Trapping and reversing neuromuscular blocking agent by anionic pillar[5]arenes: Understanding the structure-affinity-reversal effects.

Selective relaxant binding agents (SRBA) have great potential in clinical surgeries for the precise reversal of neuromuscular blockades. Understanding the relationship between the structure-affinity-reversal effects of SRBA and neuromuscular blockade is crucial for the design of new SRBAs, which has rarely been explored. Seven anionic pillar[5]arenes (AP5As) with different aliphatic chains and anionic groups at both edges were designed. Their binding affinities to the neuromuscular blocking agent decamonium bromide (DMBr) were investigated using 1H NMR, isothermal titration calorimetry (ITC), and theoretical calculations. The results indicate that the capture of DMBr by AP5As is primarily driven by electrostatic interactions, ion-dipole interactions and C-H‧‧‧π interactions. The optimal size matching between the carboxylate AP5As and DMBr was ∼0.80. The binding affinity increased with an increase in the charge quantity of AP5As. Further animal experiments indicated that the reversal efficiency increased with increasing binding affinity for carboxylate or phosphonate AP5As. However, phosphonate AP5As exhibited lower reversal efficiencies than carboxylate AP5As, despite having stronger affinities with DMBr. By understanding the structure-affinity-reversal relationships, this study provides valuable insights into the design of innovative SRBAs for reversing neuromuscular blockade.

pH/ROS dual stimuli-responsive anionic flexible supramolecular organic frameworks for synergistic therapy.

Supramolecular organic frameworks (SOFs) have emerged as a promising class of organic porous materials with vast potential as nanocarriers for combination therapy. Here, we successfully construct an anionic flexible supramolecular organic framework (TPP-SOF) by leveraging multiple host-guest interactions. TPP-SOF is fabricated by the hierarchical orthogonal assembly between anionic water-soluble dimacrocyclic host (P5CD), porphyrin photosensitizers (TPP), and ROS-sensitive thioketal linked adamantane dimer (Ada-S-Ada). TPP-SOF exhibits pH-dependent activation of 1O2 production, which further facilitates the cleavage of Ada-S-Ada linker and promotes the disintegration of the framework. Moreover, leveraging electrostatic and hydrophobic interactions, the anionic TPP-SOF serves as an effective platform for loading cationic photosensitizer IR780 and chemotherapeutic prodrug PhenPt(IV), leading to the formation of supramolecular nanoparticles (IR780/Pt@TPP-SOF) for synergistic therapy. The obtained nanoparticles exhibit good stability, efficient generation of 1O2, and photothermal performance. In vitro and in vivo studies indicate that IR780/Pt@TPP-SOF exhibits remarkable synergistic chemo/PDT/PTT effects under 808 and 660 nm light irradiation. This study showcases a deep insight for the development of SOFs and a new approach for delivering cationic drugs and constructing synergistic combination therapy systems. STATEMENT OF SIGNIFICANCE: In this work, a pH/ROS-responsive anionic flexible supramolecular organic framework, TPP-SOF, was innovatively designed by the hierarchical orthogonal assembly, to co-deliver cationic photosensitizer IR780 and prodrug PhenPt(IV) for synergistic cancer therapy. The drug-loaded TPP-SOF is termed IR780/Pt@TPP-SOF, in which the photoactivity of porphyrin within TPP-SOF could be activated under acidic conditions, the 1O2 generated by the photosensitizers could break the thioketal bonds in Ada-S-Ada, leading to the disassembly of the framework and releasing the drugs. This supramolecular drug delivery system displays good biocompatibility and exhibits remarkable synergistic chemo/PDT/PTT effects.

Supramolecular detoxification of nitrogen mustard via host-guest encapsulation by carboxylatopillar[5]arene.

