High-Throughput Method for the Simultaneous Determination of Doxorubicin Metabolites in Rat Urine after Treatment with Different Drug Nanoformulations.

Doxorubicin (DOX) is one of the most effective cytotoxic agents against malignant diseases. However, the clinical application of DOX is limited, due to dose-related toxicity. The development of DOX nanoformulations that significantly reduce its toxicity and affect the metabolic pathway of the drug requires improved methods for the quantitative determination of DOX metabolites with high specificity and sensitivity. This study aimed to develop a high-throughput method based on high-performance liquid chromatography with fluorescence detection (HPLC-FD) for the quantification of DOX and its metabolites in the urine of laboratory animals after treatment with different DOX nanoformulations. The developed method was validated by examining its specificity and selectivity, linearity, accuracy, precision, limit of detection, and limit of quantification. The DOX and its metabolites, doxorubicinol (DOXol) and doxorubicinone (DOXon), were successfully separated and quantified using idarubicin (IDA) as an internal standard (IS). The linearity was obtained over a concentration range of 0.05-1.6 µg/mL. The lowest limit of detection and limit of quantitation were obtained for DOXon at 5.0 ng/mL and 15.0 ng/mL, respectively. For each level of quality control (QC) samples, the inter- and intra-assay precision was less than 5%. The accuracy was in the range of 95.08-104.69%, indicating acceptable accuracy and precision of the developed method. The method was applied to the quantitative determination of DOX and its metabolites in the urine of rats treated by novel nanoformulated poly(lactic-co-glycolic acid) (DOX-PLGA), and compared with a commercially available DOX solution for injection (DOX-IN) and liposomal-DOX (DOX-MY).

Functional self-assembled nanovesicles based on ß-cyclodextrin, liposomes and adamantyl guanidines as potential nonviral gene delivery vectors.

Multicomponent self-assembled supramolecular nanovesicles based on an amphiphilic derivative of ß-cyclodextrin and phosphatidylcholine liposomes (PC-liposomes) functionalized with four structurally different adamantyl guanidines were prepared and characterized. Incorporation efficiency of the examined adamantyl guanidines as well as size and surface charge of the prepared supramolecular nanovesicles was determined. Changes in the surface charge of the prepared nanovesicles confirmed that guanidinium groups were exposed on the surface. ITC and 1H NMR spectroscopy complemented by molecular dynamics (MD) simulations were used to elucidate the structural data and stability of the inclusion complexes of ß-cyclodextrin and adamantyl guanidines (AG1-5). The results are consistent and point to a significant contribution of the guanylhydrazone residue to the complexation process for AG1 and AG2 with ß-cyclodextrin. In order to evaluate the potential of the self-assembled supramolecular nanomaterial as a nonviral gene delivery vector, fluorescence correlation spectroscopy was used. It showed that the prepared nanovesicles functionalized with adamantyl guanidines AG1-4 effectively recognize and bind the fluorescently labelled DNA. Furthermore, gel electrophoretic assay confirmed the formation of nanoplexes of functionalized nanovesicles and plasmid DNA. These findings together suggest that the designed supramolecular nanovesicles could be successfully applied as nonviral gene delivery vectors.

Neutral glycoconjugated amide-based calix[4]arenes: complexation of alkali metal cations in water.

Cation complexation in water presents a unique challenge in calixarene chemistry, mostly due to the fact that a vast majority of calixarene-based cation receptors is not soluble in water or their solubility has been achieved by introducing functionalities capable of (de)protonation. Such an approach inevitably involves the presence of counterions which compete with target cations for the calixarene binding site, and also rather often requires the use of ion-containing buffer solutions in order to control the pH. Herein we devised a new strategy towards the solution of this problem, based on introducing carbohydrate units at the lower or upper rim of calix[4]arenes which comprise efficient cation binding sites. In this context, we prepared neutral, water-soluble receptors with secondary or tertiary amide coordinating groups, and studied their complexation with alkali metal cations in aqueous and methanol (for the comparison purpose) solutions. Complexation thermodynamics was quantitatively characterized by UV spectrometry and isothermal titration calorimetry, revealing that one of the prepared tertiary amide derivatives is capable of remarkably efficient (log K ≈ 5) and selective binding of sodium cations among alkali metal cations in water. Given the ease of the synthetic procedure used, and thus the variety of accessible analogues, this study can serve as a platform for the development of reagents for diverse purposes in aqueous media.

