Search

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.

There is a paucity of Russian medical literature reporting lumbosacral transitional vertebrae in children and adolescents. Many important aspects of the condition including two nosologies of sacralization of the L5 vertebrae and lumbalization of the S1 vertebrae have been under-explored. The objective was to establish overall frequency and frequency of certain types of lumbosacral transitional vertebrae in children and adolescents who sustained a lumbar injury and to investigate clinical manifestations of the pathology. Material and methods A comprehensive examination of 312children aged 7 to 18 years who suffered a lumbar injury was performed. Lumbosacral transitional vertebrae was radiologically diagnosed in 19 (6.09 %) subjects. Grading system of A.E. Castellvi et al. (1984) was used to classify the pathology. Results From 19 patients with lumbosacral transitional vertebrae, sacralization of the L5 vertebrae was detected in 16 (84.21 %) individuals. Lumbalization of the S1 vertebrae was diagnosed in 3 (15.79 %) children. Type II (n = 13) and subtype "b" (n = 10) were most common. No types III and IV of the disease were seen. No clinical symptoms indicating the likelihood of having lumbosacral transitional vertebrae were observed in the patients prior to the lumbar injury. Conclusion The frequency of occurrence of lumbosacral transitional vertebrae and its structure were reviewed in children and adolescents. The patients demonstrated no clinical manifestations of the condition before the children sustained lumbar injuries. Various aspects of transitional lumbar vertebrae in children and adolescents require further study.

The paper presents an analysis of the most studied Neolithic cultures of the forest belt from Scandinavia and the Eastern Baltic States to the Volga-Kama region and the Urals (7th-4th Millennia BC). The analysis was carried out using the following elements of the Neolithic package: ceramics, polished woodworking tools, long-term dwellings, large burial grounds, shrines and imported items. In the course of the study, the materials representing 16 archaeological cultures of this region were collected by the author. As a result, the most developed Neolithic cultures of the forest belt were identified, with due account of the currently existing data. The most common features – ceramics and polished woodworking tools – were also identified. The rare feature is the presence of shrines. Conclusions are made on the level of development of the studied cultures.

Cancer is one of the most common diseases in developed countries. Recently, gene therapy has emerged as a promising approach to cancer treatment and has already entered clinical practice worldwide. RNA interference-based therapy is a promising method for cancer treatment. However, there are a number of limitations that require vectors to deliver therapeutic nucleic acids to target tissues and organs. Active research is currently underway to find highly effective, low-toxic nanomaterials capable of acting as nanocarriers. In this study, we demonstrated for the first time the ability of symmetrical polyamidoamine dendronized thiacalix[4]arenes (PAMAM-calix-dendrimers) to form stable positively charged complexes with siRNAs, protect them from enzymatic degradation, and efficiently deliver gene material to HeLa cells. A distinctive feature of PAMAM-calix-dendrimers was the unusual decrease in hemo- and cytotoxicity with increasing generation, while these compounds did not cause toxic effects at concentrations required for siRNA binding and delivery. A comparative analysis of the efficiency of complex formation of PAMAM-calix-dendrimers and classical PAMAM dendrimers with siRNAs was also performed. The findings may facilitate the creation of novel unique gene delivery systems for cancer nanomedicine development.

Amyloid fibroproliferation leads to organ damage and is associated with a number of neurodegenerative diseases affecting populations worldwide. There are several ways to protect against fibril formation, including inhibition. A variety of organic compounds based on molecular recognition of amino acids within the protein have been proposed for the design of such inhibitors. However, the role of macrocyclic compounds, i.e., thiacalix[4]arenes, in inhibiting fibrillation is still almost unknown. In the present work, the use of water-soluble thiacalix[4]arene derivatives for the inhibition of hen egg-white lysozyme (HEWL) amyloid fibrillation is proposed for the first time. The binding of HEWL by the synthesized thiacalix[4]arenes (logKa = 5.05-5.13, 1:1 stoichiometry) leads to the formation of stable supramolecular systems capable of stabilizing the protein structure and protecting against fibrillation by 29-45%. The macrocycle conformation has little effect on protein binding strength, and the native HEWL secondary structure does not change via interaction. The synthesized compounds are non-toxic to the A549 cell line in the range of 0.5-250 µg/mL. The results obtained may be useful for further investigation of the anti-amyloidogenic role of thiacalix[4]arenes, and also open up future prospects for the creation of new ways to prevent neurodegenerative diseases.

