Search

The supramolecular palladium complex G-Pd, formed via self-assembly of the Pd-complex of guanidinium pillar[5]arene with Pd 2+ , was used to encapsulate doxorubicin to form G-Pd@DOX. The nanoparticles exhibit responsiveness to glutathione, controlled drug release, the ability to damage mitochondria, and potent anticancer activity while maintaining low toxicity towards normal cells. This work provides a good example for the application of pillararene-based palladium complexes in cancer therapy and is significant for the discovery of new medicines from supramolecular coordination complexes.

Cholesterol (CHO) is an essential constituent of human cellular tissues and a crucial activity indicator for the clinical diagnosis and prevention of various diseases. Abnormal CHO levels can lead to various cardiovascular diseases, including coronary heart disease, cerebral thrombosis, and atherosclerosis. Thus, developing simple and effective methods for CHO detection is of great significance. Herein, a novel calix[6]arene-modified photonic hydrogel biosensor (PAAH@SCX6) was developed for naked-eye monitoring of CHO based on supramolecular host-guest interactions between 4-sulfocalix[6]arene (SCX6) and CHO molecules. This sensor was constructed by embedding Fe 3 O 4 colloidal nanocrystal cluster chains into a poly(acrylamide- co -acrylic acid) smart hydrogel (PAAH), followed by incorporation of plentiful SCX6 units into the PAAH via hydrogen bonding interactions. The specific recognition of SCX6 to CHO leads to the volume expansion of the hydrogel, causing a shift in the photonic band gap and a change in the hydrogel's structural color. The sensor demonstrated a linear detection range of 2.83-5.20 mM, covering the typical CHO levels in the human body. Importantly, the PAAH@SCX6 biosensor showed high selectivity and satisfactory stability, making it highly suitable for practical applications. Such a photonic hydrogel-based biosensor provides a convenient, simple, and efficient strategy for visual CHO detection.

Herein, the presented results show that previously studied DNA/RNA-interacting bis-imidazole-calix[4]arene systems can, in aqueous solutions, efficiently bind a series of biorelevant transition metal cations by coordination with the two imidazole arms at the small rim of their macrocyclic basket. The SCXRD and NMR results structurally characterised the complexes formed by referent bis-imidazole-calix[4]arene with Cu 2+ and Zn 2+ . In solid-state (crystal), the bis-anilino derivative/Cu 2+ complex, only upon exposure to the air, undergoes intramolecular dehydrogenative coupling of two neighbouring aniline units, yielding an azo bridge at the large rim of the calix[4]arene basket. In the biorelevant aqueous solution, the comparison of fluorometric titrations of referent calix[4]arene, with its analogues having one or two pyrene units grafted at the opposite (large) rim, revealed moderate-to-strong affinity towards transition metal cations, and, more importantly, a strong impact of pyrene on the binding affinity towards some cations. The pyrene arm(s) significantly diminished the affinity of the calix[4]arene-imidazole ligand towards Cu + and strongly increased the affinity towards divalent Co 2+ and Cd 2+ cations. Moreover, the fluorometric response of some studied derivatives was strappingly sensitive to cation type. Since the counter-anion plays only a marginal role, such a change in selectivity is attributed to the intramolecular interaction of pyrene(s) with the calix[4]arene-imidazole system, sterically controlling the metal cation binding site.

Acurate and sensitive determination of hazards from food contact materials is important to monitor food safety. It is necessary to excavate efficient adsorbent for simultaneous recognition and adsorption of food hazards of trace level for sample preparation. In this work, β-cyclodextrin and calix[4]arene were employed as hybrid functional monomers to prepare macrocyclic porous organic polymer (β-CD-CX4 POP). It was proved that the supramolecular cavities of β-CD-CX4 POP could form inclusion complexes with fluorescent whitening agents (FWAs) through host-guest recognition, which greatly improved the adsorption performance. The hydrophobic cavities of β-cyclodextrin and calix[4]arene of β-CD-CX4 POP exhibited synergistic effect for simultaneous recognition of FWAs. The high-throughput enrichment of FWAs was realized by β-CD-CX4 POP membranes coupled with a multiple-channel syringe pump. Based on membrane-based solid-phase extraction combined with UHPLC-MS/MS, a sensitive analytical method was established to determine six FWAs. The LODs was in range of 3-50 ng/L with the linear range of 0.02-100 μg/L. The developed method was used to quantify FWAs in bread wrapper and bread, and the spiked recoveries ranged from 78.1%-119% with RSD of 2.3%-9.7%. This work indicated that β-CD-CX4 POP was promising for the simultaneous recognition and adsorption of FWAs migrating from food contact materials., 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 © 2024. Published by Elsevier B.V.)

Many active pharmaceutical ingredients have a specific bitter taste. To enhance patient compliance and treatment efficacy, taste-masking agents are crucial in oral drug formulations. Confronting numerous bitter drug molecules with varied structures, the pharmaceutical field strives to explore and develop universal and effective masking approaches. Here, we reported sulfonated azocalix[4]arene (SAC4A), a universal supramolecular masking agent with deep cavity that provides stronger hydrophobic effect and larger interaction area during recognition, allowing high binding affinity to bitter drug molecules. Moreover, bitter drugs could deeply buried in the cavity, with the bitterness effectively masked. As a result, SAC4A can bind to 16 different bitter drugs with high affinities, encompassing alkaloids, flavonoids, terpenoids, and more, while maintaining high biocompatibility. As anticipated, SAC4A effectively masks the unpalatable bitter taste associated with these drugs. Consequently, SAC4A is a promising universal and effective supramolecular masking agent.