Dehydroacetic Acid Derivatives Bearing Amide or Urea Moieties as Effective Anion Receptors.

Derivatives of dehydroacetic acid comprising amide or urea subunits have been synthesized and their anion-binding properties investigated. Among a series of halides and oxyanions, the studied compounds selectively bind acetate and dihydrogen phosphate in acetonitrile and dimethyl sulfoxide. The corresponding complexation processes were characterized by means of 1 H NMR titrations, which revealed a 1:1 complex stoichiometry in most cases, with the exception of dihydrogen phosphate, which formed 2:1 (anion/ligand) complexes in acetonitrile. The complex stability constants were determined and are discussed with respect to the structural properties of the receptors, the hydrogen-bond-forming potential of the anions, and the characteristics of the solvents used. Based on the spectroscopic data and results of Monte Carlo simulations, the amide or urea groups were affirmed as the primary binding sites in all cases. The results of the computational methods indicate that an array of both inter- and intramolecular hydrogen bonds can form in the studied systems, and these were shown to play an important role in defining the overall stability of the complexes. Solubility measurements were carried out in both solvents and the thermodynamics of transfer from acetonitrile to dimethyl sulfoxide were characterized on a quantitative level. This has afforded a detailed insight into the impact of the medium on the complexation reactions.

A comprehensive study of the complexation of alkali metal cations by lower rim calix[4]arene amide derivatives.

The complexation of alkali metal cations by lower rim N,N-dihexylacetamide (L1) and newly synthesized N-hexyl-N-methylacetamide (L2) calix[4]arene tertiary-amide derivatives was thoroughly studied at 25 °C in acetonitrile (MeCN), benzonitrile (PhCN), and methanol (MeOH) by means of direct and competitive microcalorimetric titrations, and UV and 1H NMR spectroscopies. In addition, by measuring the ligands' solubilities, the solution (transfer) Gibbs energies of the ligands and their alkali metal complexes were obtained. The inclusion of solvent molecules in the free and complexed calixarene hydrophobic cavities was also investigated. Computational (classical molecular dynamics) investigations of the studied systems were also carried out. The obtained results were compared with those previously obtained by studying the complexation ability of an N-hexylacetamidecalix[4]arene secondary-amide derivative (L3). The stability constants of 1 : 1 complexes were determined in all solvents used (the values obtained by different methods being in excellent agreement), as were the corresponding complexation enthalpies and entropies. Almost all of the examined reactions were enthalpically controlled. The most striking exceptions were reactions of Li+ with both ligands in methanol, for which the entropic contribution to the reaction Gibbs energy was substantial due the entropically favourable desolvation of the smallest lithium cation. The thermodynamic stabilities of the complexes were quite solvent dependent (the stability decreased in the solvent order: MeCN > PhCN ≫ MeOH), which could be accounted for by considering the differences in the solvation of the ligand and free and complexed alkali metal cations in the solvents used. Comparison of the stability constants of the ligand L1 and L2 complexes clearly revealed that the higher electron-donating ability of the hexyl with respect to the methyl group is of considerable importance in determining the equilibria of the complexation reactions. Additionally, the quite strong influence of intramolecular hydrogen bond formation in compound L3 (not present in ligands L1 and L2) and that of the inclusion of solvent molecules in the calixarene hydrophobic cone were shown to be of great importance in determining the thermodynamic stability of the calixarene-cation complexes. The experimental results were fully supported by those obtained by MD simulations.

Adamantane in Drug Delivery Systems and Surface Recognition.

