Synthesis, Physicochemical Studies, Molecular Dynamics Simulations, and Metal-Ion-Dependent Antiproliferative and Antiangiogenic Properties of Cone ICL670-Substituted Calixarenes.
ABSTRACT: Iron chelators, through their capacity to modulate the iron concentration in cells, are promising molecules for cancer chemotherapy. Chelators with high lipophilicity easily enter into cells and deplete the iron intracellular pool. Consequently, iron-dependent enzymes, such as ribonucleotide reductase, which is over-expressed in cancer cells, become nonfunctional. A series of calixarene derivatives substituted at the lower rim by ICL670, a strong FeIII chelator, have been synthesized. Physicochemical properties and antiproliferative, angiogenesis, and tumorigenesis effects of two calixarenes mono- (5a) or disubstituted (5b) with ICL670 have been studied. These compounds form metal complexes in a ratio of one to two ligands per FeIII atom as shown by combined analyses of the protometric titration curves and ESIMS spectra. The grafting of an ICL670 group on a calixarene core does not significantly alter the acid-base properties, but improves the iron-chelating and lipophilicity properties. The best antiproliferative and anti-angiogenic results were obtained with calixarene ligand 5a, which possesses the highest corresponding properties. Analyses of molecular dynamics simulations performed on the two calixarenes provide three-dimensional structures of the complexes and proved 5a to be the most stable upon complexation.
Project description:Methylene-bridged calixarenes have emerged as extremely versatile ligand supports in the formation of new polymetallic clusters possessing fascinating magnetic properties. Metal ion binding rules established for this building block allow one to partially rationalise the complex assembly process. The ability to covalently link calixarenes at the methylene bridge provides significantly improved control over the introduction of different metal centres to resulting cluster motifs. Clusters assembled from bis-calixarenes and transition metal ions or 3d-4f combinations display characteristic features of the analogous calixarene supported clusters, thereby demonstrating an enhanced and rational approach towards the targeted synthesis of complex and challenging structures.
Project description:Self-aggregating calixarenes carrying four DOTA ligands on the upper rim for stable complexation of paramagnetic GdIII-ions have already been proposed as MRI probes. In this work, we investigate the luminescence properties of TbIII-DOTA-calixarene-4OPr containing four propyl-groups and compare them with those of the analog substituted with a phthalimide chromophore (TbIII-DOTA-calixarene-3OPr-OPhth). We show that, given its four aromatic rings, the calixarene core acts as an effective sensitizer of Tb-centered luminescence. Substituents on the lower rim can modulate the aggregation behavior, which in turn determines the luminescence properties of the compounds. In solid state, the quantum yield of the phthalimide derivative is almost three times as high as that of the propyl-functionalized analog demonstrating a beneficial role of the chromophore on Tb-luminescence. In solution, however, the effect of the phthalimide group vanishes, which we attribute to the large distance between the chromophore and the lanthanide, situated on the opposite rims of the calixarene. Both quantum yields and luminescence lifetimes show clear concentration dependence in solution, related to the strong impact of aggregation on the luminescence behavior. We also evidence the variability in the values of the critical micelle concentration depending on the experimental technique. Such luminescent calixarene platforms accommodating stable lanthanide complexes can be considered valuable building blocks for the design of dual MR/optical imaging probes.
Project description:Inhibition of H3N2 influenza PA endonuclease activity by a panel of anionic calix[n]arenes and ?-cyclodextrin sulfate has been studied. The joint experimental and theoretical results reveal that the larger, more flexible and highly water-soluble sulfonato-calix[n]arenes have high inhibitory activity, with para-sulfonato-calixarene, SC8, having an IC50 value of 6.4 ?M. Molecular docking calculations show the SC8 can interact at both the polyanion binding site and also the catalytic site of H3N2 influenza PA endonuclease.
Project description:Lithiation and subsequent reaction with CO(2) was applied to calixarenes with different, equal or mixed, ether functions at the lower-rim site as well as tert-butylated or non-tert-butylated upper-rim positions. Whereas this reaction fails for symmetric calixarene ethers with alkoxy residues greater than methoxy, the carboxylation of mixed methoxy-propoxy calixarene ethers is possible. In connection with this, several new monobridge-substituted calixarenes were characterized with respect to their conformational behaviour in solution and the X-ray crystal structure of one key intermediate is taken into consideration.
