New Carboxytriazolyl Amphiphilic Derivatives of Calix[4]arenes: Aggregation and Use in CuAAC Catalysis.

This work focuses on the synthesis of a new series of amphiphilic derivatives of calix[4]arenes for the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The aggregation properties of synthesized calix[4]arenes were studied using various techniques (fluorescence spectroscopy, nanoparticle tracking analysis, and dynamic light scattering). Increasing the length of the alkyl substituent led to stronger hydrophobic interactions, which increased polydispersity in solution. The zwitterionic nature of the synthesized calix[4]arenes was established using different types of dyes (Eosin Y for anionic structures and Rhodamine 6G for cationic structures). The synthesized calix[4]arenes were used as organic stabilizers for CuI. The catalytic efficiency of CuI-calix[4]arene was compared with that of the phase transfer catalyst tetrabutylammonium bromide (TBAB) and the surfactant sodium dodecyl sulfate (SDS). For all calixarenes, the selectivity in the CuAAC reaction was higher than that observed when TBAB and SDS were estimated.

Aggregation, Cytotoxicity and DNA Binding in a Series of Calix[4]arene Amphiphile Containing Aminotriazole Groups.

The present work focuses on the study of the aggregation and complexing properties of calixarenes as potential DNA condensation agents for gene delivery. In the current study, 1,4-triazole derivatives of calix[4]arenes 7 and 8 containing monoammonium fragments were synthesized. The synthesized compound's structure was characterized by using various spectroscopic techniques (FTIR, HRESI MS, ¹H NMR and ¹³C NMR). The interactions between a series of calix[4]arene-containing aminotriazole groups (triazole-containing macrocycles with diethylenetriammonium fragments (3 and 4) and triazole-containing macrocycles with monoammonium fragments (7 and 8)) and calf thymus DNA were carried out via UV absorption, fluorescence spectroscopy, dynamic light scattering and zeta potential measurements. The role of the binding forces of calixarene-DNA complexes was analyzed. Photophysical and morphological studies revealed the interaction of the calixarenes 3, 4 and 8 with ct-DNA, which transformed the fibrous structure of ct-DNA to completely condensed compact structures that are 50 nm in diameter. The cytotoxic properties of calixarenes 3, 4, 7 and 8 against cancerous cells (MCF7, PC-3) as well as a healthy cell line (HSF) were investigated. Compound 4 was found to have the highest toxic effect on MCF7 breast adenocarcinoma (IC50 3.3 µM).

New Supramolecular Hypoxia-Sensitive Complexes Based on Azo-Thiacalixarene.

Hypoxia accompanies many human diseases and is an indicator of tumor aggressiveness. Therefore, measuring hypoxia in vivo is clinically important. Recently, complexes of calix[4]arene were identified as potent hypoxia markers. The subject of this paper is new hypoxia-sensitive host-guest complexes of thiacalix[4]arene. We report a new high-yield synthesis method for thiacalix[4]arene with four anionic carboxyl azo fragments on the upper rim (thiacalixarene L) and an assessment of the complexes of thiacalixarene L with the most widespread cationic rhodamine dyes (6G, B, and 123) sensitivity to hypoxia. Moreover, 1D and 2D NMR spectroscopy data support the ability of the macrocycles to form complexes with dyes. Rhodamines B and 123 formed host-guest complexes of 1:1 stoichiometry. Complexes of mixed composition were formed with rhodamine 6G. The association constant between thiacalixarene L and rhodamine 6G is higher than for other dyes. Thiacalixarene L-dye complexes with rhodamine 6G and rhodamine B are stable in the presence of various substances present in a biological environment. The UV-VIS spectrometry and fluorescence showed hypoxia responsiveness of the complexes. Our results demonstrate that thiacalixarene L has a stronger binding with dyes compared with the previously reported azo-calix[4]arene carboxylic derivative. Thus, these results suggest higher selective visualization of hypoxia for the complexes with thiacalixarene L.

