Host-guest Interactions Research Articles

Supramolecular chemistry in cyclodextrin inclusion complexes: The formation rules of terpenes/β-cyclodextrin inclusion complexes

Supramolecular chemistry of cyclodextrins (CDs) inclusion complexes is a hot research topic at present, but current studies often focus on the host-guest interaction between CDs and hydrophobic substances, while ignoring the self-assembly behavior of the host and guest during the inclusion process. Based on the spatial structures, six representative terpenes were selected in this study, and the stoichiometric ratio between terpenes and β-cyclodextrin (β-CD) was investigated by isothermal titration calorimetry (ITC) method. Meanwhile, the constructed inclusion complexes (ICs) were characterized by nuclear magnetic resonance, X-ray diffraction, scanning electron microscope, etc. On this basis, the assembly process of β-CD and terpenes was investigated firstly by molecular simulation method, and the inclusion process between β-CD and terpenes was further studied in terms of the formation of individual ICs and ICs aggregates. Results showed that hydrophobic interaction and van der Waals force were the main driving forces of the reaction between terpenes and β-CD, and the formation of ICs, β-CD molecule aggregation, terpene aggregation, and ICs aggregation occurred simultaneously during the inclusion process of terpenes and β-CD. To sum up, this study may provide certain thinking and reference for the subsequent supramolecular chemical research on CDs.

Flexible Mesopores in Nanoscrolls: Extraordinarily Large Alteration of Pore Sizes and Their Reversibility.

Flexible porous materials have gained considerable interest for their potential applications in selective absorption and controlled release/storage of specific molecules or compounds. Here, nanoscrolls are proposed as a type of inorganic solids with reversibly flexible mesopores. Nanoscrolls exhibit a rolled-up structure composed of nanosheets with a 1D rod-like morphology, possessing two distinct nanospaces. The first space comprises 1D tubular mesopores located at the center of the rod, while the second space exists in the interlayer regions on the wall of the mesopore, resulting from the layer stacking caused by the scrolling of nanosheets. By replacing the interlayer cations on the nanoscroll walls with other cations, a drastic alteration in the size of the 1D mesopores is observed. For instance, exchanging bulky dodecylammonium cations with small NH4 + cations leads to a substantial change in pore size, with differences ranging from 10 to 20nm-a notably larger variation compared to previous reports on flexible porous materials. Importantly, the alteration of pore size induced by the exchange reaction is found to be reversible. This reversible alteration in pore size holds promise for applications in host-guest chemistry involving large moieties such as nanoparticles and enzymes.

Host–Guest Interaction and Hydrogen Bonding Cross-Linking Actuated Smart Two-Dimensional Photonic Hydrogel Sensor of l-Histidine

Host–Guest Interaction and Hydrogen Bonding Cross-Linking Actuated Smart Two-Dimensional Photonic Hydrogel Sensor of <scp>l</scp>-Histidine

GSH-responsive bithiophene Aza-BODIPY@HMON nanoplatform for achieving triple-synergistic photoimmunotherapy

Photoimmunotherapy represents an innovative approach to enhancing the efficiency of immunotherapy in cancer treatment. This approach involves the fusion of immunotherapy and phototherapy (encompassing techniques like photodynamic therapy (PDT) and photothermal therapy (PTT)). Boron-dipyrromethene (BODIPY) has the potential to trigger immunotherapy owing to its excellent PD and PT efficiency. However, the improvements in water solubility, bioavailability, PD/PT combined efficiency, and tumor tissue targeting of BODIPY require introduction of suitable carriers for potential practical application. Herein, a disulfide bond-based hollow mesoporous organosilica (HMON) with excellent biocompatibility and GSH-responsive degradation properties was used as a carrier to load a bithiophene Aza-BODIPY dye (B5), constructing a sample chemotherapy reagent-free B5@HMON nanoplatform achieving triple-synergistic photoimmunotherapy. HMON, involving disulfide bond, is utilized to improve water solubility, tumor tissue targeting, and PD efficiency by depleting GSH and enhancing host-guest interaction between B5 and HMO. The study reveals that HMON’s large specific surface area and porous properties significantly enhance the light collection and oxygen adsorption capacity. The HMON’s rich mesoporous structure and internal cavity achieved a loading rate of B5 at 11 %. It was found that the triple-synergistic nanoplatform triggered a stronger anti-tumor immune response, including tumor invasion, cytokine production, calreticulin translocation, and dendritic cell maturation, eliciting specific tumor-specific immunological responses in vivo and in vitro. The BALB/c mouse model with 4T1 tumors was used to assess tumor suppression efficiency in vivo, showing that almost all tumors in the B5@HMON group disappeared after 14 days. Such a simple chemotherapy reagent-free B5@HMON nanoplatform achieved triple-synergistic photoimmunotherapy.