Taspase 1 is a unique protease not only pivotal for embryonic development but also implicated in leukemias and solid tumors. As such, this enzyme is a promising while still challenging therapeutic target, and with its protein structure featuring a flexible loop preceding the active site a versatile model system for drug development. Supramolecular ligands provide a promising complementary approach to traditional small-molecule inhibitors. Recently, the multivalent arrangement of molecular tweezers allowed the successful targeting of Taspase 1's surface loop. With this study we now want to take the next logic step und utilize functional linker systems that not only allow the implementation of novel properties but also engage in protein surface binding. Consequently, we chose two different linker types differing from the original divalent assembly: a backbone with aggregation-induced emission (AIE) properties to enable monitoring of binding and a calix[4]arene scaffold initially pre-positioning the supramolecular binding units. With a series of four AIE-equipped ligands with stepwise increased valency we demonstrated that the functionalized AIE linkers approach ligand binding affinities in the nanomolar range and allow efficient proteolytic inhibition of Taspase 1. Moreover, implementation of the calix[4]arene backbone further enhanced the ligands' inhibitory potential, pointing to a specific linker contribution., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

A new calix[4]triazacrown-5-derived fluorescence chemosensor (AntUr-AzClx) at cone conformation was synthesized to afford an effective fluorescent probe, which enables an enhancement in the fluorescence intensity specifically in the presence of Co 2+ metal ions as well as a turnoff response for hazardous dichromate anions. 1 H-NMR, 13 C-NMR, ESI-MS, and elemental analysis techniques were used to characterize the structure of the anthracene-appended calix[4]triazacrown-5 (AntUr-AzClx). The metal ion-binding ability of AntUr-AzClx was evaluated against Co 2+ , Ba 2+ , Ni 2+ , Pb 2+ , and Zn 2+ ions. On the basis of various metal ion recognition phenomena, AntUr-AzClx exhibited outstanding selectivity for only the Co 2+ ion among other metal ions. Also, the calix[4]triazacrown-5-derived fluorescence chemosensor showed high sensitivity towards the Co 2+ ion with a very low limit of detection (LOD) 0.142 μmol L -1 . In addition, anion binding abilities of AntUr-AzClx against various anions such Cr 2 O 7 2- , HCO 3 - , CO 3 2- , NO 3 - , SO 3 2- , SO 4 2- , N 3 - , F - , and I - demonstrated that AntUr-AzClx enables selective and highly sensitive detection of the Cr 2 O 7 2- anion with an excellent LOD of 4.182 nmol L -1 in DMF/PBS (1/1, v/v; pH: 7.05). Furthermore, the calix[4]triazacrown-5-derived fluorescence chemosensor displayed a significant sensing behavior to detect the presence of dichromate anions even in real samples., (© 2024 John Wiley & Sons Ltd.)

Organophosphate (OP) intoxication has become a severe common health matter all over the world. For the treatment of acute OP poisoning, the effective intracerebral delivery of acetylcholinesterase reactivators is crucial. Here, an amphiphilic hydrazide-pillar[5]arene (HP5A-6C), which could be readily integrated into liposomal bilayers' zwitterionic disaturated phosphatidylcholine (DSPC), was synthesized. A T7 peptide-containing guest (G) was attached on the surface via a noncovalent interaction to make mixed liposomes a particularly appealing candidate for brain-targeting delivery. Such coassembly could remain stable at room temperature for up to 6 weeks, and safety evaluations initially verified its fine biological compatibility. The hydrophilic interiors of T7/HP5A-6C@DSPC could further load HI-6 with 89.70% encapsulation efficiency. Support for brain-targeting potency came from imaging results. Notably, intravenous injection of HI-6-loaded vesicles exhibited a remarkable therapeutic effect on paraoxon (POX)-poisoned mice, effectively alleviating seizures and brain damage and significantly increasing the improving survival rate to 60% over the course of 7 days.

C -tetra(4-methoxyphenyl)calix[4]resorcinarene was synthesized by hydrochloric acid-catalysed cyclocondensation of resorcinol and 4-methoxybenzaldehyde. Under these conditions, the reaction produces a conformational mixture of crown and chair structural conformers, which were separated and characterized by chromatographic and spectroscopic techniques. The antioxidant activity of both conformers was measured by using the DPPH assay, through which it was observed that the chair conformer showed greater antioxidant activity (IC 50 = 47.46 ppm) than the crown conformer (IC 50 = 78.46 ppm). Additionally, it was observed that the mixture of both conformers presented lower antioxidant activity than either conformer in isolation. The results found suggest that the chair conformer has efficient antioxidant activity that makes it a potential target for further research.

Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N -methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 10 6 M -1 , which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10 -7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.

Calix[n]arenes, macrocycles constituted of 4-8 phenol moieties linked through methylene bridges, are stable molecules that can be selectively functionalised at the upper or lower rim. It has already been demonstrated that calixarene derivatives can be biologically or pharmacologically active compounds. More recently, suitably functionalised calixarenes and calixarene analogues (dihomooxacalixarenes, thiacalixarenes, calix[4]resorcinols, azacalixarenes, calixpyrroles, and pillarenes) were found to act as anticancer agents, at least in in vitro assays. We are reporting on the latest progress in this research field.

Polyamines are essential analytes due to their critical role in various biological processes and human health in general. Due to their role as regulators for cell growth and proliferation (putrescine and spermine), as neuroprotectors, gero-, and cardiovascular protectors (spermidine), and as bacterial growth indicators (cadaverine), rapid, simple, and cost-effective methods for polyamine detection in biofluids are in demand. The present study focuses on the development and investigation of self-assembled and fluorescent host⋅dye chemo-sensors based on sulfonated pillar[5]arene for the specific detection of polyamines. Binding studies, as well as stability and functionality assessments of the turn-on chemosensors for selective polyamine detection in saline and biologically relevant media, are shown. Furthermore, the practical applicability of the developed chemo-sensors is demonstrated in biofluids such as human urine and saliva., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Natural gap junctions are a type of channel protein responsible for intercellular signalling and mass communication. However, the scope of applications for these proteins is limited as they cannot be prepared at a large scale and are unable to spontaneously insert into cell membranes in vitro. The construction of artificial gap junctions may provide an alternative strategy for preparing analogues of the natural proteins and bottom-up building blocks necessary for the synthesis of artificial cells. Here we show the construction of artificial gap junction channels from unimolecular tubular molecules consisting of alternately arranged positively and negatively charged pillar[5]arene motifs. These molecules feature a hydrophobic-hydrophilic-hydrophobic triblock structure that allows them to efficiently insert into two adjacent plasma membranes and stretch across the gap between the two membranes to form gap junctions. Similar to natural gap junction channels, the synthetic channels could mediate intercellular signal coupling and reactive oxygen species transmission, leading to cellular activity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

A new antibacterial system (HG) based on the host-guest chemistry between pillar[5]arene and a zwitterionic guest was fabricated. The HG complex displayed excellent antibacterial and biofilm formation inhibition and dispersal activities against E. coli , S. aureus and MRSA.