The adamantane moiety is widely applied in design and synthesis of new drug delivery systems and in surface recognition studies. This review focuses on liposomes, cyclodextrins, and dendrimers based on or incorporating adamantane derivatives. Our recent concept of adamantane as an anchor in the lipid bilayer of liposomes has promising applications in the field of targeted drug delivery and surface recognition. The results reported here encourage the development of novel adamantane-based structures and self-assembled supramolecular systems for basic chemical investigations as well as for biomedical application.

Thermodynamic study of dihydrogen phosphate dimerisation and complexation with novel urea- and thiourea-based receptors.

Complexation of dihydrogen phosphate by novel thiourea and urea receptors in acetonitrile and dimethyl sulfoxide was studied in detail by an integrated approach by using several methods (isothermal titration calorimetry, ESI-MS, and (1)H NMR and UV spectroscopy). Thermodynamic investigations into H2PO4(-) dimerisation, which is a process that has been frequently recognised, but rarely quantitatively described, were carried out as well. The corresponding equilibrium was taken into account in the anion-binding studies, which enabled reliable determination of the complexation thermodynamic quantities. In both solvents the thiourea derivatives exhibited considerably higher binding affinities with respect to those containing the urea moiety. In acetonitrile, 1:1 and 2:1 (anion/receptor) complexes formed, whereas in dimethyl sulfoxide only the significantly less stable complexes of 1:1 stoichiometry were detected. The solvent effects on the thermodynamic parameters of dihydrogen phosphate dimerisation and complexation reactions are discussed.

Surface modified liposomes by mannosylated conjugates anchored via the adamantyl moiety in the lipid bilayer.

The aim of the present study was to encapsulate mannosylated 1-aminoadamantane and mannosylated adamantyltripeptides, namely [(2R)-N-(adamant-1-yl)-3-(α,ß-d-mannopyranosyloxy)-2-methylpropanamide and (2R)-N-[3-(α-d-mannopyranosyloxy)-2-methylpropanoyl]-d,l-(adamant-2-yl)glycyl-l-alanyl-d-isoglutamine] in liposomes. The characterization of liposomes, size and surface morphology was performed using dynamic light scattering (DLS) and atomic force microscopy (AFM). The results have revealed that the encapsulation of examined compounds changes the size and surface of liposomes. After the concanavalin A (ConA) was added to the liposome preparation, increase in liposome size and their aggregation has been observed. The enlargement of liposomes was ascribed to the specific binding of the ConA to the mannose present on the surface of the prepared liposomes. Thus, it has been shown that the adamantyl moiety from mannosylated 1-aminoadamantane and mannosylated adamantyltripeptides can be used as an anchor in the lipid bilayer for carbohydrate moiety exposed on the liposome surface.

The effect of specific solvent-solute interactions on complexation of alkali-metal cations by a lower-rim calix[4]arene amide derivative.

Complexation of alkali-metal cations with calix[4]arene secondary-amide derivative, 5,11,17,23-tetra(tert-butyl)-25,26,27,28-tetra(N-hexylcarbamoylmethoxy)calix[4]arene (L), in benzonitrile (PhCN) and methanol (MeOH) was studied by means of microcalorimetry, UV and NMR spectroscopies, and in the solid state by X-ray crystallography. The inclusion of solvent molecules (including acetonitrile, MeCN) in the calixarene hydrophobic cavity was also investigated. The classical molecular dynamics (MD) simulations of the systems studied were carried out. By combining the results obtained using the mentioned experimental and computational techniques, an attempt was made to get an as detailed insight into the complexation reactions as possible. The thermodynamic parameters, that is, equilibrium constants, reaction Gibbs energies, enthalpies, and entropies, of the investigated processes were determined and discussed. The stability constants of the 1:1 (metal:ligand) complexes measured by different methods were in very good agreement. Solution Gibbs energies of the ligand and its complexes with Na(+) and K(+) in methanol and acetonitrile were determined. It was established that from the thermodynamic point of view, apart from cation solvation, the most important reason for the huge difference in the stability of these complexes in the two solvents lay in the fact that the transfer of complex species from MeOH to MeCN was quite favorable. That could be at least partly explained by a more exergonic inclusion of the solvent molecule in the complexed calixarene cone in MeCN as compared to MeOH, which was supported by MD simulations. Molecular and crystal structures of the lithium cation complex of L with the benzonitrile molecule bound in the hydrophobic calixarene cavity were determined by single-crystal X-ray diffraction. As far as we are aware, for the first time the alkali-metal cation was found to be coordinated by the solvent nitrile group in a calixarene adduct. According to the results of MD simulations, the probability of such orientation of the benzonitrile molecule included in the ligand cone was by far the largest in the case of LiL(+) complex. Because of the favorable PhCN-Li(+) interaction, L was proven to have the highest affinity toward the lithium ion in benzonitrile, which was not the case in the other solvents examined (in acetonitrile, sodium complex was the most stable, whereas in methanol, complexation of lithium was not even observed). That could serve as a remarkable example showing the importance of specific solvent-solute interactions in determining the equilibrium in solution.

