Stereodesign of chiral para-substituted calix[4]arenes

According to the hypothesis that the chirality of molecule hosts is a cause of their enantioselectivity, the chirality of para-substituted calix[4]arenes was analyzed quantitatively. The relationship between types of para-substituents and the dissymmetry of the 2D (two-dimensional) entrance into the cavity and the whole 3D (three-dimensional) cavity of calix[4]arenes was studied by means of the enantiomer dissimilarity factor (EDF) method for quantitative evaluation of molecular chirality. The design of the most chiral, and probably enantioselective, para-substituted calix[4]arenes was planned such that all four substituents should be different and the two largest should be near each other (adjacent). It was, on the other hand, shown that the 2D chiral entrance determines chirality of the whole 3D structures of these molecules. This phenomenon is interpreted as an example of the chirality transition from 2D into 3D space.Electronic Supplementary Material available.     

Syntheses and structural studies of calix[4]arene-nucleoside and calix[4]arene-oligonucleotide hybrids

We have synthesized three types of calix[4]arene– nucleoside hybrid efficiently by amide bond formation between the amine functional groups of 1,3-diaminocalix[4]arene and the carboxyl groups of thymidine nucleoside derivatives. X-ray crystallography of a homocoupled calix[4]arene–nucleoside hybrid revealed an interesting hydrogen bonding pattern between thymine bases and the amide linkages. We designed the calix[4]arene–oligonucleotide hybrids (5′-AAAAGATATCAAXTTGATATCTTTT-3′, 5′-T₁₂-X-T₁₂-3′, and 5′-A₁₂-X-T₁₂-3′) to be V-shaped oligodeoxyribonucleotides and synthesized them by using a calix[4]arene–nucleoside hybrid (X) as a key building block. Thermal denaturation experiments, monitored by UV spectroscopy at 260 and 284 nm, and circular dichroism spectra of the calix[4]arene–oligonucleotide hybrids suggest that the modified oligonucleotides indeed adopt V-shaped conformations, making them suitable for use as building blocks in the construction of programmed oligonucleotide nanostructures.     

Voltage-dependent block of endothelial volume-regulated anion channels by calix[4]arenes

We have studiedthe effects of calix[4]arenes on the volume-regulated anionchannel (VRAC) currents in cultured calf pulmonary artery endothelialcells. TS- and TS-TM-calix[4]arenes induced a fastinhibition at positive potentials but were ineffective at negativepotentials. Maximal block occurred at potentials between 30 and 50 mV.Lowering extracellular pH enhanced the block and shifted the maximuminhibition to more negative potentials. Current inhibition was alsoaccompanied by an increased current noise. From the analysis of thecalix[4]arene-induced noise, we obtained a single-channelconductance of 9.3 ± 2.1 pS (n = 9) at +30 mV. The voltage- and time-dependent block were describedusing a model in which calix[4]arenes bind to a site at anelectrical distance of 0.25 inside the channel with an affinity of 220 µM at 0 mV. Binding occludes VRAC at moderately positive potentials,but calix[4]arenes permeate the channel at more positivepotentials. In conclusion, our data suggest an open-channel block ofVRAC by calix[4]arenes that also depends on the protonationof the binding site within the pore.

     

Antiproliferative effect on HepaRG cell cultures of new calix[4]arenes

Cell cycle progression is dependent on the intracellular iron level, and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing alkyl acid and alkyl ester groups at the lower rim, designed as potential iron chelators. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670 (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in human hepatocarcinoma HepaRG cell cultures using the MTT assay. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicate that their antiproliferative effect is due to their cytotoxicity. The efficiency of these compounds, comparable to that of ICL670, was independent of iron depletion. This effect remains to be further explored. Moreover, it also shows that novel substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.     

Dissymmetric calix[4]arenes: Optical resolution of some conformationally fixed derivatives

Various possibilities to obtain intrinsically chiral calix[4]arenes are discussed. The enantiomers of three 1,3-dietheresters and one monoether compound derived from dissymmetric calix[4]arenes with C₄ symmetry were separated by HPLC using chiral stationary phases and characterized by their CD spectra. © 1993 Wiley-Liss, Inc.     

