidly and shows distinct endosomal distribution after 2 hours. This distribution pattern shows colocalization with lysosomal staining. The uptake is not altered by inhibition of clathrin or caveolae dependent pathways nor by depletion of the cellular ATP-pool. Immediately after uptake the probe is localized in the Golgi and brefeldin A treatment prevents transport to lysosomes. Pulse chase experiments with bafilomycin A1, monensin, and sodium azide showed that accumulation and retention of the probe in lysosomes is primarily driven by the activity of vacuolar ATPases. The NBD labeled calix[4]arene provides a very stable and sensitive marker for lysosomes, and has a considerable advantage over some commercially available lysosomal markers in so far that the fluorescent signal is stable even when the cells are incubated in dye-free medium after staining.


Subject(s)
Calixarenes/pharmacokinetics , Fluorescent Dyes/pharmacokinetics , Lysosomes/metabolism , Phenols/pharmacokinetics , Animals , Biological Transport , Brefeldin A/pharmacology , CHO Cells , Calixarenes/pharmacology , Caveolae/metabolism , Clathrin/antagonists & inhibitors , Clathrin/metabolism , Cricetinae , Cricetulus , Endosomes/metabolism , Fluorescent Dyes/pharmacology , Golgi Apparatus/metabolism , HeLa Cells , Humans , Lysosomes/drug effects , Macrolides/pharmacology , Monensin/pharmacology , Phenols/pharmacology , Sodium Azide/pharmacology , Tumor Cells, Cultured , Vacuolar Proton-Translocating ATPases/metabolism
10.
Org Lett ; 8(4): 549-52, 2006 Feb 16.
Article in English | MEDLINE | ID: mdl-16468708

ABSTRACT

[structure: see text] Chiral calix[4]arene alpha-aminophosphonic acids were obtained through diastereoselective Pudovik-type addition of sodium ethyl phosphites to the chiral calixarene imines, removal of chiral auxiliary groups, and mild dealkylation of phosphonate fragments. The diacids obtained show inhibitory activity toward porcine kidney alkaline phosphatase that depends considerably on the absolute configuration of the alpha-carbon atoms.


Subject(s)
Alkaline Phosphatase/antagonists & inhibitors , Calixarenes/chemical synthesis , Calixarenes/pharmacology , Kidney/enzymology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Phosphites/chemistry , Alkaline Phosphatase/metabolism , Animals , Calixarenes/chemistry , Calixarenes/pharmacokinetics , Molecular Structure , Organophosphonates/chemistry , Organophosphonates/pharmacokinetics , Stereoisomerism , Swine
11.
J Am Chem Soc ; 127(4): 1114-5, 2005 Feb 02.
Article in English | MEDLINE | ID: mdl-15669846

ABSTRACT

We report that the efflux of 5(6)-carboxyfluorescein anions from neutral egg yolk phosphatidylcholine vesicles is mediated by oligo/polyarginines only in the presence of activating amphiphilic anions. Screening of anion activators reveals best synergism for amphiphilic carboxylates (fullerene > calix[4]arene approximately coronene > pyrene > calix[6]arene > alkyl), whereas amphiphilic sulfates show less satisfactory activation despite often lower effective concentrations. The analogous alcohols and one calix[4]arene diphosphate were inactive. These results are discussed in the context of a tentative anion carrier mechanism, where interactions with bilayer (interface-directed translocation) and carrier (arene-templated carboxylate-guanidinium pairing) contribute to activator efficiencies. Applied to HeLa cells, pyrenebutyrate is shown to significantly increase the uptake of a fluorescently labeled octaarginine in a concentration-dependent manner.


Subject(s)
Calixarenes/pharmacokinetics , Drug Carriers/pharmacokinetics , Fullerenes/pharmacokinetics , Peptides/pharmacokinetics , Polycyclic Compounds/pharmacokinetics , Pyrenes/pharmacokinetics , Anions , Calixarenes/chemistry , Cell Membrane/chemistry , Cell Membrane/metabolism , Drug Carriers/chemistry , Fullerenes/chemistry , HeLa Cells , Humans , Membranes, Artificial , Peptides/chemistry , Phosphatidylglycerols/chemistry , Polycyclic Compounds/chemistry , Pyrenes/chemistry
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