Calix[4]arene Polyamine Triazoles: Synthesis, Aggregation and DNA Binding.

Artificial gene delivery systems are in great demand from both scientific and practical biomedical points of view. In this paper, we present the synthesis of a new click chemistry calix[4]arene precursor with free lower rim and new water-soluble calixarene triazoles with 12 amino-groups on the upper rim (one with free phenol hydroxyl groups and two another containing four butyl or tetradecyl fragments). Aggregation in the series of amino-triazole calixarenes of different lipophilicity (calixarene with free phenol hydroxyl groups or butyl and tetradecyl fragments on the lower rim) was studied using dynamic light scattering and fluorescent pyrene probe. It was found that calix[4]arene with a free lower rim, like alkyl-substituted butyl calix[4]arene, forms stable submicron aggregates 150-200 nm in size, while the more lipophilic tetradecyl -substituted calix[4]arene forms micellar aggregates19 nm in size. Using UV-Vis spectroscopy, fluorimetry and CD, it was shown that amino-triazole calix[4]arenes bind to calf thymus DNA by classical intercalation. According to DLS and TEM data, all studied macrocycles cause significant DNA compaction, forming stable nanoparticles 50-20 nm in size. Among all studied calix[4]arenes the most lipophilic tetradecyl one proved to be the best for both binding and compaction of DNA.

Novel PEPPSI-Type NHC Pd(II) Metallosurfactants on the Base of 1H-Imidazole-4,5-dicarboxylic Acid: Synthesis and Catalysis in Water-Organic Media.

Carrying out organic reactions in water has attracted much attention. Catalytic reactions in water with metallosurfactants, which have both a metallocenter and the surface activity necessary for solubilizing hydrophobic reagents, are of great demand. Herein we proposed new approach to the synthesis of NHC PEPPSI metallosurfactants based on the sequential functionalization of imidazole 4,5-dicarboxylic acid with hydrophilic oligoethylene glycol and lipophilic alkyl fragments. Complexes of different lipophilicity were obtained, and their catalytic activity was studied in model reduction and Suzuki-Miyaura reactions. A comparison was made with the commercial PEPPSI-type catalytic systems designed by Organ. It was found that the reduction reaction in an aqueous solution of the metallosurfactant with the tetradecyl lipophilic fragment was three times more active than the commercially available PEPPSI complexes, which was associated with the formation of stable monodisperse aggregates detected by DLS and TEM.

New Calix[4]arene-Fluoresceine Conjugate by Click Approach-Synthesis and Preparation of Photocatalytically Active Solid Lipid Nanoparticles.

New fluorescent systems for photocatalysis, sensors, labeling, etc., are in great demand. Amphiphilic ones are of special interest since they can form functional colloidal systems that can be used in aqueous solutions. A new macrocycle platform for click chemistry and its adduct with o-propargylfluoresceine was synthesized and characterized using modern physical techniques. Nanosized solid lipid nanoparticles (SLNs) from the calixarene-fluoresceine adduct were synthesized through the solvent injection technique and well-characterized in the solution and in solid state using light-scattering and microscopy methods. The maximum fluorescence intensity of the SLNs was found to be in the pH range from 7 to 10. The Förster resonance energy transfer (FRET) efficiency from SLNs to rhodamine 6g was found to be 97.8%. Finally, pure SLNs and the FRET system SLNs-Rh6G were tested in model photocatalytic ipso oxidative hydroxylation of phenylboronic acid under blue LED light. The SLNs-Rh6G system was found to be the best, giving an almost qualitative phenol yield, which was shown by HPLC-UV analysis.

Oxyethylated Fluoresceine-(thia)calix[4]arene Conjugates: Synthesis and Visible-Light Photoredox Catalysis in Water-Organic Media.

