Structure–Activity Relationship of the Thiacalix[4]arenes Family with Sulfobetaine Fragments: Self-Assembly and Cytotoxic Effect against Cancer Cell Lines

Regulating the structure of macrocyclic host molecules and supramolecular assemblies is crucial because the structure–activity relationship often plays a role in governing the properties of these systems. Herein, we propose and develop an approach to the synthesis of the family of sulfobetaine functionalized thiacalix[4]arenes with regulation of the self-assembly and cytotoxic effect against cancer cell lines. The dynamic light scattering method showed that the synthesized macrocycles in cone, partial cone and 1,3-alternate conformations form submicron-sized particles with Ag+ in water, but the particle size and polydispersity of the systems studied depend on the macrocycle conformation. Based on the results obtained by 1H and 1H-1H NOESY NMR spectroscopy and transmission electron microscopy for the macrocycles and their aggregates with Ag+, a coordination scheme for the Ag+ and different conformations of p-tert-butylthiacalix[4]arene functionalized with sulfobetaine fragments was proposed. The type of coordination determines the different shapes of the associates. Cytotoxic properties are shown to be controlled by the shape of associates, with the highest activity demonstrated by thiacalix[4]arenes in partial cone conformation. This complex partial cone/Ag+ is two times higher than the reference drug imatinib mesylate. High selectivity against cervical carcinoma cell line indicates the prospect of their using as components of new anticancer system

Surfactant Effect on the Physicochemical Characteristics of Solid Lipid Nanoparticles Based on Pillar[5]arenes

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

Structure–Activity Relationship of the Thiacalix[4]arenes Family with Sulfobetaine Fragments: Self-Assembly and Cytotoxic Effect against Cancer Cell Lines

Regulating the structure of macrocyclic host molecules and supramolecular assemblies is crucial because the structure–activity relationship often plays a role in governing the properties of these systems. Herein, we propose and develop an approach to the synthesis of the family of sulfobetaine functionalized thiacalix[4]arenes with regulation of the self-assembly and cytotoxic effect against cancer cell lines. The dynamic light scattering method showed that the synthesized macrocycles in cone, partial cone and 1,3-alternate conformations form submicron-sized particles with Ag+ in water, but the particle size and polydispersity of the systems studied depend on the macrocycle conformation. Based on the results obtained by 1H and 1H-1H NOESY NMR spectroscopy and transmission electron microscopy for the macrocycles and their aggregates with Ag+, a coordination scheme for the Ag+ and different conformations of p-tert-butylthiacalix[4]arene functionalized with sulfobetaine fragments was proposed. The type of coordination determines the different shapes of the associates. Cytotoxic properties are shown to be controlled by the shape of associates, with the highest activity demonstrated by thiacalix[4]arenes in partial cone conformation. This complex partial cone/Ag+ is two times higher than the reference drug imatinib mesylate. High selectivity against cervical carcinoma cell line indicates the prospect of their using as components of new anticancer system

Albumin/Thiacalix[4]arene Nanoparticles as Potential Therapeutic Systems: Role of the Macrocycle for Stabilization of Monomeric Protein and Self-Assembly with Ciprofloxacin

The therapeutic application of serum albumin is determined by the relative content of the monomeric form compared to dimers, tetramers, hexamers, etc. In this paper, we propose and develop an approach to synthesize the cone stereoisomer of p-tert-butylthiacalix[4]arene with sulfobetaine fragments stabilization of monomeric bovine serum albumin and preventing aggregation. Spectral methods (UV-vis, CD, fluorescent spectroscopy, and dynamic light scattering) established the influence of the synthesized compounds on the content of monomeric and aggregated forms of BSA even without the formation of stable thiacalixarene/protein associates. The effect of thiacalixarenes on the efficiency of protein binding with the antibiotic ciprofloxacin was shown by fluorescence spectroscopy. The binding constant increases in the presence of the macrocycles, likely due to the stabilization of monomeric forms of BSA. Our study clearly shows the potential of this macrocycle design as a platform for the development of the fundamentally new approaches for preventing aggregation

Unusually High Efficiency of β‑Cyclodextrin Clathrate Preparation by Water-Free Solid-Phase Guest Exchange

An effective preparation procedure is offered for β-cyclodextrin (bCD) clathrates with volatile guests of moderate hydrophilicity, which otherwise require a finely tuned optimization of the bCD/water/guest ratio. The proposed procedure includes guest exchange in a water-free bCD matrix. As a result, more stable clathrates with a higher inclusion capacity can be prepared than by direct saturation of dried or hydrated bCD. To find an optimal preparation method, the structure–property relationships were studied for four different ways of bCD clathrate formation with guests of varying molecular structure. The study was much simplified by used procedures excluding direct contact of guest and water liquids with bCD. Besides, in clathrate preparation experiments, the thermodynamic activities of water and guest were varied independently, which makes explicit the role of water in this process. Hydration of bCD reduces its inclusion threshold for hydrophobic guests by their activity (relative vapor pressure), giving favorable hydration effect for their inclusion. Besides, water competes with hydrophilic guests for binding sites in bCD at high water activities. Together with bCD dehydration by excess of hydrophilic guests, these observations give a complete thermodynamic picture, which may be fruitful for elaboration of guest encapsulation techniques by cyclodextrins

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

Decasubstituted Pillar[5]arene Derivatives Containing <i>L</i>-Tryptophan and <i>L</i>-Phenylalanine Residues: Non-Covalent Binding and Release of Fluorescein from Nanoparticles

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 (lgKa = 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