An Integrated approach (thermodynamic, structural, and computational) to the study of complexation of alkali-metal cations by a lower-rim calix[4]arene amide derivative in acetonitrile.

The calix[4]arene secondary-amide derivative L was synthesized, and its complexation with alkali-metal cations in acetonitrile (MeCN) was studied by means of spectrophotometric, NMR, conductometric, and microcalorimetric titrations at 25 °C. The stability constants of the 1:1 (metal/ligand) complexes determined by different methods were in excellent agreement. For the complexation of M(+) (M = Li, Na, K) with L, both enthalpic and entropic contributions were favorable, with their values and mutual relations being quite strongly dependent on the cation. The enthalpic and overall stability was the largest in the case of the sodium complex. Molecular and crystal structures of free L, its methanol and MeCN solvates, the sodium complex, and its MeCN solvate were determined by single-crystal X-ray diffraction. The inclusion of a MeCN molecule in the calixarene hydrophobic cavity was observed both in solution and in the solid state. This specific interaction was found to be stronger in the case of metal complexes compared to the free ligand because of the better preorganization of the hydrophobic cone to accept the solvent molecule. Density functional theory calculations showed that the flattened cone conformation (C(2) point group) of L was generally more favorable than the square cone conformation (C(4) point group). In the complex with Na(+), L was in square cone conformation, whereas in its adduct with MeCN, the conformation was slightly distorted from the full symmetry. These conformations were in agreement with those observed in the solid state. The classical molecular dynamics simulations indicated that the MeCN molecule enters the L hydrophobic cavity of both the free ligand and its alkali-metal complexes. The inclusion of MeCN in the cone of free L was accompanied by the conformational change from C(2) to C(4) symmetry. As in solution studies, in the case of ML(+) complexes, an allosteric effect was observed: the ligand was already in the appropriate square cone conformation to bind the solvent molecule, allowing it to more easily and faster enter the calixarene cavity.

Gamma Radiation- and Ultraviolet-Induced Polymerization of Bis(amino acid)fumaramide Gel Assemblies.

Controlling the polymerization of supramolecular self-assembly through external stimuli holds great potential for the development of responsive soft materials and manipulation at the nanoscale. Vinyl esters of bis(leu or val)fumaramide (1a and 2a) have been found to be gelators of various organic solvents and were applied in this investigation of the influence of organogelators' self-assembly on solid-state polymerization induced by gamma and ultraviolet irradiation. Here, we report our investigation into the influences of self-assemblies of bis(amino acid vinyl ester)fumaramides on gamma-ray- and ultraviolet-induced polymerization. The gelator molecules self-assembled by non-covalent interactions, mainly through hydrogen bonds between the amide group (CONH) and the carboxyl group (COO), thus forming a gel network. NMR and FTIR spectroscopy were used to investigate and characterize supramolecular gels. TEM and SEM microscopy were used to investigate the morphology of gels and polymers. Morphology studies showed that the gels contained a filamentous structure of nanometer dimensions that was exhaustive in a three-dimensional network. The prepared derivatives contained reactive alkyl groups suitable for carrying out the polymerization reaction initiated by gamma or ultraviolet radiation in the supramolecular aggregates of selected gels. It was found that the polymerization reaction occurred only in the network of the gel and was dependent on the structure of aggregates or the proximity and orientation of double bonds in the gel network. Polymers were formed by the gels exposure to gamma and ultraviolet radiation in toluene, and water/DMF gels with transcripts of their gel structure into polymers. The polymeric material was able to immobilize various solvents by swelling. Furthermore, methyl esters of bis(leu and val)fumaramide (1b and 2b) were synthesized; these compounds showed no gelling properties, and the crystal structure of the valine derivative 2b was determined.