Host-Guest Interactions of Ruthenium(II) Arene Complexes with Cucurbit[7/8]uril.

Cucurbit[n]urils (CB[n]s) have been recognized for their chemical and thermal stability, and their ability to bind many neutral and cationic guest molecules makes them excellent hosts in a range of supramolecular applications. In drug delivery, CB[n]s can enhance drug solubility, improve chemical and physical drug stability, and allow for triggered and controlled release. This study aimed to investigate the ability of CB[7] and CB[8] as molecular hosts to bind ruthenium(II) arene complexes that are current anticancer lead structures in the area of metallodrugs. Both, experimental and computational methods, led to insights into the binding preferences and geometries of [RuII(cym)Cl2]2 (1; cym = η6-p-cymene), [RuII(cym)(dmb)Cl2]) (2; cym = η6-p-cymene; dmb = 1,3-dimethylbenzimidazol-2-ylidene), and [RuII(cym)(pta)Cl2] (3, RAPTA-C; cym = η6-p-cymene; pta = 1,3,5-triaza-7-phospha-adamantane) with CB[7] and CB[8]. Competition experiments by mass spectrometry revealed clear preferences of 2 for CB[8] and 3 for CB[7]. Based on a comparison of the associated interaction energies from quantum chemical calculations as well as experimental data, 3@CB[7] clearly prefers a binding mode, where the pta ligand is located inside the cavity of the host, and the metal ion interacts with two of the carbonyl groups on the rim of CB[7]. In contrast, complex 2 binds in two different orientations with interaction energies similar to those of both CB[n]s, with the cym ligand being either inside or outside of the cavity. These findings suggest that ruthenium(II) arene complexes are able to form stable host-guest interactions with CB[n]s, which can be exploited as drug delivery vehicles in further metallodrug development to improve their chemical stability.

Investigation of sorptive interactions between volatile organic compounds and supramolecules at dynamic oscillation using bulk acoustic wave resonator virtual sensor arrays

Supramolecules are considered as promising materials for volatile organic compounds (VOCs) sensing applications. The proper understanding of the sorption process taking place in host-guest interactions is critical in improving the pattern recognition of supramolecules-based sensing arrays. Here, we report a novel approach to investigate the dynamic host-guest recognition process by employing a bulk acoustic wave (BAW) resonator capable of producing multiple oscillation amplitudes and simultaneously recording multiple responses to VOCs. Self-assembled monolayers (SAMs) of β-cyclodextrin (β-CD) were modified on four BAW sensors to demonstrate the gas-surface interactions regarding oscillation amplitude and SAM length. Based on the method, a virtual sensor array (VSA) type electronic nose (e-nose) can be realized by pattern recognition of multiple responses at different oscillation amplitudes of a single sensor. VOCs analysis was realized respectively by using principal component analysis (PCA) for individual VOC identification and linear discriminant analysis (LDA) for VOCs mixtures classification.