Fluorescent derivatives attract the attention of researchers for their use as sensors, photocatalysts and for the creation of functional materials. In order to create amphiphilic fluorescent derivatives of calixarenes, a fluorescein derivative containing oligoethylene glycol and propargyl groups was obtained. The resulting fluorescein derivative was introduced into three different (thia)calix[4]arene azide derivatives. For all synthesized compounds, the luminescence quantum yields have been established in different solvents. Using UV-visible spectroscopy, dynamic light scattering, as well as transmission and confocal microscopy, aggregation of macrocycles was studied. It was evaluated that calixarene derivatives with alkyl substituents form spherical aggregates, while symmetrical tetrafluorescein-containing thiacalix[4]arene forms extended worm-like aggregates. The macrocycle containing tetradecyl fragments was found to be the most efficient in photoredox ipso-oxidation of phenylboronic acid. In addition, it was shown that in a number of different electron donors (NEt3, DABCO and iPr2EtN), the photoredox ipso-oxidation proceeds best with triethylamine. It has been shown that a low molecular weight surfactant Triton-X100 can also improve the photocatalytic abilities of an oligoethylene glycol fluorescein derivative, thus showing the importance of a combination of micellar and photoredox catalysis.

NHC Polymeric Particles Obtained by Self-Assembly and Click Approach of Calix[4]Arene Amphiphiles as Support for Catalytically Active Pd Nanoclusters.

A new polymeric NHC carrier was synthesized by sequential supramolecular self-assembly and copper-catalyzed azide-alkyne cycloaddition (CuAAC) of amphiphilic imidazolium calix[4]arenes with octyl lipophilic fragments. Obtained polytriazole-imidazolium particles were found as monodisperse submicron particles, with the average diameter of 236 ± 34 nm and average molecular weight of 1380 ± 96 kDa. Successful CuAAC polymerization has been proved using IR spectroscopy and high-resolution ESI mass spectrometry. Polymeric particles, as well as aggregates made from precursor macrocycles, were decorated by Pd clusters (2 nm) for further catalytic investigations. Pd nanoclusters, supported on the polymeric surface, were found highly catalytically active in the model reduction of p-nitrophenol, giving reaction rates an order of magnitude higher compared to literature examples. The reaction was recycled using the same catalyst five times without any loss of activity.

Single Excited Dual Band Luminescent Hybrid Carbon Dots-Terbium Chelate Nanothermometer.

The report introduces hybrid polyelectrolyte-stabilized colloids combining blue and green-emitting building blocks, which are citrate carbon dots (CDs) and [TbL]+ chelate complexes with 1,3-diketonate derivatives of calix[4]arene. The joint incorporation of green and blue-emitting blocks into the polysodium polystyrenesulfonate (PSS) aggregates is carried out through the solvent-exchange synthetic technique. The coordinative binding between Tb3+ centers and CD surface groups in initial DMF solutions both facilitates joint incorporation of [TbL]+ complexes and the CDs into the PSS-based nanobeads and affects fluorescence properties of [TbL]+ complexes and CDs, as well as their ability for temperature sensing. The variation of the synthetic conditions is represented herein as a tool for tuning the fluorescent response of the blue and green-emitting blocks upon heating and cooling. The revealed regularities enable developing either dual-band luminescent colloids for monitoring temperature changes within 25-50 °C through double color emission or transforming the colloids into ratiometric temperature sensors via simple concentration variation of [TbL]+ and CDs in the initial DMF solution. Novel hybrid carbon dots-terbium chelate PSS-based nanoplatform opens an avenue for a new generation of sensitive and customizable single excited dual-band nanothermometers.

Azocalix[4]arene-Rhodamine Supramolecular Hypoxia-Sensitive Systems: A Search for the Best Calixarene Hosts and Rhodamine Guests.