Cholinesterase inhibitors are a group of medicines that are widely used for the treatment of cognitive impairments accompanying Alzheimer's disease as well as for the treatment of pathological muscle weaknesses syndromes such as myasthenia gravis. The search for novel non-toxic and effective cholinesterase inhibitors for creating neuroprotective and neurotransmitter agents is an urgent interdisciplinary problem. For the first time, the application of water-soluble pillar[5]arenes containing amino acid residues as effective cholinesterase inhibitors was shown. The influence of the nature of aliphatic and aromatic alpha-amino acid residues (glycine, l-alanine, l-phenylalanine and l-tryptophan) on self-assembly, aggregate's stability, cytotoxicity on A549 and LEK cells and cholinesterase inhibition was studied. It was found that the studied compounds with aliphatic amino acid residues showed a low inhibitory ability against cholinesterases. It was established that the pillar[5]arene containing fragments of l-phenylalanine is the most promising inhibitor of butyrylcholinesterase (IC 50  = 0.32 ± 0.01 μM), the pillar[5]arene with l-tryptophan residues is the most promising inhibitor of acetylcholinesterase (IC 50  = 0.32 ± 0.01 μM). This study has shown a possible application of peptidomimetics based on pillar[5]arenes to inhibit cholinesterase, as well as control the binding affinity to a particular enzyme in a structure-dependent manner., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Herbicides are one of the main parts of pesticides used today. Due to the high efficiency and widespread use of glyphosate-based herbicides, the search for substances reducing their genotoxicity is an important interdisciplinary task. One possible approach for solving the problem of herbicide toxicity is to use compounds that can protect DNA from damage by glyphosate derivatives. For the first time, a method for developing DNA-protecting measures against glyphosate isopropylamine salt (GIS) damage was presented and realized, based on low-toxicity water-soluble pillar[5]arene derivatives. Two- and three-component systems based on pillar[5]arene derivatives, GIS, and model DNA from salmon sperm, as well as their cytotoxicity, were studied. The synthesized pillar[5]arene derivatives do not interact with GIS, while GIS is able to bind DNA from salmon sperm with lgKa = 4.92. The pillar[5]arene betaine derivative containing fragments of L-phenylalanine and the ester derivative with diglycine fragments bind DNA with lgKa = 5.24 and lgKa = 4.88, respectively. The study of the associates (pillar[5]arene-DNA) with GIS showed that the interaction of GIS with DNA is inhibited only by the betaine pillar[5]arene containing fragments of L-Phe (lgKa = 3.60). This study has shown a possible application of betaine pillar[5]arene derivatives for nucleic acid protection according to its competitive binding with biomacromolecules.

Sensitive systems with controlled release of drugs or diagnostic markers are attractive for solving the problems of biomedicine and antitumor therapy. In this study, new decasubstituted pillar[5]arene derivatives containing L -Tryptophan and L -Phenylalanine residues have been synthesized as pH-responsive drug nanocarriers. Fluorescein dye ( Fluo ) was loaded into the pillar[5]arene associates and used as a spectroscopic probe to evaluate the release in buffered solutions with pH 4.5, 7.4, and 9.2. The nature of the substituents in the pillar[5]arene structure has a huge influence on the rate of delivering. When the dye was loaded into the associates based on pillar[5]arene derivatives containing L -Tryptophan, the Fluo release occurs in the neutral (pH = 7.4) and alkaline (pH = 9.2) buffered solutions. When the dye was loaded into the associates based on pillar[5]arene with L -Phenylalanine fragments, the absence of release was observed in every pH evaluated. This happens as the result of different packing of the dye in the structure of the associate. This fact was confirmed by different fluorescence mechanisms (aggregation-caused quenching and aggregation-induced emission) and association constants. It was shown that the macrocycle with L -Phenylalanine fragments binds the dye more efficiently (lgK a = 3.92). The experimental results indicate that the pillar[5]arene derivatives with amino acids fragments have a high potential to be used as a pH-responsive drug delivery devices, especially for promoting the intracellular delivering, due to its nanometric size.