Calixarene‐Guest Complexes: The Next Innovation in Delivery of Drugs and Biologics

AbstractCalixarenes are third generation of macrocyclic molecules with excellent biocompatibility currently being researched extensively for their diverse potential as therapeutic candidates and for delivery of drugs and biologics. This review discusses the unique structural features which allow them to selectively bind to a wide variety of guest molecules within their hydrophobic cavity, as well as complex with other molecules on their upper and lower rims to enable their application for encapsulation of drugs for targeted and controlled release, molecular carriers for antigens and nucleic acids, and as biomedical sensors. The calixarenes’ unique host–guest chemistry enables encapsulation of lipophilic drugs in the latter's cavity, while the head groups and side chains on the upper and lower rim can be functionalized readily with various targeting moieties as peptides and biological ligands which specifically recognize and bind to cancer cells via surface receptors. The design of calixarene constructs help incorporation of multiple functionalities into a single platform. This active targeting approach enhances the accumulation of the drug at the tumor site while reducing its distribution in healthy tissues, thereby minimizing side effects. Ongoing research in exploration and optimization of calixarenes for application as targeted drug and gene delivery agents has been discussed.

Under the Influence of Water: Molecular Recognition of Organic Hydrophilic Molecules in Water with a Prismarene Host Driven by Hydration Effects.

A water-soluble prism[5]arene host can form endo-cavity complexes with hydrophilic organic substances in water by displacing frustrated water molecules from its deep cavity. Water molecules structured at both rims of the prismarene host can mediate hydrogen bonding interactions with the guest. Water-mediated hydrogen bonding interactions were invoked here to elucidate the elevated binding affinities and selectivity of the prismarene host toward hydrophilic organic guests. We show that water at the interface of a host-guest complex can act as an extension of the host structure, facilitating the accommodation of neutral guests within the binding site. This study highlights the crucial role of water in facilitating supramolecular interactions between a deep-cavity prismarene host and organic hydrophilic guests in aqueous medium.

Point-of-Care Testing of Whole Blood for Liver Injury Auxiliary Diagnosis with Biothiols Activable Chemiluminescent Probe.

Liver injury significantly affects a patient's health and quality of life. However, timely and convenient diagnosis of this disease via whole blood detection remains challenging due to the lack of user-friendly and fast readout blood test methods. Herein, we developed such a method for the swift auxiliary diagnosis of liver injury via whole blood detection using a customed point-of-care testing (POCT) system consisting of a biothiols-activatable chemiluminescent probe and a hand-held POCT device. Biothiols served as the target to build the activable chemiluminescence probe due to their abnormal level in liver injury. Compared with fluorescent and electrical POCTs, this method is more convenient and has strong universality. By incorporating cyclodextrin via host-guest chemistry, we intensified chemiluminescence while mitigating chemical hemolysis caused by the dissolution of organic molecules, making this system suitable for whole blood analysis. Preliminary assessments in aqueous solutions, living cells, and mouse models confirmed its sensitivity, reliability, and feasibility. Simply mixing blood with the probe for 30 min yielded a clear signal readout within 15 s on the POCT device. Utilizing this portable detector, the reduced biothiol level was tested in 18 liver injury patient blood samples, and the results were similar to those measured by a commercial kit and in vivo imaging system. Thus, this work provides a universal platform for the fast and convenient detection of other biomarkers in whole blood samples and opens up possibilities for the rapid clinical diagnosis of diseases, enabling patients to conduct home self-examinations with ease.

Following the Trace of Cyclodextrins on the Selenium and Tellurium Odyssey.

There is an urgent need to develop safer and more effective modalities for the treatment of numerous pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Over the past decades, cyclodextrins (CDs) have gathered great attention as potential drug carriers due to their ability to enhance their bioactivities and properties. Likewise, selenium (Se) and tellurium (Te) have been extensively studied during the last decades due to their possible therapeutical applications. Although there is limited research on the relationship between Se and Te and CDs, herein, we highlight different representative examples of the advances related to this topic as well as give our view on the future directions of this emerging area of research. This review encompasses three different aspects of this relationship: (1) modification of the structure of the different CDs; (2) formation of host-guest interaction complexes of naïve CDs with Se and Te derivatives in order to overcome specific limitations of the latter; and (3) the use of CDs as catalysts to achieve novel Se and Te compounds.