A potential hypoxia-sensitive system host-guest complex of three calixarenes (including two with four anionic carboxyl and sulphonate azo fragments on the upper rim and a newly synthesized bis-azo adduct of calixarene in the cone configuration with azo fragments on the lower rim with the most widespread cationic and zwitterionic rhodamine dyes (123, 6G and B)) was studied using UV-VIS spectrometry and fluorescence as well as 1D and 2D NMR techniques. It was found that all three calixarenes form a complex with rhodamine dyes with a 1:1 composition. The association constants of calixarene-dye complexes with sulfonate calixarenes, especially in the case of tetra-anionic calixarene, turned out to be higher compared with carboxyl calixarene due to the more intense electrostatic interactions. For the first time using an HRESI MS technique, it was shown that the treatment of rhodamine 6G and 123 with sodium dithionite (SDT) produces a non-fluorescent leuco form of the dye, and only rhodamine B can be used with SDT without the occurrence of a side reduction. Moreover, it was identified that in addition to the reduction in the azo groups, SDT causes partial cleavage of the aryl ether bonds. The found features of SDT should be taken into account when SDT is used as an azoreductase mimic.

Prediction of Optimal Conditions of Hydrogenation Reaction Using the Likelihood Ranking Approach.

The selection of experimental conditions leading to a reasonable yield is an important and essential element for the automated development of a synthesis plan and the subsequent synthesis of the target compound. The classical QSPR approach, requiring one-to-one correspondence between chemical structure and a target property, can be used for optimal reaction conditions prediction only on a limited scale when only one condition component (e.g., catalyst or solvent) is considered. However, a particular reaction can proceed under several different conditions. In this paper, we describe the Likelihood Ranking Model representing an artificial neural network that outputs a list of different conditions ranked according to their suitability to a given chemical transformation. Benchmarking calculations demonstrated that our model outperformed some popular approaches to the theoretical assessment of reaction conditions, such as k Nearest Neighbors, and a recurrent artificial neural network performance prediction of condition components (reagents, solvents, catalysts, and temperature). The ability of the Likelihood Ranking model trained on a hydrogenation reactions dataset, (~42,000 reactions) from Reaxys® database, to propose conditions that led to the desired product was validated experimentally on a set of three reactions with rich selectivity issues.

New Amphiphilic Imidazolium/Benzimidazolium Calix[4]arene Derivatives: Synthesis, Aggregation Behavior and Decoration of DPPC Vesicles for Suzuki Coupling in Aqueous Media.

In this study, new types of amphiphilic calix[4]arene derivatives bearing N-alkyl/aryl imidazolium/benzimidazolium fragments were designed and synthesized by two step transformation: Regioselective Blanc chloromethylation of distal-di-O-butyl calix[4]arene and subsequent interaction with N-Substituted imidazole/benzimidazole. Critical aggregation concentration (CAC) values were estimated using pyrene fluorescent probe. Obtained macrocycles were found to form submicron particles with electrokinetic potential +44-+57 mV in aqueous solution. For the first time it was found that amphiphilic calixarene causes the fast transformation of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) multilamellar vesicles into unilamellar ones and leads to the ordering of the lipid in membranes at the molar calixarene/DPPC ratio more than 0.07. In situ complexes of calixarene aggregates with Pd(OAc)2 were found to be active in Suzuki-Miyaura coupling of 1-bromo-4-nitrobenzene with phenylboronic acid in water. It was shown that bulky N-substituents of heterocycle decrease the catalytic activity of the aggregates. These result can be assigned to the inhibition effect of Pd(II) complex in situ formation by bulky substituents located on the aggregate surface. Embedding of the most active palladium N-heterocyclic carbene (NHC) complex with methylimidazolium headgroups into DPPC vesicles enhances its catalytic activity in Suzuki-Miyaura coupling.

New poly-imidazolium-triazole particles by CuAAC cross-linking of calix[4]arene bis-azide/alkyne amphiphiles - a prospective support for Pd in the Mizoroki-Heck reaction.