Lipidation of NOD2 Agonists with Adamantane and Stearoyl Moieties Differentially Regulates Their In Vivo Adjuvant Activity.

NOD2 is an innate immune receptor that constitutes an important target for the development of small molecule immunopotentiators with great potential to be used as vaccine adjuvants. We report here the results of an in vivo study of the adjuvant properties of a desmuramylpeptide NOD2 agonist SG29 and its lipidated analogs featuring an adamantyl moiety or a stearoyl group. These compounds have been synthesized, incorporated into liposomes, and evaluated for their in vivo adjuvant activity. The characterization of liposome formulations of examined compounds revealed that their size increased in comparison to that of empty liposomes. The introduction of a stearoyl or an adamantane lipophilic anchor into the structure of SG29, to produce SG115 and ZSB63, respectively, substantially improved the in vivo adjuvant activity. Of note, the attachment of the stearoyl moiety produced a Th2-biased immune response, while the incorporation of the adamantyl moiety greatly enhanced the production of total IgG but mostly augmented the production of IgG2a antibodies, which indicated a shift toward a Th1 immune response. The identified bona fide capacity of ZSB63 to initiate a cellular immune response thus highlights its untapped potential as an alternative vaccine adjuvant.

Positionally isomeric organic gelators: structure-gelation study, racemic versus enantiomeric gelators, and solvation effects.

Low molecular weight gelator molecules consisting of aliphatic acid, amino acid (phenylglycine), and omega-aminoaliphatic acid units have been designed. By varying the number of methylene units in the aliphatic and omega-aminoaliphatic acid chains, as defined by descriptors m and n, respectively, a series of positionally isomeric gelators having different positions of the peptidic hydrogen-bonding unit within the gelator molecule has been obtained. The gelation properties of the positional isomers have been determined in relation to a defined set of twenty solvents of different structure and polarity and analyzed in terms of gelator versatility (G(ver)) and effectiveness (G(eff)). The results of gelation tests have shown that simple synthetic optimizations of a "lead gelator molecule" by variation of m and n, end-group polarity (carboxylic acid versus sodium carboxylate), and stereochemistry (racemate versus optically pure form) allowed the identification of gelators with tremendously improved versatility (G(ver)) and effectiveness (G(eff)). Dramatic differences in G(eff) values of up to 70 times could be observed between pure racemate/enantiomer pairs of some gelators, which were manifested even in the gelation of very similar solvents such as isomeric xylenes. The combined results of spectroscopic ((1)H NMR, FTIR), electron microscopy (TEM), and X-ray diffraction studies suggest similar organization of the positionally isomeric gelators at the molecular level, comprising parallel beta-sheet hydrogen-bonded primary assemblies that form inversed bilayers at a higher organizational level. Differential scanning calorimetry (DSC) studies of selected enantiomer/racemate gelator pairs and their o- and p-xylene gels revealed the simultaneous presence of different polymorphs in the racemate gels. The increased gelation effectiveness of the racemate compared to that of the single enantiomer is most likely a consequence of its spontaneous resolution into enantiomeric bilayers and their subsequent organization into polymorphic aggregates of different energy. The latter determine the gel fiber thickness and solvent immobilization capacity of the formed gel network.

(R,S)-3-Carb-oxy-2-(isoquinolinium-2-yl)propanoate monohydrate.

The title compound, C(13)H(11)NO(4)·H(2)O, is a monohydrate of a betaine exhibiting a positively charged N-substituted isoquino-line group and a deprotonated carboxyl group. In the crystal, mol-ecules are connected via short O-H⋯O hydrogen bonds between protonated and deprotonated carboxyl groups into chains of either R or S enanti-omers along [001]. These chains are additionally connected by hydrogen bonding between water mol-ecules and the deprotonated carb-oxy groups of neighbouring mol-ecules.