Nitrogen mustard (NM), a kind of alkylating agent similar to sulfur mustard, remains a threat to public health. However, there is nearly no satisfactory antidote for nitrogen mustard. Herein, we developed a supramolecular antidote to nitrogen mustard through efficient complexation of NM by carboxylatopillar[5]arene potassium salts (CP[5]AK). The cavity of methoxy pillar[5]arene (P5A) is sufficient to encapsulate NM with an association constant of 1.27 × 102 M-1, which was investigated by 1H NMR titration, density functional theory studies and independent gradient model studies. NM degrades to the reactive aziridinium salt (2) in the aqueous phase which irreversibly alkylates DNA and proteins, causing severe tissue damage. Considering the size/charge matching with toxic intermediate 2, water-soluble CP[5]AK was selected to encapsulate the toxic aziridinium salt (2), resulting in a high association constant of 4.10 × 104 M-1. The results of protection experiments of guanosine 5'-monophosphate (GMP) by CP[5]AK indicated that the formation of a complex could effectively inhibit the alkylation of DNA. Besides, in vitro and in vivo experiments also indicated that the toxicity of the aziridinium salt (2) is inhibited with the formation of a stable host-guest complex, and CP[5]AK has a good therapeutic effect on the damage caused by NM. This study provides a new mechanism and strategy for the treatment of NM exposure-induced skin injuries.

Supramolecular Enhancement of Charge Transport through Pillar[5]arene-Based Self-Assembled Monolayers.

Intermolecular charge transport is one of the essential modes for modulating charge transport in molecular electronic devices. Supermolecules are highly promising candidates for molecular devices because of their abundant structures and easy functionalization. Herein, we report an efficient strategy to enhance charge transport through pillar[5]arene self-assembled monolayers (SAMs) by introducing cationic guests. The current density of pillar[5]arene SAMs can be raised up to about 2.1 orders of magnitude by inserting cationic molecules into the cavity of pillar[5]arenes in SAMs. Importantly, we have also observed a positive correlation between the charge transport of pillar[5]arene-based complex SAMs and the binding affinities of the pillar[5]arene-based complexation. Such an enhancement of charge transport is attributed to the efficient host-guest interactions that stabilize the supramolecular complexes and lower the energy gaps for charge transport. This work provides a predictive pattern for the regulation of intermolecular charge transport in guiding the design of next generation switches and functional sensors in supramolecular electronics.

Construction of Halogen-Bonded Organic Frameworks (XOFs) as Novel Efficient Iodinating Agents.

The structural diversity and the various applications of organic frameworks have attracted much attention in recent years. Recently, halogen-bonded organic frameworks (XOFs) became a novel member of these materials, thereby facilitating the exploration of the interesting structures as well as functions. Here we present two types of [N···I+···N] connected XOFs (XOF-TPy and XOF-TPEB) with two tridentate ligands as building blocks. XOF-TPy and XOF-TPEB were characterized by 1H NMR, UV-vis, X-ray photoelectron spectroscopy (XPS), IR, SEM, and HR-TEM. Two-dimensional (2D) structural models were established based on powder X-ray diffraction (PXRD) data and theoretical simulations. Further experiment showed that these XOFs were excellent iodinating agents for the substituted arylboronic acids with either the electron-donating or electron-withdrawing groups upon heating without any catalyst. This research not only brings further understanding to the XOFs but also extends the applications of XOFs.

Detoxification of the Toxic Sulfur Mustard Simulant by a Supramolecular Antidote in Vitro and in Vivo.

Although great potential hazards and threats still occur from sulfur mustard, there are no specific medicine or therapy for the intoxication of sulfur mustard. Herein, we have demonstrated a supramolecular approach for the detoxification of the sulfur mustard simulant CEES (4) in vitro and in vivo by carboxylatopillar[5]arene potassium salts (CP[5]AK 1) efficiently based on host-guest interactions. The encapsulation of CEES (4) by the cavity of the pillar[5]arene 2 is driven by C-H···π interactions between CEES (4) and the electron-rich cavity of pillar[5]arene 2, which was investigated by 1H NMR titration, density functional theory studies, and the independent gradient model studies. CEES (4) is degradated to the reactive sulfonium salts quickly in aqueous media, resulting in the alkylation of DNA and proteins. The sulfonium salts can be encapsulated by CP[5]AK 1 efficiently, which accelerates the degradation of the sulfonium salts about 14 times. The cell and animal experiments indicated that the bioactivities of the sulfonium salts are inhibited with the formation of stable host-guest complexes, and CP[5]AK 1 has a good therapeutic effect on the damages caused by CEES (4) at either pre- or post-treatments. Due to the low cytotoxicity and good therapeutic effect, the anionic pillar[5]arenes are expected to be developed as specific antidotes against sulfur mustard (HD).

Evaluating the genesis and dominant processes of groundwater salinization by using hydrochemistry and multiple isotopes in a mining city.

