A supramolecular electrochemical probe based on a tetrazole derivative pillar[5]arene/methylene blue system.

For the first time, an original synthetic approach has been developed that enables the introduce ten tetrazole fragments into the pillar[5]arene structure. A supramolecular electrochemical probe was assembled for the first time from the obtained macrocycles and an electrochemically active signal converter: methylene blue (MB) dye. The ability of pillar[5]arene containing tetrazole fragments to selectively bind MB was confirmed by UV-vis and 2D 1H-1H NOESY spectroscopy. The stoichiometry of the resulting pillar[5]arene/MB complex = 1 : 2. This new supramolecular probe pillar[5]arene/MB allowed the detection of changes in the electrochemical signals of MB implemented in the supramolecular complex depending on the presence or absence of some metal ions (Zn2+ and Co2+) that do not exert their own redox activity. This will find further applications for the enhancement of the range of analytes detected by their influence on host-guest complexation and for the design of biosensors based on specific DNA-MB interactions.

Metallo-Supramolecular Coordination Polymers Based on Amidopyridine Derivatives of Pillar[5]arene and Cu(II) and Pd(II) Cations: Synthesis and Recognition of Nitroaromatic Compounds.

Decasubstituted pillar[5]arenes containing amidopyridine fragments have been synthesized for the first time. As was shown by UV-vis spectroscopy, the pillar[5]arenes with p-amidopyridine fragments form supramolecular associates with Cu(II) and Pd(II) cations in methanol in a 2:1 ratio. Using a sol-gel approach these associates are transformed into metallo-supramolecular coordination polymers (supramolecular gels) which were characterized as amorphous powders by scanning electron microscopy (SEM) and dynamic light scattering (DLS). The powders are able to selectively adsorb up to 46% of nitrophenols from water and were incorporated into an electrochemical sensor to selectively recognize them in aqueous acidic solution.

Water-soluble pillar[5]arene sulfo-derivatives self-assemble into biocompatible nanosystems to stabilize therapeutic proteins.

Pillar[5]arenes containing sulfonate fragments have been shown to form supramolecular complexes with therapeutic proteins to facilitate targeted transport with an increased duration of action and enhanced bioavailability. Regioselective synthesis was used to obtain a water-soluble pillar[5]arene containing the fluorescent label FITC and nine sulfoethoxy fragments. The pillar[5]arene formed complexes with the therapeutic proteins binase, bleomycin, and lysozyme in a 1:2 ratio as demonstrated by UV-vis and fluorescence spectroscopy. The formation of stable spherical nanosized macrocycle/binase complexes with an average particle size of 200 nm was established by dynamic light scattering and transmission electron microscopy. Flow cytometry demonstrated the ability of macrocycle/binase complexes to penetrate into tumor cells where they exhibited significant cytotoxicity towards A549 cells at 10-5-10-6 M while maintaining the enzymatic activity of binase.

Supramolecular Amphiphiles Based on Pillar[5]arene and Meroterpenoids: Synthesis, Self-Association and Interaction with Floxuridine.

In recent years, meroterpenoids have found wide biomedical application due to their synthetic availability, low toxicity, and biocompatibility. However, these compounds are not used in targeted drug delivery systems due to their high affinity for cell membranes, both healthy and in cancer cells. Using the approach of creating supramolecular amphiphiles, we have developed self-assembling systems based on water-soluble pillar[5]arene and synthetic meroterpenoids containing geraniol, myrtenol, farnesol, and phytol fragments. The resulting systems can be used as universal drug delivery systems. It was shown by turbidimetry that the obtained pillar[5]arene/synthetic meroterpenoid systems do not interact with the model cell membrane at pH = 7.4, but the associates are destroyed at pH = 4.1. In this case, the synthetic meroterpenoid is incorporated into the lipid bilayer of the model membrane. The characteristics of supramolecular self-assembly, association constants and stoichiometry of the most stable pillar[5]arene/synthetic meroterpenoid complexes were established by UV-vis spectroscopy and dynamic light scattering (DLS). It was shown that supramolecular amphiphiles based on pillar[5]arene/synthetic meroterpenoid systems form monodisperse associates in a wide range of concentrations. The inclusion of the antitumor drug 5-fluoro-2'-deoxyuridine (floxuridine) into the structure of the supramolecular associate was demonstrated by DLS, 19F, 2D DOSY NMR spectroscopy.