Direct separation of cone-shaped tri-O-alkylated chiral calix[4]arenes by enantioselective HPLC

The direct HPLC separation of eight inherently chiral atropisomeric calix[4]arenes has been achieved using Chiralcel OD phase. A rationale is given for the variation of the enantioselectivity as a function of the O-alkyl or O-aryl groups. In closely related structures hydrogen bond formation between the free hydroxyl of the analyte and the chiral phase plays an important role in the chiral recognition process. © 1993 Wiley-Liss, Inc.     

Conjugation, immunoreactivity, and immunogenicity of calix[4]arenes; model study to potential calix[4]arene-based Ac3+ chelators.

For the development of calix[4]arene-based radiotherapeutic agents, the conjugation to biomolecules and immunogenicity in mice of potential 225Ac3+-chelating calix[4]arenes were studied. A calix[4]arene triethyl ester isothiocyanate and a bis(calix[4]arene) hexacarboxylic acid, containing a masked thiol functionality, were used in conjugation experiments to a mouse monoclonal antibody and serum albumins. All characterization techniques indicate that only the calix[4]arene carboxylic acid is successfully conjugated to the biomolecules. The immunoreactivity of the conjugates is not impaired when up to 6 equiv of calixarene are bound to the monoclonal antibody. Animal tests indicated that the immunogenicity toward the calix[4]arene is strongly influenced by the nature of the carrier, the dosage, and the injection method. No immune response occurred when a homologous carrier was used or when a heterologous carrier was applied at a dosage of 10 microg per immunization via intravenous injection. Under all other conditions, the presence of antibodies directed against the calix[4]arene was demonstrated. Thus, for the application in radioimmunotherapy, the conjugation of a calix[4]arene to a humanized antibody will probably not lead to an immune response, and the immunoreactivity will not be disturbed.     

Dinuclear Ti and Ti complexes supported by calix[4]arene ligands. Binding alkali-metal cations inside and outside the cavity of calix[4]arenes

New dinuclear Ti^IV and Ti^III complexes with the calix[4]arene ligand C₂₈H₂₀O₄H₄ (H₄L) have been isolated from the reaction of Ti(NMe₂)₄, H₄L, and Na (or KC₈) in THF. X-ray analyses revealed a similar core structure for the two complexes Na₄(THF)₈[Ti^IV ₂(μ-O)₂L₂] (1) and K₄(THF)₈[Ti^III ₂(μ-NMe₂)₂L₂] (2). Two titanium atoms are bridged by two oxygen atoms in 1 and by two dimethylamido groups in 2 and are also supported by two deprotonated calix[4]arene ligands in a cone conformation. This resulted in a similar Ti?Ti separation of about 3.29 Å in 1 and 3.28 Å in 2 and in a distorted octahedral environment for each Ti center in both complexes. In contrast, in a novel complex 3, Na₂(THF)₆[Ti^III ₂L₂], two Ti^III atoms are supported only by two deprotonated ligands. This results in a five-coordinate environment for both titanium(III) centers with the separation between them being 3.133(1) Å.     

Unusual reactivity of copper(I) complexes of functionalised calix[4]arenes

Two functionalised calix[4]arenes, 5,11,17,23-tetra-tert-butyl-25,27-bis(2-pyridylmethoxy)calix[4]arene (L¹) and 5,11,17,23-tetra-tert-butyl-25,27-bis(2-pyridylmethoxy)-26,28-dibutoxycalix[4]arene (L³), were prepared and characterised. The copper(I) complexes of both calix[4]arenes were synthesised and their reactivities were analysed and compared. The presence of the metal induced a radical in the case of L¹ whereas no such radical was observed in the metal complex of ligand L³.     

Computational investigation of a new ion-pair receptor for calix[4]pyrrole

Theoretical studies of a new ion-pair receptor, meso-octamethylcalix[4]pyrrole (OMCP), and its interactions with the halide anions F(-), Cl(-), and Br(-) and the cesium halides CsF, CsCl, and CsBr have been performed. Geometries, binding energies, and binding enthalpies were evaluated with the restricted hybrid Becke three-parameter exchange functional (B3LYP) method using the 6-31+G(d) basis set and relativistic effective core potentials. The optimized geometric structures were used to perform natural bond orbital (NBO) analysis. The two typical types of hydrogen bonds, N-H…X(-) and C-H…X(-), were investigated. The results indicate that hydrogen bonding interactions are dominant, and that the halide anions (F(-), Cl(-), and Br(-)) offer lone pair electrons to the σ*(N-H) or σ*(C-H) antibonding orbitals of OMCP. In addition, electrostatic interactions between the lone pair electrons of the halide anion and the LP* orbitals of Cs(+) as well as cation-π interactions between the metal ion and π-orbitals of the pyrrole rings have important roles to play in the Cs(+)?OMCP?X(-) complexes. The current study further demonstrates that this easy-to-make OMCP host compound functions as not only an anion receptor but also an ion-pair receptor.     