Novel monosubstituted pillar[5]arenes with one or two terminal carboxyl groups were synthesized by the reaction of succinic anhydride with pillar[5]arene derivative containing a diethylenetriamine function. The ability for non-covalent self-assembly in chloroform, dimethyl sulfoxide, as well as in tetrahydrofuran-water system was studied. The ability of the synthesized macrocycles to form different types of associates depending on the substituent nature was established. The formation of stable particles with average diameter of 192 nm in chloroform and of 439 nm in DMSO was shown for pillar[5]arene containing two carboxyl fragments. Solid lipid nanoparticles (SLN) based on monosubstituted pillar[5]arenes were synthesized by nanoprecipitation in THF-water system. Minor changes in the structure of the macrocycle substituent can dramatically influence the stability and shape of SLN (spherical and rod-like structures) accordingly to DLS and TEM. The presence of two carboxyl groups in the macrocycle substituent leads to the formation of stable spherical SLN with an average hydrodynamic diameter of 364-454 nm. Rod-like structures are formed by pillar[5]arene containing one carboxyl fragment, which diameter is about of 50-80 nm and length of 700-1000 nm. The synthesized stable SLN open up great prospects for their use as drug storage systems.

Novel monosubstituted pillar[5]arenes containing both amide and carboxyl functional groups were synthesized. Solid lipid nanoparticles based on the synthesized macrocycles were obtained. Formation of spherical particles with an average hydrodynamic diameter of 250 nm was shown for pillar[5]arenes containing N-(amidoalkyl)amide fragments regardless of their concentration. It was established that pillar[5]arene containing N-alkylamide fragments can form spherical particles with two different sizes (88 and 223 nm) depending on its concentration. Mixed solid lipid nanoparticles based on monosubstituted pillar[5]arenes and surfactant (dodecyltrimethylammonium chloride) were obtained for the first time. The surfactant made it possible to level the effect of the macrocycle concentration. It was found that various types of aggregates are formed depending on the macrocycle/surfactant ratio. Changing the macrocycle/surfactant ratio allows to control the charge of the particles surface. This controlled property will lead to the creation of molecular-scale porous materials that selectively interact with various types of substrates, including biopolymers.

In this paper, we report the development of the novel self-assembling systems based on oppositely charged Pillar[5]arenes and surfactants for encapsulation of diagnostic dye DAPI. For this purpose, the aggregation behavior of synthesized macrocycles and surfactants in the presence of Pillar[5]arenes functionalized by carboxy and ammonium terminal groups was studied. It has been demonstrated that by varying the molar ratio in Pillar[5]arene-surfactant systems, it is possible to obtain various types of supramolecular systems: host-guest complexes at equimolar ratio of Pillar[5]arene-surfactant and interpolyelectrolyte complexes (IPECs) are self-assembled materials formed in aqueous medium by two oppositely charged polyelectrolytes (macrocycle and surfactant micelles). It has been suggested that interaction of Pillar[5]arenes with surfactants is predominantly driven by cooperative electrostatic interactions. Synthesized stoichiometric and non-stoichiometric IPECs specifically interact with DAPI. UV-vis, luminescent spectroscopy and molecular docking data show the structural feature of dye-loaded IPEC and key role of the electrostatic, π-π-stacking, cation-π interactions in their formation. Such a strategy for the design of supramolecular Pillar[5]arene-surfactant systems will lead to a synergistic interaction of the two components and will allow specific interaction with the third component (drug or fluorescent tag), which will certainly be in demand in pharmaceuticals and biomedical diagnostics.

Novel water-soluble multifunctional pillar[ 5 ]arenes containing amide-ammonium-amino acid moiety were synthesized. The compounds demonstrated a superior ability to bind (1S)-(+)-10-camphorsulfonic acid ( S -CSA) and methyl orange dye depending on the nature of the substituent, resulting in the formation one-to-one complexes with both guests. The formation of host-guest complexes was confirmed by ultraviolet (UV), circular dichroism (CD) and 1 H NMR spectroscopy. This work demonstrates the first case of using S -CSA as a chiral template for the non-covalent self-assembly of architectures based on pillar[5]arenes. It was shown that pillar[ 5 ]arenes with glycine or L-alanine fragments formed aggregates with average hydrodynamic diameters (d) of 165 and 238 nm, respectively. It was established that the addition of S -CSA to the L-alanine-containing derivative led to the formation of micron-sized aggregates with d of 713 nm. This study may advance the design novel stereoselective catalysts and transmembrane amino acid channels.