The increasing salinization of groundwater renders it challenging to maintain the water quality. Moreover, knowledge regarding the characteristics and mechanism of groundwater salinization in mining areas remains limited. This study represents the first attempt of combining the hydrochemical, isotope (δD, δ18O, δ37Cl, and 87Sr/86Sr) and multivariate statistical analysis methods to explore the origin, control, and influence of fluoride enrichment in mining cities. The TDS content of groundwater ranged from 275.9 mg/L to 2452.0 mg/L, and 54% of the groundwater samples were classified as class IV water according to China's groundwater quality standards (GB/T 14848-2017), indicating a decline in the water quality of the study area. The results of the groundwater ion ratio and isotope discrimination analysis showed that dissolution and evaporation involving water-rock interactions and halite were the main driving processes for groundwater salinization in the study area. In addition to the hydrogeological and climatic conditions, mine drainage inputs exacerbated the increasing salinity of the groundwater in local areas. The mineral dissolution, cation exchange, and evaporation promoted the F- enrichment, while excessive evaporation and salinity inhibited the F- enrichment. Gangue accumulation and infiltration likely led to considerable F- enrichment in individual groundwater regions. Extensive changes in the groundwater salinity indicated differences in the geochemical processes that controlled the groundwater salinization. Given the particularity of the study area, the enrichment of salinization and fluoride triggered by mining activities cannot be ignored.

Halogen-Bonded Organic Framework (XOF) Based on Iodonium-Bridged N⋠⋠⋠I+ ⋠⋠⋠N Interactions: A Type of Diphase Periodic Organic Network.

Due to the fascinating structures and wide applications, porous materials with open frameworks have attracted more and more attentions. Herein, a novel two-dimensional (2D) halogen-bonded organic framework (XOF-TPPE) was successfully designed and fabricated by iodonium-bridged N⋅⋅⋅I+ ⋅⋅⋅N interactions between pyridyl groups and I+ for the first time. The formation of XOF-TPPE and its linear analogue was monitored by 1 H NMR, UV-Vis, X-ray photoelectron spectroscopy (XPS), IR, SEM, TEM, HRTEM and selected-area electron diffraction (SAED). The structural model of XOF-TPPE was established based on powder X-ray diffraction (PXRD) data and theoretical simulations. Significantly, synchrotron small-angle X-ray scattering (SAXS), DLS and UV-Vis spectroscopy experiments suggested that XOF-TPPE still maintains a stable 2D framework structure in solutions. This research opens up a novel avenue for the development of organic frameworks materials, and may bring new promising applications for the field of porous materials.

Enantioselective palladium-catalyzed diarylation of unactivated alkenes.

Enantioselective Pd-catalyzed diarylation of unactivated alkenes between arenediazonium salts and arylboronic acids has been developed. This method provides an efficient route to dihydrobenzofurans with all-carbon quaternary centers in good yields with 88-99% ee. This reaction proceeding under mild and open-flask conditions is compatible with a variety of functional groups, including cyano, ketone, ester, amide, bromine and free hydroxyl groups.

Pd-Catalyzed Enantioselective Double Heck Reaction.

An asymmetric Pd-catalyzed intramolecular followed by an intermolecular double Heck reaction of arenediazonium salts with simple alkenes is disclosed. This reaction features mild reaction conditions, simple operation, and excellent functional group tolerance and provides a rapid access to functionalized dihydrobenzofurans bearing all-carbon quaternary centers in good regioselectivity (>95/5) and enantioselectivity (90-99% ee).

Multivalent and Photoresponsive Assembly of Dual-Cavity Baskets in Water.

Large unilamellar vesicles [1]n , composed of bolaamphiphilic baskets 1, were found to complex photoresponsive guest 3 and divalent 4 to, respectively, give stable vesicular assemblies [12 -3]n and [12 -43 ]n . With the assistance of 1 H NMR spectroscopy, electron microscopy, and dynamic light scattering, it was deduced that [12 -3]n vesicles comprise ternary [12 -3] organized into a curved membrane in which a pair of baskets entraps a laterally positioned dicationic 3. In the case of [12 -43 ]n vesicles, however, the spectroscopic results suggest that three guest molecules 4 insert vertically between four baskets 1 to give pentanary [12 -43 ] packed into the membrane of [12 -43 ]n . Importantly, nanostructured [12 -3]n and [12 -43 ]n retain rhodamine B (RhB) in their reservoir (fluorescence microscopy) and can be switched from one into another using UV light, with a disproportionate release of RhB dye. The reported complexes, organized into photoresponsive capsular materials, are rather unprecedented, demonstrating the potential of multivalency for creating functional structures of great interest in the areas of catalysis and delivery.