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.     

Modulation of cell proliferation in rat liver cell cultures by new calix[4]arenes

Cell cycle progression is dependent on intracellular iron level and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing two aspartic/glutamic acid, ornithine groups or hydrazide function at the lower rim, designed as potential iron chelators. The synthesis only afforded calix[4]arenes in the cone conformation. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670A (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in the rat hepatoma cell line Fao by measuring mitochondrial succinate dehydrogenase activity. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicated that among all tested compounds, monohydrazidocalix[4]arene 2 which is not cytotoxic in Fao cells exhibits interesting antiproliferative activity. This effect, independent on iron depletion, remains to be further explored. Moreover, it also shows that new substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.     

Lipase-catalyzed regioselective acylation of resorcin[4]arenes

Immobilized lipase from Mucor miehei (RML) catalyzed the regioselective acylation of the C-2 side-chain of the C-alkyl resorcin[4]arene tetra-alcohol 1 in the 1,2-alternate form in organic solvents using vinyl acetate as acylating reagent. The influence of reaction parameters and solvent choice were also studied. Docking simulations allowed the determination of the binding geometry of 1, revealing the importance of Trp88 residue in stabilizing the Michaelis–Menten complex between enzyme and substrate.     

Enantioselective resolution of racemic flurbiprofen methyl ester by lipase encapsulated mercapto calix[4]arenes capped Fe3O4 nanoparticles

This work presents the synthesis of new mercapto calix[4]arenes derivatives (4 and 5). These derivatives were capped on Fe₃O₄ magnetic nanoparticles and subsequently encapsulated with Candida rugosa through sol–gel method to furnish enc-4 and enc-5, respectively, to enhance catalytic activity and enantioselectivity of lipase for hydrolysis reaction of racemic flurbiprofen methyl ester. Catalytic activity and enantioselectivity of enc-4 and enc-5 were assayed at different pH and temperature conditions and it was found that the resultant encapsulated enzyme exhibited higher thermal and operational stabilities compared to the free lipase in which enc-5 showed the excellent rate of enantioselectivity (E = 176) for S-flurbiprofen better than free lipase (E = 137) at pH 7 and 35 °C for 48 h. The time study shows that enantioselectivity reached the maximum value of E = 244 after 72 h. Catalytic activity  of these materials was hardly affected by 20 and 23% after five usages of enc-4 and enc-5, respectively.

     

Electronic absorption spectroscopy for the investigation of the solution binding of gold, palladium, mercury and silver salts to the lower rim substituted calix[4]arenes 25,26,27,28-(2-N,N-dimethyldithiocarbamoylethoxy)calix[4]arene and 25,26,27,28-(2-methylthioethoxy)calix[4]arene

The two uncharged compounds 25,26,27,28-(2-N,N-di methyldithiocarbamoylethoxy)calix[4]arene (1) and 25,26,27,28- (2-methylthioethoxy)calix[4]arene (2) are effective extractants for transferring Hg(II), Ag(I), Pd(II) and Au(III) from aqueous solution into chloroform. The electronic absorption spectra of 1 and 2 show additional bands at long wavelength upon complexation with AuCl₄⁻, PdCl₄²⁻ and PdBr₄²⁻, and analogous bands for Hg²⁺ and Ag⁺ with 1. For 1 these new bands are considered to be either of the charge transfer type or transitions within the C=S moiety. These new bands for the complexes with 2 are assigned to LMCT transitions of the S → M type. These spectral features are used to obtain information about the solution structures of the complexes that are formed between these metal ions and both 1 and 2.     

Anisotropy decay study on the host-guest interaction of distally dialkylated calix[4]arenes with 1-chloro-4-(trifluoromethyl)benzene

The 'host' properties of distally dialkylated calix[4]arenes and 4-tert-butylcalix[4]arenes in the presence of 1-chloro-4-(trifluoromethyl)benzene (BFT) were studied in chloroform solvent by intensity-independent spectrofluorometric method. The anisotropy decay experiments were found as suitable method to indicate the host-guest complex formation but it is unable to determine the strength of supramolecular interaction.     