Chemotherapy is one of the most employed strategies in clinical treatment of cancer. However, reducing medication adverse effects and improving the biological activity remains a significant issue for chemotherapy. We developed a pH and Ca 2+ -responsive pillar[5]arene-based supramolecular nanodrug delivery system (NDDS) WP5⊃EV@DOX to address the aforementioned challenges. The formation of this NDDS began with the spontaneous formation of supramolecular nanodrug carrier WP5⊃EV in water from PEG-modified pillar[5]arene and the bipyridilium salt derivative EV through simple host-guest interaction. Then the antitumor drug doxorubicin DOX was efficiently loaded with a high encapsulation rate of 84.6 %. Cytotoxicity results indicated that the constructed nanoplatform not only reduced DOX toxicity and side effects on normal cell (293T), but also significantly enhanced the antitumor activity on cancer cell (HepG2). Moreover, in vivo experiments showed that WP5⊃EV@DOX had a longer half-life and higher bioavailability in the blood of mice compared to the nake drug DOX, with increases to 212 % and 179 %, respectively. Therefore, WP5⊃EV@DOX has great potential in tumor therapy and provides a new idea for host-guest drug delivery system., (© 2024 Wiley-VCH GmbH.)

Stimuli-responsive supramolecular chemotherapy, particularly in response to cancer biomarkers, has emerged as a promising strategy to overcome the limitations associated with traditional chemotherapy. Spermine (SPM) is known to be overexpressed in certain cancers. In this study, we introduced a novel supramolecular chemotherapy system triggered by SPM. The system featured pyridine salts of a diphenylanthracene derivative (PyEn) and a complementary water-soluble pillar[5]arene (WP5C5) with long alkyl chains. The diphenylanthracene unit of PyEn is effectively encapsulated within the long alkyl chains of WP5C5, resulting in a substantial reduction in the cytotoxicity of PyEn towards normal cells. The therapeutic effect of PyEn is selectively triggered intracellularly through SPM, leading to the endosomal release of PyEn and concurrent in situ cytotoxicity. This supramolecular chemotherapy system exhibits notable tumor inhibition against SPM-overexpressed cancers with reduced side effects on normal tissues. The supramolecular strategy for intracellular activation provides a novel tool with potential applications in chemotherapeutic interventions, offering enhanced selectivity and reduced cytotoxicity to normal cells.

An extraction chromatography resin, prepared by the impregnation of bis-octyloxy-calix[4]arene-mono-crown-6 (BOCMC)onto an acrylic ester based polymeric support material, gave excellent uptake data for the removal of radio-cesium (Cs-137) from nitric acid feed solutions. The weight distribution coefficient (K d ) value of >300 obtained during the present study at 3 M HNO 3 was the highest reported so far while using a calix-crown-6 based extraction chromatographic resin material. Analogous resin reported previously has yielded a K d value <100 at comparable feed conditions. The sorbed metal ions could be efficiently desorbed with de-ionized water. Kinetic modeling of the uptake data indicated that both the film and the intra-particle diffusion mechanism are simultaneously operating in the sorption of Cs + ion onto the BOCMC resin. The metal ion sorption data were fitted to the sorption isotherm models and did not conform to the chemisorptions of physisorption models and indicated a pi-pi interaction between the benzene rings of the calix-crown-6 ligand and the Cs + ion. The reusability of the resins was quite satisfactory after 5 cycles and the radiation stability of the resin material was very good upto an absorbed dose of 500 kGy. The results of column studies were quite encouraging with 15 mL (9 bed volumes) as the breakthrough volume while the elution was complete in about 12 bed volumes of de-ionized water., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The unique properties of pillar[5]arene, including hydrophobic cavities, π-π conjugated and easy modification, make it a promising candidate as stationary phase for HPLC. Herein, we fabricated a novel propanediamine modified pillar[5]arene bonded silica as the stationary phase (PDA-BP5S) for reversed-phase liquid chromatography (RPLC). Benefiting from the significant hydrophobicity, π-π conjugative, p-π effect, and hydrogen bonding, the PDA-BP5S packed column showed high separation performance of versatile analytes involving polycyclic aromatic hydrocarbons, alkyl benzenes, phenols, arylamine, phenylethane/styrene/ phenylacetylene, toluene/m-xylene/mesitylene, halobenzenes, benzenediol and nitrophenol isomers. Especially, the separation of halobenzenes appeared to be controlled by both the size of the halogen substituents and the strength of the noncovalent bonding interactions, which was further confirmed by molecular dynamics simulation. The satisfactory separation and repeatability revealed the promising prospects of amine-pillar[5]arene-based stationary phase for RPLC., 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 © 2024 Elsevier B.V. All rights reserved.)

In this report, we firstly synthesized nitro calix [4] resorcinarene compound (referred as KA30) and characterized it though proton ( 1 H) nuclear magnetic resonance (NMR) spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and Fourier Transform Infra-red (FTIR) spectroscopy. KA30 was applied as functionalizing agent for the formation of silver nanoparticles (KA30-AgNPs). These NPs were confirmed as highly selective and extremely sensitive colorimetric sensor for ultra-low level detection of emamectin (EMA) as a novel report. Significant aspect of the sensor is its unique detection range between 0.0005 and 29.5 μM via color change from yellow to colorless with hypochromic-bathochromic shift exhibiting limit of detection (LOD) and limit of quantification (LOQ) as 0.12 nM and 0.4 nM respectively. The sensor was applied to colorimetrically and optically detect EMA in real samples of serum, urine and food. The sensor was further allied with smartphone for real-time, and on-site detection of EMA and results were validated through UPLC., Competing Interests: Declaration of competing interest The authors of this manuscript declare no competing interest that can affect the work the reported work., (Copyright © 2023. Published by Elsevier Ltd.)