Oxalyl retro-peptide gelators. Synthesis, gelation properties and stereochemical effects.

In this work we report on gelation properties, self-assembly motifs, chirality effects and morphological characteristics of gels formed by chiral retro-dipeptidic gelators in the form of terminal diacids (1a-5a) and their dimethyl ester (1b-5b) and dicarboxamide (1c-5c) derivatives. Terminal free acid retro-dipeptides (S,S)-bis(LeuLeu) 1a, (S,S)-bis(PhgPhg) 3a and (S,S)-bis(PhePhe) 5a showed moderate to excellent gelation of highly polar water/DMSO and water/DMF solvent mixtures. Retro-peptides incorporating different amino acids (S,S)-(LeuPhg) 2a and (S,S)-(PhgLeu) 4a showed no or very weak gelation. Different gelation effectiveness was found for racemic and single enantiomer gelators. The heterochiral (S,R)-1c diastereoisomer is capable of immobilizing up to 10 and 4 times larger volumes of dichloromethane/DMSO and toluene/DMSO solvent mixtures compared to homochiral (S,S)-1c. Based on the results of (1)H NMR, FTIR, CD investigations, molecular modeling and XRPD studies of diasteroisomeric diesters (S,S)-1b/(S,R)-1b and diacids (S,S)-1b/(S,R)-1a, a basic packing model in their gel aggregates is proposed. The intermolecular hydrogen bonding between extended gelator molecules utilizing both, the oxalamide and peptidic units and layered organization were identified as the most likely motifs appearing in the gel aggregates. Molecular modeling studies of (S,S)-1a/(S,R)-1a and (S,S)-1b/(S,R)-1b diasteroisomeric pairs revealed a decisive stereochemical influence yielding distinctly different low energy conformations: those of (S,R)-diastereoisomers with lipophilic i-Bu groups and polar carboxylic acid or ester groups located on the opposite sides of the oxalamide plane resembling bola amphiphilic structures and those of (S,S)-diasteroisomers possessing the same groups located at both sides of the oxalamide plane. Such conformational characteristics were found to strongly influence both, gelator effectiveness and morphological characteristics of gel aggregates.

Supramolecular ionogels prepared with bis(amino alcohol)oxamides as gelators: ionic transport and mechanical properties.

Supramolecular ionogels composed of an ionic liquid (IL) immobilized in a network of self-assembled low-molecular weight molecules have been attracting considerable interest due to their applicability as smart electrolytes for various electrochemical applications. Despite considerable scientific effort in this field, the design of a mechanically and thermally stable yet highly conductive supramolecular ionogels still remains a challenge. In this article, we report on a series of novel ionogels of three ILs containing different cations (imidazolium/pyrrolidinium) and anions (tetrafluoroborate/bis(trifluoromethylsulfonyl)imide) prepared using (S,S)-bis(amino alcohol)oxamides as gelators. The gelation behaviour of the oxamide compound depends strongly on the structural features of amino alcohol substituents. Among them, (S,S)-bis(valinol)oxamide (capable of gelling all three ILs) and (S,S)-bis(phenylalaninol)oxamide (capable of gelling ILs based on bis(trifluoromethylsulfonyl)imide with a concentration as low as ≈0.2 wt%) are highly efficient. All investigated supramolecular ionogels retain the high ionic conductivity and ion diffusion coefficients of their parent IL, even for high gelator concentrations. Further, at low temperatures we observe an enhancement of the ionic conductivity in ionogels of (i) 1-butyl-3-methylimidazolium tetrafluoroborate which can be attributed to specific interactions between ionic species and gelator molecules and (ii) 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide due to inhibited crystallization. In contrast to ionic transport, mechanical strength of the ionogels shows a wider variation depending on the type and concentration of the oxamide gelator. Among all the ionogels, that of 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide prepared with 1 wt% (S,S)-bis(phenylalaninol)oxamide exhibits the best performance: optical transparency, stability over a wide temperature range, high conductivity and high mechanical strength. The results presented here reveal the versatile nature of bis(amino alcohol)oxamides as gelators and their high potential for preparing functionalized IL-based materials.