Towards new nanoporous biomaterials: self-assembly of sulfopillar[5]arenes with vitamin D3 into supramolecular polymers.

Novel water-soluble, deca-substituted pillar[5]arenes containing thiasulfate and thiacarboxylate fragments were synthesized and characterized. UV-vis, 2D 1H-1H NOESY and DOSY NMR spectroscopy revealed the ability of pillar[5]arenes containing thiasulfate fragments to form an inclusion complex with cholecalciferol (vitamin D3) in a 1 : 2 ratio (lg Kass = 2.2). Using DLS and SEM it was found that upon concentration and/or evaporation of the solvent, the supramolecular polymer (pillar[5]arene/vitamin D3 (1 : 2)) forms a porous material with an average wall diameter of 53 nm. It was shown that the supramolecular polymer is stable during photolysis by UV radiation (k1 = 1.7 × 10-5 s-1).

Water-soluble betaines and amines based on thiacalix[4]arene scaffold as new cholinesterase inhibitors.

Novel ammonium and betaine derivatives of p-tert-butylthiacalix[4]arene in cone and 1,3-alternate conformation were synthesized with high yields for the first time. The obtained compounds form in water spherical nanoparticles. It was shown by molecular docking calculations and in vitro experiments that amino and betaine derivatives can inhibit acetylcholinesterase and butyrylcholinesterase on the level of pyridostigmine while the toxicity of the obtained compounds is much lower than that of pyridostigmine.

Antimicrobial Activity of Calixarenes and Related Macrocycles.

Calixarenes and related macrocycles have been shown to have antimicrobial effects since the 1950s. This review highlights the antimicrobial properties of almost 200 calixarenes, resorcinarenes, and pillararenes acting as prodrugs, drug delivery agents, and inhibitors of biofilm formation. A particularly important development in recent years has been the use of macrocycles with substituents terminating in sugars as biofilm inhibitors through their interactions with lectins. Although many examples exist where calixarenes encapsulate, or incorporate, antimicrobial drugs, one of the main factors to emerge is the ability of functionalized macrocycles to engage in multivalent interactions with proteins, and thus inhibit cellular aggregation.

Supramolecular neuromuscular blocker inhibition by a pillar[5]arene through aqueous inclusion of rocuronium bromide.

A water-soluble pillar[5]arene, decafunctionalized with thioether and carboxylate fragments, was synthesized as a structural analogue of Sugammadex. Its ability to restore the contraction of the diaphragm muscle by encapsulating the muscle relaxant rocuronium bromide was demonstrated. Using UV-vis, NMR and fluorescence spectroscopy, it was shown that the muscle relaxant is associated with the pillar[5]arene with an association constant of 4500 M-1 and a stoichiometry of 1 : 1. The structure of the inclusion complex of the pillar[5]arene with rocuronium bromide was additionally investigated by quantum chemical methods.

p-tert-Butylthiacalix[4]arenes functionalized by N-(4'-nitrophenyl)acetamide and N,N-diethylacetamide fragments: synthesis and binding of anionic guests.

New p-tert-butylthiacalix[4]arenes, which are mono-, 1,2-di- and tetrasubstituted at the lower rim containing N-(4'-nitrophenyl)acetamide and N,N-diethylacetamide groups in cone and partial cone conformations have been synthesized. Their complexation ability towards a number of tetrabutylammonium salts n-Bu4NX (X = F-, Cl-, Br-, I-, CH3CO2-, H2PO4-, NO3-) was studied by UV spectroscopy. The effective receptor for the anions studied as well as selective receptors for F-, CH3CO2- and H2PO4- ions, which based on the synthesized thiacalix[4]arenes, have been obtained. It was shown that p-tert-butylthiacalix[4]arene tetrasubstituted at the lower rim by N-(4'-nitrophenyl)acetamide moieties bonded to the anions studied with association constants within the range of 3.55 × 103-7.94 × 105 M-1. Besides, the binding selectivity for F-, Cl-, CH3CO2-, and H2PO4- anions against other anions was in the range of 4.1-223.9. Substituting one or two fragments in the macrocycle with N,N-diethylacetamide groups significantly reduces the complexation ability of the receptor. In contrast to the 1,3-disubstituted macrocycle containing two N-(4'-nitrophenyl)acetamide moieties, the 1,2-disubstituted thiacalix[4]arene, which contains only one such fragment and a N,N-diethylacetamide moiety, selectively binds F- anions.