Antibody-drug conjugates (ADCs), which combine the precise targeting capabilities of antibodies with the powerful cytotoxicity of small-molecule drugs, have evolved into a promising approach for tumor treatment. However, the traditional covalent coupling method requires the design of a specific linker tailored to the properties of the small-molecule drugs, which greatly limits the development of ADCs and the range of drugs that can be used. Herein, a novel type of antibody-calixarene drug conjugates (ACDCs) that function similarly to ADCs by delivering drugs to their targets using antibodies but without the requirement of covalent conjugation of the drugs with antibodies is presented. By replacement of conventional linkers with supramolecular linkers, the ACDCs can load various chemotherapeutic drugs through host-guest interactions. Furthermore, ACDCs are readily reduced upon reaching the hypoxic microenvironment, resulting in rapid release of the drugs. With this precise drug encapsulation and controlled release mechanism, ACDCs deliver drugs to tumor tissues effectively and achieve a significantly enhanced antitumor effect. Considering that the ACDCs can be easily prepared by combining antibody-calixarene conjugates derived from tumor-targeting antibodies with various small-molecule drugs, ACDCs may provide a promising platform technology to accelerate ADC development and thus improve the therapeutic efficacy of chemotherapy.

Efficient delivery of therapeutic agents to the lesion site or specific cells is an important way to achieve "toxicity reduction and efficacy enhancement". Macrocycles have always provided many novel ideas for drug or gene loading and delivery processes. Specifically, macrocycles represented by crown ethers, cyclodextrins, cucurbit[n]urils, calix[n]arenes, and pillar[n]arenes have unique properties, which are different cavity structures, good biocompatibility, and good stability. Benefited from these diverse properties, a variety of supramolecular drug delivery systems can be designed and constructed to effectively improve the physical and chemical properties of guest molecules as needed. This review provides an outlook on the current application status and main limitations of macrocycles in supramolecular drug delivery systems.

Achieving high guest loading and multiguest-binding capacity holds crucial significance for advancement in separation, catalysis, and drug delivery with synthetic receptors; however, it remains a challenging bottleneck in characterization of high-stoichiometry guest-binding events. Herein, we describe a large-sized coordination cage (MOC-70-Zn 8 Pd 6 ) possessing 12 peripheral pockets capable of accommodating multiple guests and a high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)-based method to understand the solution host-guest chemistry. A diverse range of bulky guests, varying from drug molecules to rigid fullerenes as well as flexible host molecules of crown ethers and calixarenes, could be loaded into open pockets with high capacities. Notably, these hollow cage pockets provide multisites to capture different guests, showing heteroguest coloading behavior to capture binary, ternary, or even quaternary guests. Moreover, a pair of commercially applied drugs for the combination therapy of chronic lymphocytic leukemia (CLL) has been tested, highlighting its potential in multidrug delivery for combined treatment.

Nano-assemblies based on perphenazine modified pillar[5]arene were constructed successfully for synergistic photothermal and photodynamic (I&II) cancer therapy.

Aim: This study aimed to enhance the aqueous dissolution of SRPK inhibitor N -(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340). Materials & Methods: A complex with p -sulfonic calix[6]arene (Host) and SRPIN340 (Guest) was prepared, studied via 1 H nuclear magnetic resonance (NMR) and theoretical calculations and biologically evaluated on cancer cell lines. Results & conclusion: The 1:1 host (H)/guest (G) complex significantly enhanced the aqueous dissolution of SRPIN340, achieving 64.8% water solubility as determined by 1 H NMR quantification analysis. The H/G complex reduced cell viability by 75% for HL60, ∼50% for Nalm6 and Jurkat, and ∼30% for B16F10 cells. It exhibited greater cytotoxicity than free SRPIN340 against Jurkat and B16F10 cells. Theoretical studies indicated hydrogen bond stabilization of the complex, suggesting broader applicability of SRPIN340 across diverse biological systems.

This study investigated the efficacy of a new chrysin-loaded calixarene-cyclodextrin ternary drug delivery system (DDS) in reversing liver fibrosis in a mouse model of chronic diabetes. The system was designed to enhance the solubility and bioavailability of chrysin (CHR) and calixarene 0118 (OTX008). Adult male CD1 mice received streptozotocin (STZ) injections to induce diabetes. After 20 weeks, they underwent intraperitoneal treatments twice weekly for a two-week period. Histological analyses revealed that long-term hyperglycaemia increased liver fibrosis and altered hepatic ultrastructure, characterized by lipid accumulation, hepatic stellate cell activation, and collagen deposition. The treatment with the chrysin-loaded DDS restored liver structure closely to normal levels, as opposed to the minimal impact observed with sulfobutylated β-cyclodextrin (SBECD) alone. The treatment significantly decreased serum activities of alanine /aspartate transaminases and reduced the gene expression of collagen type I (Col-I). It also modulated the transforming growth factor beta 1 (TGF-β1)/Smad signalling pathway, inhibiting the activation and proliferation of hepatic stellate cells. The treatment led to a downregulation of the TGF-β1 gene and its receptors TGFβR1 and TGFβR2, together with a decrease in Smad 2 and 3 mRNA levels. Conversely, Smad 7 mRNA expression was increased by the DDS. Furthermore, it downregulated galectin-1 (Gal-1) gene and protein levels, which correlated with fibrotic markers. In conclusion, the chrysin-loaded calixarene-cyclodextrin ternary DDS presents a promising therapeutic approach for diabetic liver fibrosis, effectively targeting fibrotic pathways and restoring hepatic function and structure., 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 © 2024. Published by Elsevier Inc.)

Calixarenes are displaying great potential for the development of new drug delivery systems, diagnostic imaging, biosensing devices and inhibitors of biological processes. In particular, calixarene derivatives are able to interact with many different enzymes and function as inhibitors. By screening of the potential drug target database (PDTD) with a reverse docking procedure, we identify and discuss a selection of 100 proteins that interact strongly with calix[4]arene. We also discover that leucine (23.5 %), isoleucine (11.3 %), phenylalanines (11.3 %) and valine (9.5 %) are the most frequent binding residues followed by hydrophobic cysteines and methionines and aromatic histidines, tyrosines and tryptophanes. Top binders are peroxisome proliferator-activated receptors that already are targeted by commercial drugs, demonstrating the practical interest in calix[4]arene. Nuclear receptors, potassium channel, several carrier proteins, a variety of cancer-related proteins and viral proteins are prominent in the list. It is concluded that calix[4]arene, which is characterized by facile access, well-defined conformational characteristics, and ease of functionalization at both the lower and higher rims, could be a potential lead compound for the development of enzyme inhibitors and theranostic platforms., (© 2024 Wiley-VCH GmbH.)