Assembly and Folding of Twisted Baskets in Organic Solvents.

A synthetic method for obtaining enantiopure and twisted baskets of type (P)-3 is described. These chiral cavitands were found to fold quinoline gates, at the rim of their twisted platform, in acetonitrile and give molecular capsules that assemble into large unilamellar vesicles. In a less polar dichloromethane, however, cup-shaped (P)-3 packed into vesicles but with the quinoline gates in an unfolded orientation. The ability of twisted baskets to form functional nanostructured materials could be of interest for building stereoselective sensors and catalysts.

Two-Dimensional Supramolecular Polymers Embodying Large Unilamellar Vesicles in Water.

We hereby describe a strategy for obtaining novel topological nanostructures consisting of dual-cavity basket 1, forming a curved monolayer of large unilamellar vesicles in water (CAC < 0.25 µM), and bivalent guests 4/5 populating the cavities of such bolaamphiphilic hosts. On the basis of the results of (1)H NMR spectroscopy, electron microscopy, and dynamic light scattering measurements, we postulated that divalent guest molecules 4/5 cover the curved vesicular surface in a lateral fashion to satisfy the complexation [2 + 2] valency and thereby give stable two-dimensional supramolecular polymers [1⊂4]n and [1⊂5]n. The results of experimental studies are also supported with coarse-grained molecular dynamics simulations and molecular mechanics. Our discovery about the assembly of novel vesicular structures could be of interest for stabilization/functionalization of liposomal surfaces as well as detection of polyvalent molecules and removal of targeted substances from aqueous environments.

Temperature-Responsive Chiral (A)6B Supramolecular Cages Based on Conformational Preferences.

Two chiral (A)6B-typed supramolecular cages were constructed from hydrogen-bonded C6 -symmetric zinc porphyrin hexamers and chiral C3-symmetric pyridyl hexadentates with a core of 1,3,5-triphenylbenzene. Circular dichroism and molecular simulations revealed that the symmetry of the supramolecular cages switched from pseudo-C3v to C3 with the rotational confinement of the biphenyl backbones at low temperatures, which generated conformationally chiral transfer and amplification. This unique phenomenon suggests a new strategy to develop smart materials with high sensitivity and excellent reversibility.

Dual-cavity basket promotes encapsulation in water in an allosteric fashion.

We prepared dual-cavity basket 1 to carry six (S)-alanine residues at the entrance of its two juxtaposed cavities (289 Å(3)). With the assistance of (1)H NMR spectroscopy and calorimetry, we found that 1 could trap a single molecule of 4 (K1 = 1.45 ± 0.40 × 10(4) M(-1), ITC), akin in size (241 Å(3)) and polar characteristics to nerve agent VX (289 Å(3)). The results of density functional theory calculations (DFT, M06-2X/6-31G*) and experiments ((1)H NMR spectroscopy) suggest that the negative homotropic allosterism arises from the guest forming C-H···π contacts with all three of the aromatic walls of the occupied basket's cavity. In response, the other cavity increases its size and turns rigid to prevent the formation of the ternary complex. A smaller guest 6 (180 Å(3)), akin in size and polar characteristics to soman (186 Å(3)), was also found to bind to dual-cavity 1, although giving both binary [1⊂6] and ternary [1⊂62] complexes (K1 = 7910 M(-1) and K2 = 2374 M(-1), (1)H NMR spectroscopy). In this case, the computational and experimental ((1)H NMR spectroscopy) results suggest that only two aromatic walls of the occupied basket's cavity form C-H···π contacts with the guest to render the singly occupied host flexible enough to undergo additional structural changes necessary for receiving another guest molecule. The structural adaptivity of dual-cavity baskets of type 1 is unique and important for designing multivalent hosts capable of effectively sequestering targeted guests in an allosteric manner to give stable supramolecular polymers.

Ubiquitous assembly of amphiphilic baskets into unilamellar vesicles and their recognition characteristics.