Sensitive and accurate monitoring of urinary albumin and point-of-care testing using a fluorescent probe with anti-interference capacity against exogenous drugs

Fluorescent probes have been reported for monitoring urinary albumin (u-ALB) to enable early diagnosis of kidney diseases and facilitate regular point-of-care testing (POCT) for chronic kidney disease (CKD) patients. However, the albumin can bind hydrophobic drugs through host-guest interactions, which may result in decreased accuracy of probes at regular drug sites and hamper POCT of albuminuria since CKD patients often need to take medications routinely. Herein, we reported a novel fluorescent probe (NC-2) by molecular engineering of a reported AIEgen (NC-1). The introduction of a non-conjugated ring moiety to the molecular rotor granted the NC-2 enhanced sensitivity with a limit of detection in urine of 8.7 mg/L, which is below l the threshold of microalbuminuria (30 mg/L). Moreover, the NC-2 was found to preferentially bind to the FA1 site of ALB, conferring it with excellent anti-interference capacities against exogenous drug molecules and metabolites. Simulation experiments using lab-spiked urine samples containing common drugs taken by CKD patients demonstrated that the probe could provide satisfied detecting accuracy (80–90 %). Furthermore, a paper-based device was constructed and achieved on-site detection of u-ALB in qualitative and semi-quantitative manners. Findings in this work were of great significance to the development of fluorescent probes for accurate detection of ALB in complex urine samples and the further achievement of fluorescence-based POCT for CKD.

Structural Basis of Cucurbituril-Containing Self-Assembled Supramolecular Chiral Materials.

Macrocycle-based host-guest complexation offers an intriguing protocol in producing chiroptical materials, while the bulky size and dynamic exchange between hosts and guests hinders the ordered aggregation to afford the long-range chiral arrangement. It remains great challenges in assembling cucurbit[n]urils (CB[n]s) included complexes to induce supramolecular chirality ascribed to the excellent water solubility and flexible packing. Herein, we unveiled the structural basis on the formation of chiroptical coassemblies from CB[n] (n=6, 7) complexes. Perylene diimides (PDIs) with cationic chiral pendants formed complexes in the aqueous media, which selectively showed chiroptical properties. Chlorination at the bay position, increasing alkyl length of cationic chiral pendants or reducing the number of polyaromatic rings would hinder the chiral aggregation. In a comprehensive manner, CB[6] favors ordered aggregation into one-dimensional fibrous nanoarchitectures that greatly facilitates the supramolecular chirality. In contrast, CB[7] with larger cavity and water solubility shrinks the ordered arrangement of complexes, reducing the formation possibility of supramolecular chiral nanoarchitectures. This work suggests the great potential of CB[6] in the preparation and manipulation of supramolecular chiral assemblies, shedding light on the macrocycle-based functional chiroptical materials.

Natural product synthesis by a nanoporous In-MOF Catalyst: Crystallographic insight by incorporating substrate inside its nanopores

Metal-organic frameworks (MOFs) are promising candidates as nanoporous heterogeneous catalysts over other solid catalysts. Herein, utilizing a new tetra-acid ligand and employing high-valent Indium metal source we have strategically developed a 3D robust nanoporous framework, IITKGP-53, which retained its crystallinity over a wide range of pH solutions (2–12). Considering the green synthesis approach IITKGP-53 was explored as a heterogeneous catalyst toward one-pot three-component Strecker reaction under solvent-free condition, with low catalyst loading for a broad range of substrates. Considering practical utility, biologically important natural product, Girgensohnine, was synthesized for the first time by using this catalyst with excellent conversion rate. The substrate binding sites inside the nanopores and host–guest interactions were verified crystallographically by obtaining a substrate inside nanopores of this MOF (aniline@IITKGP-53) and computational modeling. An in-depth theoretical investigation unveiled the most plausible transition states for the first time. This study inaugurates the usage of nanoporous MOFs as heterogeneous catalysts for natural product synthesis.