Chiral enantiomers, especially the enantiomers of chiral drugs often exhibit different pharmacological activity, metabolism and toxicity, thus it is of great research significance to scientifically and reasonably develop single chiral drugs with low toxicity and high efficiency. Among them, high performance liquid chromatographic techniques based on chiral stationary phases (CSPs) has become one of the most attractive methods used to evaluate the enantiomeric purity of single-enantiomers compound of pharmacological relevance. In this work, pillar[5]arene functionalized with L- and D-histidine, respectively, were modified on the surface of mesoporous silica as novel chiral stationary phases called L/DHis-BP5-Sil. Notably, L/D-histidine had the characteristics of low steric hindrance and easy derivatization. Although the π-π interaction of imidazole group was weaker than that of benzene ring, the benzene ring bonding imidazole-conjugated ring in the structure produced better enantioseparation effect. The results showed that L/DHis-BP5-Sil can separate a variety of complex structural enantiomers with excellent reproducibility, thermal stability and separation performance. Hence, the unique advantage of the highly selective separation of L/DHis-BP5-Sil provides new insights into the enantioseparation field., 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 © 2024. Published by Elsevier B.V.)

In this study, 4-sulfo-1,8-naphthalimide calixarene of derivatives were prepared (3 and 4) then transparent biofilms of the Ag salts of these compounds were formed in the presence of hyaluronic acid (HA), and antimicrobial properties were investigated. In chemosensor studies, the sensing ability behavior of 3 and 4 towards some cations and anions was investigated by fluorescence spectroscopy. It was observed that the prepared chemosensors show selectivity towards Hg(II) and Cr(VI). Ligand-ion interaction occurs according to the photo-induced electron transfer (PET) mechanism. The stoichiometric ratio was calculated by using Stern-Volmer plot method and binding constant K sv values were found as 5.2 × 10 7  M -1 and 5.5 × 10 7  M -1 for 3-Hg(II) and 4-Hg(II) complexes, respectively and 4.0 × 10 7  M -1 and 4.3 × 10 7  M -1 for 3-Cr(VI) and 4-Cr(VI) complexes. The detection limits of the complexes of 3-Hg(II) and 4-Hg(II) are 6.35 × 10 -12 and 6.81 × 10 -12 , while those of 3-Cr(VI) and 4-Cr(VI) are 1.41 × 10 - 11 and 8.37 × 10 -12 , respectively. As a result of the antimicrobial test performed with these compounds, it was observed that the most effective material was HA-3Ag, which showed a significant antibacterial effect against Sarcina lutea (S. lutea) at a minimum inhibitory concentration (MIC) value of 0.097 mg/mL., 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 © 2024 Elsevier B.V. All rights reserved.)

Functionalized calix[4]pyrroles are at forefront of host-guest aided molecular sensors. They offer unique platform for flexible functionalization to develop receptors suitable for different applications. In this context, calix[4]pyrrole derivative (TACP) was functionalized with an acidic group to investigate its binding behavior with different amino acids. The acid functionalization facilitated host-guest interactions through hydrogen bonding and increase the solubility of ligand in 90% aqueous media. The results indicated that TACP exhibited significant fluorescence enhancement in the presence of tryptophan while no considerable changes were observed with other amino acids. The other complexation properties such as LOD and LOQ were determined to be 25 µM and 22 µM respectively with 1:1 stoichiometry. In addition, the proposed binding phenomena were further confirmed through computational docking studies and NMR complexation study. Overall, this work highlights the potential of acid functionalization in developing molecular sensors for amino acid detection using calix[4]pyrrole derivatives.Communicated by Ramaswamy H. Sarma.

The complex pathologies in Alzheimer's disease (AD) severely limit the effectiveness of single-target pharmic interventions, thus necessitating multi-pronged therapeutic strategies. While flexibility is essentially demanded in constructing such multi-target systems, for achieving optimal synergies and also accommodating the inherent heterogeneity within AD. Utilizing the dynamic reversibility of supramolecular strategy for conferring sufficient tunability in component substitution and proportion adjustment, amphiphilic calixarenes are poised to be a privileged molecular tool for facilely achieving function integration. Herein, taking β-amyloid (Aβ) fibrillation and oxidative stress as model combination pattern, a supramolecular multifunctional integration is proposed by co-assembling guanidinium-modified calixarene with ascorbyl palmitate and loading dipotassium phytate within calixarene cavity. Serial pivotal events can be simultaneously addressed by this versatile system, including 1) inhibition of Aβ production and aggregation, 2) disintegration of Aβ fibrils, 3) acceleration of Aβ metabolic clearance, and 4) regulation of oxidative stress, which is verified to significantly ameliorate the cognitive impairment of 5×FAD mice, with reduced Aβ plaque content, neuroinflammation, and neuronal apoptosis. Confronted with the extremely intricate clinical realities of AD, the strategy presented here exhibits ample adaptability for necessary alterations on combinations, thereby may immensely expedite the advancement of AD combinational therapy through providing an exceptionally convenient platform., (© 2024 Wiley‐VCH GmbH.)

Therapeutic applications have sparked increased interest in the use of synthetic anion receptors for ion transport across lipid membranes. In this context, the construction of synthetic transmembrane transporters for the physiologically important chloride ion is currently of enormous interest. As a result, considerable effort is being devoted to the design and synthesis of artificial transmembrane chloride ion transporters. However, only inadequate progress has been made in developing macrocyclic chloride ion transporters using the fundamental principles of supramolecular chemistry, and hence this field entails fostering investigations. In this investigation, the synthesis of two new double walled trifluorophenyl/phthalimide extended calix[4]pyrrole (C4P) receptors (3 and 7) has been successfully reported. 1 H-NMR titration and HRMS studies confirmed the 1 : 1 binding stoichiometry of the chloride ion with these receptors in the solution phase (only receptor 3b was studied by 1 H-NMR). Regarding ion transport of 3b and 7, when studied in the HPTS-based vesicular system, 3b showed better activity with an EC 50 value of 0.39 μM. The detailed ion transport studies on 3b have revealed that ion transport occurs through the Cl - /NO 3 - antiport mode.