A new imidazolium amphiphilic calix[4]arene with terminal acetylene fragments in the polar region was synthesized according to a two step scheme including regioselective chloromethylation of distal di-O-butyl calix[4]arene and subsequent interaction with 1-(hex-5-yn-1-yl)-1H-imidazole. The aggregation properties (CAC, the size and zeta potential of aggregates) of alkynyl calix[4]arene as well as of previously synthesized azidopropyl calix[4]arene and their 1 : 1 mixture were disclosed. Macrocycles with azide and alkyne fragments in the polar region were covalently cross-linked under CuAAC conditions in water. Successful cross-linking of molecules has been proven by IR spectroscopy and MALDI-TOF spectrometry. The obtained polymeric particles were studied both in solution and the solid state and the presence of submicron (∼200 nm) and micron (∼1-5 µm) particles with the prevalence of the latter was found. The average molecular weight of the polymer according to the static light scattering data was found to be 639 ± 44 kDa. The obtained polymeric imidazolium-triazole particles were tested as a support for Pd(OAc)2 in the Mizoroki-Heck reaction carried out in both organic and water media. In both solvents (especially in water) the addition of imidazolium-triazole particles to Pd(OAc)2 increased the conversion of 4-iodanisole. It was found that the ratio between the products (1,1 and 1,2-substituted ethylenes) changes drastically on going from DMF to water from 1 : 5 to 1 : 40 when using supported Pd(OAc)2.

Synthesis of new p-tert-butylcalix[4]arene-based polyammonium triazolyl amphiphiles and their binding with nucleoside phosphates.

The synthesis of new calix[4]arenes adopting a cone stereoisomeric form bearing two or four azide fragments on the upper rim and water-soluble triazolyl amphiphilic receptors with two or four polyammonium headgroups via copper-catalyzed azide-alkyne cycloaddition reaction has been performed for the first time. It was found that the synthesized macrocycles form stable aggregates with hydrodynamic diameters between 150-200 nm and electrokinetic potentials about +40 to +60 mV in water solutions. Critical aggregation concentration (CAC) values were measured using a micelle method with pyrene and eosin Y as dye probes. The CAC values of tetraalkyl-substituted macrocycles 12a,b (5 µM for both) are significantly lower than those for dialkyl-substituted macrocycles 10a,b (790 and 160 µM, respectively). Premicellar aggregates of macrocycles 10a,b and 12a,b with the dye eosin Y were used for nucleotides sensing through a dye replacement procedure. It is unusual that disubstituted macrocycles 10a,b bind more effectively a less charged adenosine 5'-diphosphate (ADP) than adenosine 5'-triphosphate (ATP). A simple colorimetric method based on polydiacetylene vesicles decorated with 10b was elaborated for the naked-eye detection of ADP with a detection limit of 0.5 mM.

New NIR-emissive tetranuclear Er(III) complexes with 4-hydroxo-2,1,3-benzothiadiazolate and dibenzoylmethanide ligands: synthesis and characterization.

New tetranuclear heteroleptic complexes [Er4(dbm)6(O-btd)4(OH)2] (1) and [Er4(dbm)4(O-btd)6(OH)2] (2) (O-btd = 4-hydroxo-2,1,3-benzothiadiazolate and dbm = dibenzoylmethanide) and their solvates with toluene, THF and CH2Cl2 were prepared using two synthetic approaches. The structures of the products were confirmed by single-crystal X-ray diffraction. Magnetic properties of 1 and 2 are in good agreement with X-ray data. The effective magnetic moment (µeff) values at 300 K for 1 and 2 corresponds to a system of 4 non-interacting Er(III) ions in the ground state 4J15/2 with g = 6/5. At ambient temperature and upon excitation with λexc = 450 nm, complexes 1 and 2 exhibit luminescence at 1530 nm, i.e. in the near infra-red (NIR) region. The luminescence intensity grows with increasing the number of the (O-btd)− ligands in the complexes. This observation suggests (O-btd)− as a new efficient antenna ligand for the lanthanide-based NIR luminescence.