Correction: Supramolecular ionogels prepared with bis(amino alcohol)oxamides as gelators: ionic transport and mechanical properties.

[This corrects the article DOI: 10.1039/D0RA01249A.].

The Metal Effect on Self-Assembling of Oxalamide Gelators Explored by Mass Spectrometry and DFT Calculations.

Gels formed by self-assembly of small organic molecules are of wide interest as dynamic soft materials with numerous possible applications, especially in terms of nanotechnology for functional and responsive biomaterials, biosensors, and nanowires. Four bis-oxalamides were chosen to show if electrospray ionization mass spectrometry (ESI-MS) could be used as a prediction of a good gelator and also to shed light on the gelation processes. By inspecting the gelation of several solvent, we showed that bis(amino acid)oxalamide 1 proved to be the most efficient, also being able of forming the largest observable assemblies in the gas phase. The formation of singly charged assemblies holding from one up to six monomer units is the outcome of the strong intermolecular H-bonds, particularly among terminal carboxyl groups. The variation of solvents from polar aprotic towards polar protic did not have any significant effects on the size of the assemblies. The addition of a salt such as NaOAc or Mg(OAc)2, depending on the concentration, altered the assembling. Computational analysis at the DFT level aided in the interpretation of the observed trends and revealed that individual gelator molecules spontaneously assemble to higher aggregates, but the presence of the Na+ cation disrupts any gelator organization since it becomes significantly more favorable for gelator molecules to bind Na+ cations up to the 3:1 ratio than to self-assemble, being fully in line with experimental observations reported here. Graphical Abstract ᅟ.

Antitumor potential of crown ethers: structure-activity relationships, cell cycle disturbances, and cell death studies of a series of ionophores.

The present paper demonstrates the antiproliferative ability and structure-activity relationships (SAR) of 14 crown and aza-crown ether analogues on five tumor-cell types. The most active compounds were di-tert-butyldicyclohexano-18-crown-6 (3), which exhibited cytotoxicity in the submicromolar range, and di-tert-butyldibenzo-18-crown-6 (5) (IC50 values of approximately 2 microM). Also, 3 and 5 induced marked influence on the cell cycle phase distribution--strong G1 arrest, followed by the induction of apoptosis. A computational SAR modeling effort offers insight into possible mechanisms of crown ether biological activity, presumably involving penetration into cell membranes, and points out structural features of molecules important for this activity. The results reveal that crown ethers possess marked tumor-cell growth inhibitory activity, the extent of which depends on the characteristics of the hydrophilic macrocylic cavity and the surrounding hydrophobic ring. Our work supports the hypothesis that crown ether compounds inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis.

Solvation Effect on Complexation of Alkali Metal Cations by a Calix[4]arene Ketone Derivative.

The medium effect on the complexation of alkali metal cations with a calix[4]arene ketone derivative (L) was systematically examined in methanol, ethanol, N-methylformamide, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile. In all solvents the binding of Na+ cation by L was rather efficient, whereas the complexation of other alkali metal cations was observed only in methanol and acetonitrile. Complexation reactions were enthalpically controlled, while ligand dissolution was endothermic in all cases. A notable influence of the solvent on NaL+ complex stability could be mainly attributed to the differences in complexation entropies. The higher NaL+ stability in comparison to complexes with other alkali metal cations in acetonitrile was predominantly due to a more favorable complexation enthalpy. The 1H NMR investigations revealed a relatively low affinity of the calixarene sodium complex for inclusion of the solvent molecule in the calixarene hydrophobic cavity, with the exception of acetonitrile. Differences in complex stabilities in the explored solvents, apart from N,N-dimethylformamide and acetonitrile, could be mostly explained by taking into account solely the cation and complex solvation. A considerable solvent effect on the complexation equilibria was proven to be due to an interesting interplay between the transfer enthalpies and entropies of the reactants and the complexes formed.