The identification and detection of pesticides is crucial to protecting both the environment and human health. However, it can be challenging to conveniently and rapidly differentiate between different types of pesticides. We developed a supramolecular fluorescent sensor array, in which calixarenes with broad-spectrum encapsulation capacity served as recognition receptors. The sensor array exhibits distinct fluorescence change patterns for seven tested pesticides, encompassing herbicides, insecticides, and fungicides. With a reaction time of just three minutes, the sensor array proves to be a rapid and efficient tool for the discrimination of pesticides. Furthermore, this supramolecular sensing approach can be easily extended to enable real-time and on-site visual detection of varying concentrations of imazalil using a smartphone with a color scanning application. This work not only provides a simple and effective method for pesticide identification and quantification, but also offers a versatile and advantageous platform for the recognition of other analytes in relevant fields.

The development of artificial receptors that combine ultrahigh-affinity binding and controllable release for active guests holds significant importance in biomedical applications. On one hand, a complex with an exceedingly high binding affinity can resist unwanted dissociation induced by dilution effect and complex interferents within physiological environments. On the other hand, stimulus-responsive release of the guest is essential for precisely activating its function. In this context, we expanded hydrophobic cavity surface of a hypoxia-responsive azocalix[4]arene, affording Naph-SAC4A. This modification significantly enhanced its aqueous binding affinity to 10 13  M -1 , akin to the naturally occurring strongest recognition pair, biotin/(strept-)avidin. Consequently, Naph-SAC4A emerges as the first artificial receptor to simultaneously integrate ultrahigh recognition affinity and actively controllable release. The markedly enhanced affinity not only improved Naph-SAC4A's sensitivity in detecting rocuronium bromide in serum, but also refined the precision of hypoxia-responsive doxorubicin delivery at the cellular level, demonstrating its immense potential for diverse practical applications., (© 2024 Wiley-VCH GmbH.)

The supramolecular-based macrocyclic amphiphiles have fascinating attention and find extensive utilization in the pharmaceutical industry for efficient drug delivery. In this study, we designed and synthesized a new supramolecular amphiphilic macrocycle to serve as an efficient nanocarrier, achieved by treating 4-hydroxybenzaldehyde with 1-bromotetradecane. The derivatized product was subsequently treated with resorcinol to cyclize, resulting in the formation of a calix(4)-resorcinarene-based supramolecular amphiphilic macrocycle. The synthesized macrocycle and intermediate products were characterized using mass spectrometry, IR, and 1 H NMR spectroscopic techniques. The amphotericin-B (Amph-B)-loaded and unloaded amphiphiles were screened for biocompatibility studies, vesicle formation, particle shape, size, surface charge, drug entrapment, in-vitro release profile, and stability through atomic force microscopy (AFM), Zetasizer, HPLC, and FT-IR. Amph-B -loaded macrocycle-based niosomal vesicles were investigated for in-vivo bioavailability in rabbits. The synthesized macrocycle exhibited no cytotoxicity against normal mouse fibroblast cells and was found to be hemocompatible and safe in mice following an acute toxicity study. The drug-loaded macrocycle-based vesicles appeared spherical, nano-sized, and homogeneous in size, with a notable negative surface charge. The vesicles remained stable after 30 days of storage. The results of Amph-B oral bioavailability and pharmacokinetics revealed that the newly tailored niosomal formulation enhanced drug solubility, protected drug degradation at gastric pH, facilitated sustained drug release at the specific target site, and delayed plasma drug clearance. Incorporating such advanced niosomal formulations in the field of drug delivery systems has the potential to revolutionize therapeutic outcomes and improve the quality of patient well-being., Competing Interests: Declaration of Competing Interest The authors claim that there are no known competing financial interests or personal relationships that may have a potential impact on the work described in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The action of calix[4]arenes C-424, C-425 and C-1193 has been investigated on suspended cholesterol/egg phosphatidylcholine lipid bilayer in a voltage-clamp mode. Comparative analysis with the membrane action by calix[4]arene-bis-α-hydroxymethylphosphonic acid (C-99) has shown that the substitution of bridge carbons for sulphur and addition of another methyl group to two alkyl tales in the lower rim of former dipropoxycalix[4]arene C-99 transformed mobile carrier that C-99 created in lipid bilayer (Shatursky et al., 2014) into a transmembrane pore as exposure of the bilayer membrane to sulphur-containing derivative dibutoxythiocalix[4]arene C-1193 resulted in microscopic transmembrane current patterns indicative of a channel-like mode of facilitated diffusion. Within all calix[4]arenes tested a net steady-state voltage-dependent transmembrane current was readily achieved only after addition of calix[4]-arene C-1193. In comparison with the membrane action of C-99 the current induced by calix[4]-arene C-1193 exhibited a much weakened anion selectivity passing slightly more current at positive potentials applied from the side of bilayer membrane to which the calix[4]-arene was added. Testing C-1193 for the membrane action against smooth muscle cells of rat uterus or swine myometrium and synaptosomes of rat brain nerve terminals revealed an increase in intracellular concentration of Ca 2+ with reduction of the effective hydrodynamic diameter of the smooth muscle cells and enhanced basal extracellular level of neurotransmitters (glutamate and γ-aminobutyric acid) after C-1193-induced depolarization of the nerve terminals., 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 © 2024 Elsevier Ltd. All rights reserved.)