Chiral calix[4]arenes bearing amino alcohol functionality as membrane carriers for transport of chiral amino acid methylesters and mandelic acid

Novel chiral calix[4]arene derivatives bearing amino alcohol moieties at the lower rim have been synthesized from the reaction of p-tert-butylcalix[4]arene diester with various amino alcohols. The transport of amino acid esters (phenylglycine, phenylalanine, and tryptophan methyl esters hydrochloride) and mandelic acid were studied through chloroform bulk liquid membrane system using chiral calix[4]arenes 15-20. All these receptors have been found to act as carriers for transport of aromatic amino acid methylesters and mandelic acid from the aqueous source phase to the aqueous receiving phase. The influence of calixarene and guest structures upon transport through liquid membrane is discussed.     

New strapped calix[4]pyrrole based receptor for anions

Calix[4]pyrrole bearing catechol-derived diether strap linked via alkyl chains has been synthesized and characterized for the first time. The strap with 1,2-diether link is providing a relatively constrained geometry on its side of the calix[4]pyrrole moiety. As a result only one isomer (cis-type) of the receptor formed during reaction. The crystal structure reveals two molecules of methanol bound to the host. This calix[4]pyrrole also exhibits enhanced binding towards halide anions compared to simple calix[4]pyrrole apart from showing binding towards dihydrogenphosphate and acetate ions. The association constants are quite similar to that found for orcinol strapped calix[4]pyrrole towards halide anions in general, but having a higher preference for chloride than bromide ion in particular. Further it shows very strong preference towards fluoride ion.     

Anti-mycobacterial activities of some cationic and anionic calix[4]arene derivatives

Various polycharged calix[4]arenes were assayed as anti-mycobacterial agents against Mycobacterium tuberculosis, H(37)Rv strain. The sulfonate, carboxylate and phosphonate anionic species displayed no activity. Cationic derivatives integrating four aminoethyl groups at the upper rim and two 6,6'-dimethyl-2,2'-bipyridyl- or 4,4'-dimethyl-2,2'-bithiazolyl subunits at the lower rim were also found inactive against M. tuberculosis, while the unsubstituded and the 5,5'-dimethyl-2,2'-bipyridyl-analogues exhibited MIC values of 3.2 and 0.8μM respectively. Introduction of guanidinoethyl groups at the upper rim resulted, except for the 6,6'-dimethyl-2,2'-bipyridyl-derivative, in high anti-mycobacterial activities for the unsubstituted, the 5,5'-dimethyl-2,2'-bipyridyl- and the 4,4'-dimethyl-2,2'-bithiazolyl analogues, with MIC values of 0.8, 0.8 and 1.6μM, respectively, similar to those of current commercial anti-tuberculosis agents. The five more active substances were also evaluated against the isoniazid-resistant strain MYC5165, resulting in highly interesting micromolar or sub-micromolar MIC and IC(50), ca. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents.     

Computational studies of modified [Fe3S4] clusters: why iron is optimal

This work reports density functional computations of metal-substituted models of biological [Fe3S4] clusters in oxidation states [MFe2S4](+/0/-1) (M=Mn, Fe, Co, Ni, Cu, Zn, and Mo). Geometry optimization with a dielectric screening model is shown to provide a substantial improvement in structure, compared to earlier used standard procedures. The error for average Fe-S bonds decreased from 0.038A to 0.016A with this procedure. Four density functionals were compared, B3LYP, BP86, TPSS, and TPSSh. B3LYP and to a lesser extent TPSSh energies were inconsistent with experiment for the oxidized [Fe3S4]+ cluster. BP86 (and to a slightly lesser extent TPSS) was within expected theoretical and experimental uncertainties for all oxidation states, the only qualitative error being 5kJ/mol in favor of the M(S)=3/2 configuration for the [Fe3S4]+ cluster, so BP86 was used for quantitative results. Computed reorganization energies and reduction potentials point directly towards the [Fe3S4] cluster as the superior choice of electron carrier, with the [ZnFe2S4] cluster a close second. In addition, partially and fully Mo-substituted clusters were investigated and found to have very low reorganization energies but too negative reduction potentials. The results provide a direct rationale why any substitution weakens the cluster as an electron carrier, and thus why the [Fe3S4] composition is optimal in the biological clusters.