An amphiphilic basket of type 1 (339 Å(3)) has been found to assemble into unilamellar vesicles in water. The assembled host encapsulates organophosphonates (OPs) (119-185 A(3)) with a particularly high affinity (Ka ∼ 10(5) M(-1)) toward dimethyl phenylphosphonate (185 Å(3)) whose size and shape resemble that of soman (186 Å(3)). Importantly, the entrapment of OPs prompts a phase transformation of vesicular 1 into nanoparticles or larger vesicles as a function of the shape of the host-guest complex.

Soy sauce classification by geographic region and fermentation based on artificial neural network and genetic algorithm.

This work demonstrated the possibility of using artificial neural networks to classify soy sauce from China. The aroma profiles of different soy sauce samples were differentiated using headspace solid-phase microextraction. The soy sauce samples were analyzed by gas chromatography-mass spectrometry, and 22 and 15 volatile aroma compounds were selected for sensitivity analysis to classify the samples by fermentation and geographic region, respectively. The 15 selected samples can be classified by fermentation and geographic region with a prediction success rate of 100%. Furans and phenols represented the variables with the greatest contribution in classifying soy sauce samples by fermentation and geographic region, respectively.

Recognition characteristics of an adaptive vesicular assembly of amphiphilic baskets for selective detection and mitigation of toxic nerve agents.

We used isothermal titration calorimetry to investigate the affinity of basket 1 (470 Å(3)) for trapping variously sized and shaped organophosphonates (OPs) 2-12 (137-244 Å(3)) in water at 298.0 K. The encapsulation is, in each case, driven by favorable entropy (TΔS° = 2.9 kcal/mol), while the enthalpic component stays small and in some cases endothermic (ΔH° ≥ -1 kcal/mol). Presumably, a desolvation of basket 1 and OP guests permits the inclusion complexation at room temperature via a "classical" hydrophobic effect. The amphiphilic basket 1 shows a greater affinity (ΔG° ≈ -5 to -6 kcal/mol), both experimentally and computationally, for encapsulating larger organophosphonates whose size and shape correspond to VX-type agents (289 A(3)). Importantly, baskets assemble into a vesicular nanomaterial (DH ≈ 350 nm) that in the presence of neutral OP compounds undergoes a phase transition to give nanoparticles (DH ≈ 250 nm). Upon the addition of an anionic guest to basket 1, however, there was no formation of nanoparticles and the vesicles grew into larger vesicles (DH ≈ 750 nm). The interconversion of the different nanostructures is reversible and, moreover, a function of the organophosphonate present in solution. On the basis of (1)H NMR spectroscopic data, we deduced that neutral guests insert deep into the basket's cavity to change its shape and thereby promote the conversion of vesicles into nanoparticles. On the contrary, the anionic guests reside at the northern portion of the host to slightly affect its shape and geometric properties, thereby resulting in the vesicles merely transforming into larger vesicles.

On the nature of the transition state characterizing gated molecular encapsulations.

Gated molecular encapsulations, with baskets of type 1, are postulated to occur by the mechanism in which solvent molecule penetrates the inner space of 1, through one of its apertures, while the residing guest simultaneously departs the cavity. In the transition state of the exchange, three pyridine-based gates are proposed to assume an open position with both incoming solvent and departing guest molecules interacting with the concave surface of the host. The More O'Ferrall-Jencks diagram and linear free energy relationships (LFERs) suggest a more advanced departure of the guest when bigger solvents partake in the displacement.

Assembly of amphiphilic baskets into stimuli-responsive vesicles. Developing a strategy for the detection of organophosphorus chemical nerve agents.

We designed basket 1 to comprise a C3-symmetric hydrophobic cage (477 Å(3)) at its southern edge and three polar ammonium caps at the northern edge. This amphiphilic molecule was observed to assemble into large unilamellar vesicles (350 nm, TEM) in water and thereby entrap dimethyl phenylphosphonate (184 Å(3)) in its cavity (K(app) = (1.97 ± 0.02) × 10(3) M(-1)). The entrapment of the organophosphonate, akin to soman in size (186 Å(3)), triggers the transformation of the vesicular material into nanoparticles (100 nm, TEM). Stimuli-responsive vesicles, containing baskets of type 1 in their bilayer membrane, are unique assemblies and important for obtaining novel sensing devices.