Nanomedicines often rely on noncovalent self-assembly and encapsulation for drug loading and delivery. However, challenges such as reproducibility issues due to the multicomponent nature, off-target activation caused by premature drug release, and complex pharmacokinetics arising from assembly dissociation have hindered their clinical translation. In this study, we introduce an innovative design concept termed single molecular nanomedicine (SMNM) based on macrocyclic carrier-drug conjugates. Through the covalent linkage of two chemotherapy drugs to a hypoxia-cleavable macrocyclic carrier, azocalix[4]arene, we obtained two self-included complexes to serve as SMNMs. The intramolecular inclusion feature of the SMNMs has not only demonstrated comprehensive shielding and protection for the drugs but also effectively prevented off-target drug leakage, thereby significantly reducing their side effects and enhancing their antitumor therapeutic efficacy. Additionally, the attributes of being a single component and molecularly dispersed confer advantages such as ease of preparation and good reproducibility for SMNMs, which is desirable for clinical applications.

We report the synthesis of a series of amphiphilic p-sulfonatocalix[4]arenes with varying alkyl chain lengths (CX4-Cn) and their application as efficient counterion activators for membrane transport of cell-penetrating peptides (CPPs). The enhanced membrane activity is confirmed with the carboxyfluorescein (CF) assay in vesicles and by the direct cytosolic delivery of CPPs into CHO-K1, HCT 116, and KTC-1 cells enabling excellent cellular uptake of the CPPs into two cancer cell lines. Intracellular delivery was confirmed by fluorescence microscopy after CPP entry into live cells mediated by CX4-Cn, which was also quantified after cell lysis by fluorescence spectroscopy. The results present the first systematic exploration of structure-activity relationships for calixarene-based counterion activators and show that CX4-Cn are exceptionally effective in cellular delivery of CPPs. The dodecyl derivative, CX4-C12, serves as best activator. A first mechanistic insight is provided by efficient CPP uptake at 4 °C and in the presence of the endocytosis inhibitor dynasore, which indicates a direct translocation of the CPP-counterion complexes into the cytosol and highlights the potential benefits of CX4-Cn for efficient and direct translocation of CPPs and CPP-conjugated cargo molecules into the cytosol of live cells., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

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.

Supramolecular chirality-mediated selective interaction among native assemblies is essential for precise disease diagnosis and treatment. Herein, to fully understand the supramolecular chiral binding affinity-achieved therapeutic efficiency, supramolecular chiral nanoparticles (WP5⊃D/L-Arg+DOX+ICG) with the chirality transfer from chiral arginine (D/L-Arg) to water-soluble pillar[5]arene (WP5) are developed through non-covalent interactions, in which an anticancer drug (DOX, doxorubicin hydrochloride) and a photothermal agent (ICG, indocyanine green) are successfully loaded. Interestingly, the WP5⊃D-Arg nanoparticles show 107 folds stronger binding capability toward phospholipid-composed liposomes compared with WP5⊃L-Arg. The enantioselective interaction further triggers the supramolecular chirality-specific drug accumulation in cancer cells. As a consequence, WP5⊃D-Arg+DOX+ICG exhibits extremely enhanced chemo-photothermal synergistic therapeutic efficacy (tumor inhibition rate of 99.4%) than that of WP5⊃L-Arg+DOX+ICG (tumor inhibition rate of 56.4%) under the same condition. This work reveals the breakthrough that supramolecular chiral assemblies can induce surprisingly large difference in cancer therapy, providing strong support for the significance of supramolecular chirality in bio-application., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Protein-calixarenes binding plays an increasingly central role in many applications, spanning from molecular recognition to drug delivery strategies and protein inhibition. These ligands obey a specific bio-supramolecular chemistry, which can be revealed by computational approaches, such as molecular dynamics simulations. In this paper, we rely on all-atom, explicit-solvent molecular dynamics simulations to capture the electrostatically driven association of a phosphonated calix-[4]-arene with cytochome-C, which critically relies on surface-exposed paired lysines. Beyond two binding sites identified in direct agreement with the x-ray structure, the association has a larger structural impact on the protein dynamics. Then, our simulations allow a direct comparison to analogous calixarenes, namely, sulfonato, similarly reported as "molecular glue." Our work can contribute to a robust in silico predictive tool to assess binding sites for any given protein of interest for crystallization, with the specificity of a macromolecular cage whose endo/exo orientation plays a role in the binding., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Carrier-based polymeric membrane potentiometric sensors are an ideal tool for detecting ionic species. However, in the fabrication of these sensors, the screening of carriers still relies on empirical trial- and error-based optimization, which requires tedious and time-consuming experimental verification. In this work, computer-aided screening of carriers is applied in the preparation of polymeric membrane potentiometric sensors. Molecular docking is used to study the host-guest interactions between receptors and targets. Binding energies are employed as the standard to screen the appropriate carrier. As a proof-of-concept experiment, the antibiotic ciprofloxacin is selected as the target model. A series of supramolecular macrocyclic receptors including cyclodextrins, cucurbiturils and calixarenes are chosen as potential receptors. The proposed sensor based on the receptor calix[4]arene screened by molecular docking shows a lower detection limit of 0.5 μmol L -1 for ciprofloxacin. It can be expected that the proposed computer-aided screening technique of carriers can provide a simple but highly efficient method for the fabrication of carrier-based electrochemical and optical sensors.

Biogenic amines (BAs) are biologically active nitrogen-containing compounds formed during the food spoilage process and are often related as key markers of food quality, safety, and freshness. Because their presence in foods at high levels can cause significant health problems, researchers have been focused on developing novel strategies and methods for early detection and capture of these analytes. Herein, water-soluble sulfonated calix[ n ]arene macrocycles (SC4, SC6, and SC8) and a pH-sensitive dye (4'-hydroxy-10-methylpyranoflavylium) were investigated as host-guest systems for BA sensing. The hosts were able to bind the flavylium cation of the dye with association constants of 10 3 to 10 4 M -1 . The dye complexation also allowed tuning its p K a from 6.72 (free) toward high values: 7.68 (SC4), 7.79 (SC6), and 8.45 (SC8). These data were crucial to optimize the host-guest complexes as optical sensing systems for putrescine/tyramine (pH 7.2-7.6), yielding a colorimetric redshift from yellow to red. The BA sensing was also demonstrated by fluorescence quenching for the calix[ n ]arene/dye complexes and fluorescence recovery after the addition of BAs. 1 H NMR spectroscopy was used to demonstrate the interaction mode, confirming an encapsulation-driven mechanism. Overall, these host-guest systems demonstrated great potential for the detection of BAs, one of the main key markers of food spoilage.