Complex formation of d-metal ions at the interface of Tb(III)-doped silica nanoparticles as a basis of substrate-responsive Tb(III)-centered luminescence.

The complex formation of d-metal ions at the interface of Tb(III)-doped silica nanoparticles modified by amino groups is introduced as a route to sensing d-metal ions and some organic molecules. Diverse modes of surface modification (covalent and noncovalent) are used to fix amino groups onto the silica surface. The interfacial binding of d-metal ions and complexes is the reason for the Tb(III)-centered luminescence quenching. The regularities and mechanisms of quenching are estimated for the series of d-metal ions and their complexes with chelating ligands. The obtained results reveal the interfacial binding of Cu(II) ions as the basis of their quantitative determination in the concentration range 0.1-2.5 µM by means of steady-state and time-resolved fluorescence measurements. The variation of chelating ligands results in a significant effect on the quenching regularities due to diverse binding modes (inner or outer sphere) between amino groups at the interface of nanoparticles and Fe(III) ions. The applicability of the steady-state and time-resolved fluorescence measurements to sense both Fe(III) ions and catechols in aqueous solution by means of Tb(III)-doped silica nanoparticles is also introduced.

The discrimination between phospholipids of diverse structure and phosphacoumarins of various hydrophobicity through fluorescent response of Tb-doped silica nanoparticles decorated by cationic surfactant.

The work represents colloids of silica nanoparticles displaying fluorescent response on biorelevant compounds exemplified by phosphacoumarins and phospholipids. The luminescent properties of the colloids arise from Tb(III) complexes doped into silica nanoparticles (SNs). The noncovalent decoration of SNs by dicationic surfactant with further interfacial binding of dye anions enables to develop colloids programmed to display a substrate induced fluorescent response. The latter results from the quenching of Tb(III) centered luminescence by dye anions through dynamic mechanism and subsequent displacement of quenching anions by the non-quenching substrates from the interface of SNs. Both negative charge and hydrophobicity of substrates are the key factors affecting the selectivity of the substrate induced fluorescent response. The peculiar effects of zwitter-ionic and anionic phospholipids on the fluorescent response have been revealed. The applicability of the fluorescent procedure in the sensing of impurities in commercial phosphatidylcholine is also introduced.

The interfacial interactions of Tb-doped silica nanoparticles with surfactants and phospholipids revealed through the fluorescent response.

The quenching effect of dyes (phenol red and bromothymol blue) on Tb(III)-centered luminescence enables to sense the aggregation of cationic and anionic surfactants near the silica surface of Tb-doped silica nanoparticles (SN) in aqueous solutions. The Tb-centered luminescence of non-decorated SNs is diminished by the inner filter effect of both dyes. The decoration of the silica surface by cationic surfactants induces the quenching through the energy transfer between silica coated Tb(III) complexes and dye anions inserted into surfactant aggregates. Thus the distribution of surfactants aggregates at the silica/water interface and in the bulk of solution greatly affects dynamic quenching efficiency. The displacement of dye anions from the interfacial surfactant adlayer by anionic surfactants and phospholipids is accompanied by the "off-on" switching of Tb(III)-centered luminescence.

Temperature induced phase separation of luminescent silica nanoparticles in Triton X-100 solutions.

The aggregation and cloud point behavior of Tb(III)-doped silica nanoparticles has been studied in Triton X-100 (TX-100) solutions at various concentration conditions by fluorimetry, dynamic light scattering, electrophoresis and transmission electron microscopy methods. The temperature responsive behavior of nanoparticles is observed at definite concentration of TX-100, where the aggregation of TX-100 at the silica/water interface is evident from the increased size of the silica nanoparticles. The reversible dehydration of TX-100 aggregates at the silica/water interface should be assumed as the main reason of the temperature induced phase separation of silica nanoparticles. The distribution of nanoparticles between aqueous and surfactant rich phases at the phase separation conditions can be modified by the effect of additives.