The synthesis of new amphiphilic p-tert-butylthiacalix[4]arenes containing peptide fragments and their interaction with DNA.

New water-soluble p-tert-butylthiacalix[4]arenes containing peptide and quaternary ammonium fragments in cone and 1,3-alternate conformations were synthesized and characterized. The interaction of the macrocycles with DNA was studied by UV-spectroscopy, DLS and TEM. It was shown that the interaction of the self-associates based on p-tert-butylthiacalix[4]arenes tetrasubstituted at the lower rim with glycine and quaternary ammonium fragments in cone and 1,3-alternate conformations with DNA led to the formation of particles of about 99-192 nm in size.

Cis-Trans and Length-Selective Molecular Discrimination of Halogenated Organic Compounds by a Crystalline Hybrid Macrocyclic Arene.

The development of adsorbents with robust molecular discrimination capabilities for halogenated organic compounds (HOCs) holds significant importance due to their potential in adsorptive separation and mitigation of associated health risks. In this study, we report a molecular discrimination behavior based on crystalline hybrid macrocyclic arene H, offering precise capture of cis-trans isomers and length-selective separation of HOCs. The activated H crystals (Hα) demonstrate exceptional discrimination and separation performance by selectively capturing trans-1,2-dichloroethylene (trans-DCE) from cis/trans-isomer mixtures with a high selectivity of 98.8%. Evidenced by single-crystal X-ray diffraction and density functional theory (DFT) calculations, this high adsorption selectivity arises from the formation of more stable complex crystals between H and the preferred guest trans-DCE. Moreover, Hα exhibits the ability to selectively trap size-matched 1,2-dibromoethane (DBE) from mixtures of alkylene dibromides with varying alkane-chain lengths, although their capture and separation are recognized to be difficult as a consequence of low-polarity bonds. The solid-state transformations between guest-free and guest-containing Hα crystals indicate their recyclability, showcasing promising prospects for potential applications.

Antibacterial Activity of Various Morphologies of Films Based on Guanidine Derivatives of Pillar[5]arene: Influence of the Nature of One Substitute on Self-assembly.

The progress of the pillar[5]arene chemistry allowed us to set out a new concept on application of the supramolecular assemblies to create antimicrobial films with variable surface morphologies and biological activities. Antibacterial films were derived from the substituted pillar[5]arenes containing nine pharmacophoric guanidine fragments and one thioalkyl substituent. Changing the only thioalkyl fragment in the macrocycle structure made it possible to control the biological activity of the resulting antibacterial coating. Pretreatment of the surface with aqueous solution of the amphiphilic pillar[5]arenes reduced the biofilm thickness by 56 ± 10% of Gram-positive Staphylococcus aureus in the case of the pillar[5]arene containing a thiooctyl fragment and by 52 ± 7% for the biofilm of Gram-negative Klebsiella pneumoniae in the case of pillar[5]arene containing a thiooctadecyl fragment. Meanwhile, the cytotoxicity of the synthesized macrocycles was examined at a concentration of 50 µg/mL, which was significantly lower than that of bis-guanidine-based antimicrobial preparations.

Toward Pathogenic Biofilm Suppressors: Synthesis of Amino Derivatives of Pillar[5]arene and Supramolecular Assembly with DNA.