We describe complex formation between a designed pentameric β-propeller and the anionic macrocycle sulfonato-calix[8]arene ( sclx 8 ), as characterized by X-ray crystallography and NMR spectroscopy. Two crystal structures and 15 N HSQC experiments reveal a single calixarene binding site in the concave pocket of the β-propeller toroid. Despite the symmetry mismatch between the pentameric protein and the octameric macrocycle, they form a high affinity multivalent complex, with the largest protein-calixarene interface observed to date. This system provides a platform for investigating multivalency.

Because they hold together molecules by means of non-covalent interactions - relatively weak and thus, potentially reversible - the anionic calixarenes have become an interesting tool for efficiently binding a large range of ligands - from gases to large organic molecules. Being highly water soluble and conveniently biocompatible, they showed growing interest for many interdisciplinary fields, particularly in biology and medicine. Thanks to their intrinsic conical shape, they provide suitable platforms, from vesicles to bilayers. This is a valuable characteristic, as so they mimic the biologically functional architectures. The anionic calixarenes propose efficient alternatives for overcoming the limitations linked to drug delivery and bioavailability, as well as drug resistance along with limiting the undesirable side effects. Moreover, the dynamic non-covalent binding with the drugs enables predictable and on demand drug release, controlled by the stimuli present in the targeted environment. This particular feature instigated the use of these versatile, stimuli-responsive compounds for sensing biomarkers of diverse pathologies. The present review describes the recent achievements of the anionic calixarenes in the field of life science, from drug carriers to biomedical engineering, with a particular outlook on their applications for the diagnosis and treatment of different pathologies., 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 Masson SAS. All rights reserved.)

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.

Since the discovery of polyphenolic resins 150 years ago, the study of polymeric compounds named calix[ n ]arene has continued to progress, and those skilled in the art perfectly know now how to modulate this phenolic ring. Consequently, calix[ n ]arenes are now used in a large range of applications and notably in therapeutic fields. In particular, the calix[4]arene exhibits multiple possibilities for regioselective polyfunctionalization on both of its rims and offers researchers the possibility of precisely tuning the geometry of their structures. Thus, in the crucial research of new antibacterial active ingredients, the design of calixarenes finds its place perfectly. This review provides an overview of the work carried out in this aim towards the development of intrinsically active prodrogues or metallic calixarene complexes. Out of all the work of the community, there are some excellent activities emerging that could potentially place these original structures in a very good position for the development of new active ingredients.

Despite their interesting stereochemistry and potential applications in (supramolecular) chemistry and chiroptical materials, inherently chiral macrocyclic compounds remain rare and are largely unexplored. We report herein a fragment coupling method to construct ABAC- and ABCD-type inherently chiral heteracalix[4]aromatics. The synthesis involves S N Ar CuI-catalyzed Ullmann coupling and aliphatic nucleophilic substitution reactions as key steps using readily available starting materials. Postmacrocyclization functionalization reactions enabled the production of amino-substituted and (benzo[ d ])imidazole-2-(thi)one-bearing heteracalix[4]aromatics. Enantiopure ABCD-type macrocycles were obtained from resolution.

Calixarenes are hallmark molecules in supramolecular chemistry as hosts for small ligands. They have also conversely proved their interest as ligands toward assisted co-crystallization of proteins. These functionalized macrocycles target positively-charged residues, and notably surface-exposed lysines, with a site-selectivity finely characterized experimentally, but that remains to be assessed. Relying on a tailored molecular dynamics simulations protocol, we explore the association of para -sulfonato-calix[4]arenes with an antifungal protein, as a small yet most competitive system with 13 surface-exposed lysines. Our computational approach probes de novo the electrostatically-driven interaction, ruled out by a competition with salt bridges, corroborating the presence of two main binding sites probed by X-ray. The attach-pull-release (APR) method provides a very good assessment of the overall binding free energy measured experimentally (-6.42 ± 0.5 vs. -5.45 kcal mol -1 by isothermal titration calorimetry). This work also probes dynamic modifications upon ligand binding, and our computational protocol could be generalized to situate the supramolecular forces ruling out the calixarene-assisted co-crystallization of proteins.

Controlled protein assembly and crystallization is necessary as a means of generating diffraction-quality crystals as well as providing a basis for new types of biomaterials. Water-soluble calixarenes are useful mediators of protein crystallization. Recently, it was demonstrated that Ralstonia solanacearum lectin (RSL) co-crystallizes with anionic sulfonato-calix[8]arene (sclx 8 ) in three space groups. Two of these co-crystals only grow at pH ≤ 4 where the protein is cationic, and the crystal packing is dominated by the calixarene. This paper describes a fourth RSL-sclx 8 co-crystal, which was discovered while working with a cation-enriched mutant. Crystal form IV grows at high ionic strength in the pH range 5-6. While possessing some features in common with the previous forms, the new structure reveals alternative calixarene binding modes. The occurrence of C 2 -symmetric assemblies, with the calixarene at special positions, appears to be an important result for framework fabrication. Questions arise regarding crystal screening and exhaustive searching for polymorphs., (open access.)

Supramolecular synthetic transporters are crucial to understand and activate the passage across lipid membranes of hydrophilic effector molecules. Herein, we introduce photoswitchable calixarenes for the light-controlled transport activation of cationic peptide cargos across model lipid bilayers and inside living cells. Our approach was based on rationally designed p -sulfonatocalix[4]arene receptors equipped with a hydrophobic azobenzene arm, which recognize cationic peptide sequences at the nM range. Activation of membrane peptide transport is confirmed, in synthetic vesicles and living cells, for calixarene activators featuring the azobenzene arm in the E configuration. Therefore, this method allows the modulation of the transmembrane transport of peptide cargos upon Z - E photoisomerization of functionalized calixarenes using 500 nm visible light. These results showcase the potential of photoswitchable counterion activators for the light-triggered delivery of hydrophilic biomolecules and pave the way for potential applications in remotely controlled membrane transport and photopharmacology applications of hydrophilic functional biomolecules.