Dual-emissive gold nanocluster / polylysine complex for ratio and visual luminescent detection

Heavy metals pollution shows a serious threat to global human and animal populations. Especially, mercury ions (Hg2+) are non-biodegradable and could accumulated through the food chain, causing severe damage to central nervous system and immune system. The sensitive and rapid detection of Hg2+ is important for human safety. In this study, based on the host–guest interaction between D-penicillamine (DPA) modified AuNCs and polylysine (PLL), a AuNCs@PLL complex system is constructed. The network of PLL enhances the luminescence properties of AuNCs through electrostatic interaction and hydrogen bonding. In combination with the blue emission of PLL, the AuNCs@PLL complex exhibits dual-emitting luminescence, which could be employed as a promising luminescent probe for Hg2+ detection. The high-affinity metallophilic Hg2+-Au+ interactions leads to the decomposition of AuNCs and consequently quenches the red emission, but the blue emission originating from PLL is unaffected. Based on this characteristic, a ratio luminescent probe targeted for quick accurate detection of Hg2+ is developed. Furthermore, paper test strips were fabricated employing the AuNCs@PLL luminescent probe for visual semi-quantitative Hg2+ detection. In addition to the benefits for sustainable development of the environment, health of the human, this study also has theoretical values for understanding the mechanism of NCs self-assembly.

Dual-lanthanide cyclodextrin-polyoxometalate fluorescent assembly for rapid and sensitive detection of ciprofloxacin

Quick screening and in-situ detection of trace antibiotics in environmental samples is needed for better control and monitoring of antibiotics pollution. Herein, a novel dual-lanthanide (Tb3+ and Eu3+) cyclodextrin-polyoxometalate fluorescent assembly (CD-LnPOM) has been developed for ciprofloxacin (CIP) detection. The "ratiometric" fluorescence response of CD-LnPOM enables specific detection of CIP within 5 s over a wide concentration range (0–100 μM) with a detection limit of 0.266 nM. When CIP presents, cyclodextrin acts as a host and encapsulates CIP in the cavity through host-guest interaction, which enhances the antenna sensitization between Tb3+ and CIP. Meanwhile, due to the more robust coordination between CIP and Tb3+, CIP blocks the energy transfer from Tb3+ to Eu3+ and recovers the sensitization of Tb3+ by POM. Based on the developed CD-LnPOM probe, a portable sensing device based on digital image color analysis is successfully demonstrated for real river water and antibiotic sludge samples. The developed fluorescent probe enables rapid and in-situ detection of trace antibiotics, which offers a new method for antibiotics screening and monitoring.

Investigation of the structural and thermodynamic properties of the inclusion complex of apixaban with natural cyclodextrins

Apixaban (APX) is an anticoagulant drug with poor aqueous solubility, limiting its bioavailability. This study investigates whether solubility can be enhanced by inclusion of APX within the native (α-, β-, and γ-) cyclodextrins (CDs). Phase solubility studies revealed an enhancement in solubility in the presence of β-CD. The complex formation constant for β-CD was found to be one order of magnitude higher than that of α-CD and γ-CD (K11 = 35, 268 and 41 M−1 for α-, β- and γ-CDs, respectively). 1H NMR spectra in DMSO confirmed the formation of the APX/β-CD complex in solution. Infrared (IR) spectroscopy and differential scanning calorimetry (DSC) confirmed the formation of an APX/β-CD inclusion complex in the solid state. Molecular dynamics (MD) simulations were employed to study the dynamics and host-guest interactions of APX with the CDs. MM-PBSA estimates of the binding free energies revealed a higher stability of the complex with β-CD compared to the other two, in agreement with the experimental results, with favorable van der Waals and electrostatic interactions, and with the former contributing much more significantly.

2,3 : 6,7-Naphthalene Bis(dicarboximide) Cyclophane: A Photofunctional Host for Ambient Delayed Fluorescence in Solution.

Harvesting triplet excitons of heavy atom-free purely organic chromophores under aerated conditions is challenging due to the quenching of long-lived triplet states by molecular oxygen and vibrational dissipation. Herein, we show a supramolecular approach of triplet harvesting via mitigating quenching pathways of a triplet harvester. Specifically, we used a host-guest system based on 2,3 : 6,7-naphthalene bis(dicarboximide)-derived cyclophane (NBICy) and carbazole derivative (EtCz). Complexation studies and single-crystal X-ray analysis showed the formation of a rigid host-guest complex (K≈104 M-1 in CCl4), resulting in triplet-exciton stabilization under aerated conditions via mitigating vibrational interference and oxygen quenching. Photophysical studies elucidate the delayed fluorescence emission from the charge-transfer state (1CT) with a quantum yield (QY) of 6-8 % under ambient conditions which increased up to 36 % in an inert atmosphere.