New amino derivatives of pillar[5]arene were obtained in three stages with good yields. It was shown that pillar[5]arene containing thiaether and tertiary amino groups formed supramolecular complexes with low molecular weight model DNA. Pillar[5]arene formed complexes with a DNA nucleotide pair at a ratio of 1:2 (macrocycle/DNA base pairs), as demonstrated by UV-visible and fluorescence spectroscopy. The association constants of pillar[5]arene with DNA were lgKass1:1 = 2.38 and lgKass1:2 = 5.07, accordingly. By using dynamic light scattering and transmission electron microscopy, it was established that the interaction of pillar[5]arene containing thiaether and tertiary amino groups (concentration of 10-5 M) with a model nucleic acid led to the formation of stable nanosized macrocycle/DNA associates with an average particle size of 220 nm. It was shown that the obtained compounds did not exhibit a pronounced toxicity toward human adenocarcinoma cells (A549) and bovine lung epithelial cells (LECs). The hypothesis about a possible usage of the synthesized macrocycle for the aggregation of extracellular bacterial DNA in a biofilm matrix was confirmed by the example of St. Aureus. It was found that pillar[5]arene at a concentration of 10-5 M was able to reduce the thickness of the St. Aureus biofilm by 15%.

Self-Healing Thiolated Pillar[5]arene Films Containing Moxifloxacin Suppress the Development of Bacterial Biofilms.

Polymer self-healing films containing fragments of pillar[5]arene were obtained for the first time using thiol/disulfide redox cross-linking. These films were characterized by thermogravimetric analysis and differential scanning calorimetry, FTIR spectroscopy, and electron microscopy. The films demonstrated the ability to self-heal through the action of atmospheric oxygen. Using UV-vis, 2D 1H-1H NOESY, and DOSY NMR spectroscopy, the pillar[5]arene was shown to form complexes with the antimicrobial drug moxifloxacin in a 2:1 composition (logK11 = 2.14 and logK12 = 6.20). Films containing moxifloxacin effectively reduced Staphylococcus aureus and Klebsiella pneumoniae biofilms formation on adhesive surfaces.

Cascade and commutative self-assembles of nanoscale three-component systems controlled by the conformation of thiacalix[4]arene.

In this work, the formation of two- and three-component supramolecular systems based on cone, partial cone, 1,3-alternate stereoisomers of heteroditopic "hosts": p-tert-butylthiacalix[4]arene containing 4-amidopyridine fragments with silver(I) cations and dicarboxylic acids in liquid and solid phases were studied by UV spectroscopy, dynamic light scattering, and atomic force microscopy methods. It has been shown that these macrocycles are coreceptors, capable of simultaneously binding silver(I) cations, dicarboxylic acids (oxalic, malonic, succinic, maleic, fumaric acids), and hydroxyl acids (glycol, tartaric acids). For the first time, by the dynamic light scattering method, it has been shown that the conformation of p-tert-butyl thiacalix[4]arenes significantly affects the type of three-component system formed: cone is characterized by the formation of cascade systems; for partial cone, intermediate systems; and for the 1,3-alternate stereoisomers, three types of three-component systems (cascade, intermediate, and commutative) were observed.

p-tert-Butyl thiacalix[4]arenes functionalized at the lower rim by amide, hydroxyl and ester groups as anion receptors.

New p-tert-butyl thiacalix[4]arenes differently substituted at the lower rim with amide, hydroxyl and ester groups were synthesized. Binding properties of the compounds toward some tetrabutylammonium salts n-Bu(4)NX (X = F(-), Cl(-), Br(-), I(-), CH(3)CO(2)(-), H(2)PO(4)(-), NO(3)(-)) were studied by UV spectroscopy. It was found that the stoichiometry of the complexes, generally, is 1 : 1, and the association constants are in the range of 10(3)-10(5) M(-1). The p-tert-butyl thiacalix[4]arenes containing secondary amide groups trisubstituted at the lower rim bind the studied anions most effectively. Selective receptors for fluoride and dihydrogen phosphate salts of tetrabutylammonium were found.

Towards Universal Stimuli-Responsive Drug Delivery Systems: Pillar[5]arenes Synthesis and Self-Assembly into Nanocontainers with Tetrazole Polymers.