Project description:Several lower-rim perfluoroalkylated (fluorous) calixarenes have been synthesized by O-alkylation of the parent calixarene. The compounds are formed in the cone conformation. They are soluble in several fluorous solvents and show promise for use in sensing, selective extractions and other applications.
Project description:There is a growing interest in the development of new iron chelators as novel promising therapeutic strategies for neurodegenerative disorders. In this article, a series of mono(catecholamine) derivatives, 2,3-bis(hydroxy)-N-(hydroxyacyl)benzamide, containing a pendant hydroxy, have been synthesized and fully characterized by nuclear magnetic resonance, Fourier transform infrared spectroscopy and mass spectrum. The thermodynamic stability of the chelators with FeIII, MgII and ZnII ions was then investigated. The chelators enable formation of (3?:?1) FeIII complexes with high thermodynamic stability and exhibited improved selectivity to FeIII ion. Meanwhile, the results of 1,1-diphenyl-2-picryl-hydrazyl assays of mono(catecholamine) derivatives indicated that they all possess excellent antioxidant properties. These results support the hypothesis that the mono(catecholamine) derivatives be used as high-affinity chelator for iron overload situations without depleting essential metal ions, such as MgII and ZnII ions.
Project description:The inclusion complexes of a new family of nonionic amphiphilic calixarenes with the anti-inflammatory hydrophobic drugs naproxen (NAP) and ibuprofen (IBP) were investigated. The effects of the alkyl chain's length and the inner core of calixarenes on the interaction of the two drugs with the calixarenes were explored. The inclusion complexes of Amphiphiles 1a-c with NAP and IBP increased the solubility of these drugs in aqueous media. The interaction of 1a-c with the drugs in aqueous media was investigated through fluorescence, molecular modeling, and ¹H-NMR analysis. TEM studies further supported the formation of inclusion complexes. The length of lipophilic alkyl chains and the intrinsic cyclic nature of cailxarene derivatives 1a-c were found to have a significant impact on the solubility of NAP and IBP in pure water.
Project description:Calixarenes constrained to 1,3-alternate conformation and functionalized at the upper rim with four and two nitronyl nitroxides have been synthesized, and characterized by X-ray crystallography, magnetic resonance (EPR and (1)H NMR) spectroscopy, and magnetic studies. Such calixarene tetraradicals and diradicals provide scaffolds for through-bond and through-space intramolecular exchange couplings.
Project description:Deep insight of the toxicity of supramolecular systems based on macrocycles is of fundamental interest because of their importance in biomedical applications. What seems to be most interesting in this perspective is the development of the macrocyclic compounds with biocompatible fragments. Here, calixresorcinarene derivatives containing N-methyl- d-glucamine moieties at the upper rim and different chemical groups at the lower rim were synthesized and investigated. These macrocycles showed a tendency to self-aggregate in aqueous solution, and their self-assembly abilities depend on the structure of the lower rim. The in vitro cytotoxic and antimicrobial activity of the calixresorcinarenes revealed the relationship of biological properties with the ability to aggregate. Compared to macrocycles with methyl groups on the lower rim, calixresorcinarenes with sulfonate groups appear to possess very similar antibacterial properties, but over six times less hemolytic activity. In some ways, this is the first example that reveals the dependence of the observed hemolytic and antibacterial activity on the lipophilicity of the calixarene structure.
Project description:A series of supramolecular calixarenes efficiently transport distinct molecular species through a liquid membrane when attached to a receptor-complementary choline handle. Calix-arene hexacarboxylic acid was highly effective at transporting different target molecules against a pH gradient. Both carboxylic- and phosphonic-acid-functionalized calixarenes effect transport without requiring a pH or ion gradient. NMR binding studies, two-phase solvent extraction, and three-phase transport experiments reveal the necessary and subtle parameters to effect the transport of molecules attached to a choline "handle". On the other hand, rescorinarene cavitands, which have similar guest recognition profiles, did not transport guest molecules. These developments reveal new approaches towards attempting synthetic-receptor-mediated selective small-molecule transport in vesicular and cellular systems.