A Benchmark Test of High-Throughput Atomistic Modeling for Octa-Acid Host–Guest Complexes

Years of massive applications of high-throughput atomistic modeling tools such as molecular docking and end-point free energy calculations in the drug industry and academic exploration have made them indispensable parts of hierarchical screening. While the similarities between host–guest and protein–ligand complexes lead to the direct extension of techniques for protein–ligand screening to host–guest systems, the practical performance of these hit identification tools remains unclear in host-–-guest binding. Recent reports on specific host–guest complexes suggest that the experience on the accuracy ladder accumulated from protein–ligand cases could be invalid in host–guest complexes, which makes it an urgent need to perform a systematic benchmark to secure solid numerical supports and guidance of practical setups. Concerning molecular docking, there still lacks a comprehensive benchmark considering popular docking programs. As for end-point reranking, quantitative and rigorous free energy estimation via end-point formulism requires establishing statistically meaningful measurements of uncertainties due to finite sampling, which is neglected or underestimated by a significant portion in almost all main-stream applications. Further, a face-to-face comparison between different screening tools is required for the design of a hierarchical workflow. To fill the above-mentioned critical gaps, in this work, using a dataset containing tens of host–guest complexes involving basket-like macromolecular hosts from the octa acid family, we extensively benchmark seven academic docking protocols and perform post-docking end-point rescoring with twenty protocols. The resulting comprehensive benchmark provides conclusive pictures of the practical value of docking and end-point screening in OA host–guest binding.

CageCavityCalc (C3): A Computational Tool for Calculating and Visualizing Cavities in Molecular Cages.

Organic(porous) and metal-organic cages are promising biomimetic platforms with diverse applications spanning recognition, sensing, and catalysis. The key to the emergence of these functions is the presence of well-defined inner cavities capable of binding a wide range of guest molecules and modulating their properties. However, despite the myriad cage architectures currently available, the rational design of structurally diverse and functional cages with specific host-guest properties remains challenging. Efficiently predicting such properties is critical for accelerating the discovery of novel functional cages. Herein, we introduce CageCavityCalc (C3), a Python-based tool for calculating the cavity size of molecular cages. The code is available on GitHub at https://github.com/VicenteMartiCentelles/CageCavityCalc. C3 utilizes a novel algorithm that enables the rapid calculation of cavity sizes for a wide range of molecular structures and porous systems. Moreover, C3 facilitates easy visualization of the computed cavity size alongside hydrophobic and electrostatic potentials, providing insights into host-guest interactions within the cage. Furthermore, the calculated cavity can be visualized using widely available visualization software, such as PyMol, VMD, or ChimeraX. To enhance user accessibility, a PyMol plugin has been created, allowing nonspecialists to use this tool without requiring computer programming expertise. We anticipate that the deployment of this computational tool will significantly streamline cage cavity calculations, thereby accelerating the discovery of functional cages.

Photoelectrochemical sensor consisting of sulfhydryl-borate ester modified A1/B1 type Pillar[5]arene-functionalized gold NPs

Recognition of mitochondrial reactive oxygen species (ROS) in cells is essential for understanding the critical roles of different ROS in biology reaction processes. In this study, an ultrasensitive and specific photoelectrochemical (PEC) sensor is constructed and applied for the capture and identification of H2O2 in cells. For the targeted detection of H2O2 in cells containing similar groups, such as •OH and O2•-, a new sulfhydryl-borate ester modified A1/B1 type pillar[5]arene (BP5) with a specific borate group is designed as a specific recognition molecule, and Au nanoparticles (Au NPs) are synthesized as the photoactive material. Specifically, the localized surface plasmon resonance (LSPR) of the Au NPs and host-guest interaction between BP5 and H2O2 increase the photocurrent signal. At the same time, specific groups on BP5 react with H2O2 to specifically recognize it. The Au@BP5/GCE shows strong photoelectrochemical response for the detection of H2O2 with limit of detection (0.33 pM, S/N=3), an extended linear range (1–60 pM), high specificity, good stability and excellent reproducibility.