In this work, we have proposed a novel universal stimulus-sensitive nanosized polymer system based on decasubstituted macrocyclic structures-pillar[5]arenes and tetrazole-containing polymers. Decasubstituted pillar[5]arenes containing a large, good leaving tosylate, and phthalimide groups were first synthesized and characterized. Pillar[5]arenes containing primary and tertiary amino groups, capable of interacting with tetrazole-containing polymers, were obtained with high yield by removing the tosylate and phthalimide protection. According to the fluorescence spectroscopy data, a dramatic fluorescence enhancement in the pillar[5]arene/fluorescein/polymer system was observed with decreasing pH from neutral (pH = 7) to acidic (pH = 5). This indicates the destruction of associates and the release of the dye at a pH close to 5. The presented results open a broad range of opportunities for the development of new universal stimulus-sensitive drug delivery systems containing macrocycles and nontoxic tetrazole-based polymers.

Nanostructured Polyelectrolyte Complexes Based on Water-Soluble Thiacalix[4]Arene and Pillar[5]Arene: Self-Assembly in Micelleplexes and Polyplexes at Packaging DNA.

Controlling the self-assembly of polyfunctional compounds in interpolyelectrolyte aggregates is an extremely challenging task. The use of macrocyclic compounds offers new opportunities in design of a new generation of mixed nanoparticles. This approach allows creating aggregates with multivalent molecular recognition, improved binding efficiency and selectivity. In this paper, we reported a straightforward approach to the synthesis of interpolyelectrolytes by co-assembling of the thiacalix[4]arene with four negatively charged functional groups on the one side of macrocycle, and pillar[5]arene with 10 ammonium groups located on both sides. Nanostructured polyelectrolyte complexes show effective packaging of high-molecular DNA from calf thymus. The interaction of co-interpolyelectrolytes with the DNA is completely different from the interaction of the pillar[5]arene with the DNA. Two different complexes with DNA, i.e., micelleplex- and polyplex-type, were formed. The DNA in both cases preserved its secondary structure in native B form without distorting helicity. The presented approach provides important advantage for the design of effective biomolecular gene delivery systems.

Nanoparticles based on the zwitterionic pillar[5]arene and Ag+: synthesis, self-assembly and cytotoxicity in the human lung cancer cell line A549.

For the first time, stable pillar[5]arene/Ag+ nanoparticles, consisting of water-soluble pillar[5]arene containing γ-sulfobetaine fragments and Ag+ ions without Ag-Ag bonds, were synthesized and characterized. The pillar[5]arene/Ag+ (ratio 1:10) nanoparticles obtained were cubic with a rib length of 100 nm and are less cytotoxic than Ag+ ions. The survival of the A549 model cells in the presence of pillar[5]arene/Ag+ (1:10) nanoparticles at a concentration of 30 and 40 µM was 76% and 55%, while in the absence of pillar[5]arene, the cell survival for free Ag+ ions at the same concentration was 30% and 10%, respectively. The results can be used to create new antibacterial materials and 2D biomedical coatings.

Progress in the Chemistry of Macrocyclic Meroterpenoids.

In the last decade, the chemistry of meroterpenoids-conjugated molecules formed from isoprenyl fragments through biosynthetic pathways-has developed rapidly. The class includes some natural metabolites and fully synthetic fragments formed through nonbiological synthesis. In the field of synthetic receptors, a range of structures can be achieved by combining fragments of different classes of organic compounds into one hybrid macrocyclic platform which retains the properties of these fragments. This review discusses the successes in the synthesis and practical application of both natural and synthetic macrocycles. Among the natural macrocyclic meroterpenoids, special attention is paid to isoprenylated flavonoids and phenols, isoprenoid lipids, prenylated amino acids and alkaloids, and isoprenylpolyketides. Among the synthetic macrocyclic meroterpenoids obtained by combining the "classical" macrocyclic platforms, those based on cyclodextrins, together with meta- and paracyclophanes incorporating terpenoid fragments, and meroterpenoids obtained by macrocyclization of several terpene derivatives are considered. In addition, issues related to biomedical activity, processes of self-association and aggregation, and the formation of host-guest complexes of various classes of macrocyclic merotenoids are discussed in detail.