A General Strategy for Enhanced Photodynamic Antimicrobial Therapy with Perylenequinonoid Photosensitizers Using a Macrocyclic Supramolecular Carrier.

Perylenequinonoid natural products are a class of photosensitizers (PSs) that exhibit high reactive oxygen species (ROS) generation and excellent activity for Type I/Type II dual photodynamic therapy. However, their limited activity against gram-negative bacteria and poor water solubility significantly restrict their potential in broad-spectrum photodynamic antimicrobial therapy (PDAT). Herein, a general approach to overcome the limitations of perylenequinonoid photosensitizers (PQPSs) in PDAT by utilizing a macrocyclic supramolecular carrier is presented. Specifically, AnBox·4Cl, a water-soluble cationic cyclophane, is identified as a universal macrocyclic host for PQPSs such as elsinochrome C, hypocrellin A, hypocrellin B, and hypericin, forming 1:1 host-guest complexes with high binding constants (≈107 m -1) in aqueous solutions. Each AnBox·4Cl molecule carries four positive charges that promote strong binding with the membrane of gram-negative bacteria. As a result, the AnBox·4Cl-PQPS complexes can effectively anchor on the surfaces of gram-negative bacteria, while the PQPSs alone cannot. In vitro and in vivo experiments demonstrate that these supramolecular PSs have excellent water solubility and high ROS generation, with broad-spectrum PDAT effect against both gram-negative and gram-positive bacteria. This work paves a new path to enhance PDAT by showcasing an efficient approach to improve PQPSs' water solubility and killing efficacy for gram-negative bacteria.

Umbrella-Shaped Amphiphiles: Internal Alkylation of an Aromatic Micelle and Its Impact on Cavity Features.

To develop new hybrid micelles with alkyl/polyaromatic core-shell structures, we synthesized umbrella-shaped amphiphiles bearing a bent anthracene dimer with a linear alkyl chain (i.e., octyl and hexadecyl groups). The amphiphiles quantitatively assemble into spherical micelles (~2-3 nm in core diameter), possessing an alkylated cavity surrounded by a polyaromatic framework, in water. The alkylation significantly enhances the stability of the micellar structures against dilution (up to 9 µM) and heat (up to >120 °C). The highly condensed hexadecyl core of the hybrid micelle, as indicated by solvatochromic guest probes, displays increased uptake ability toward large alkylated metallodyes. Interestingly, efficient uptake of aromatic macrocycles (i.e., [n]cycloparaphenylenes) by the present micelle provides pseudorotaxane-shaped host-guest composites with high emissivity (ΦF=up to 35 %). Internal multi-alkylation of an aromatic micelle can thus successfully enhance its assembly stability/guest uptake functions.

Spatial arrangements of cyclodextrin host-guest complexes in solution studied by 13C NMR and molecular modelling.

13C NMR spectroscopic analyses of Cs symmetric guest molecules in the cyclodextrin host cavity, combined with molecular modelling and solid-state X-ray analysis, provides a detailed description of the spatial arrangement of cyclodextrin host-guest complexes in solution. The chiral cavity of the cyclodextrin molecule creates an anisotropic environment for the guest molecule resulting in a splitting of its prochiral carbon signals in 13C NMR spectra. This signal split can be correlated to the distance of the guest atoms from the wall of the host cavity and to the spatial separation of binding sites preferred by pairs of prochiral carbon atoms. These measurements complement traditional solid-state analyses, which rely on the crystallization of host-guest complexes and their crystallographic analysis.

Switchable Metal-Ion Selectivity in Sulfur-Functionalised Pillar[5]arenes and Their Host-Guest Complexes.

Nucleophilic substitution of pertosylated pillar[5]arene (P-OTs) with commercially available sulfur containing nucleophiles (KSCN, KSAc, and thiophenol), yields a series of sulfur-functionalised pillar[5]arenes. DLS results and SEM images imply that these pillararene macrocycles self-assemble in acetonitrile solution, while X-ray crystallographic evidence suggests solvent-dependent assembly in the solid state. The nature of the sulfur substituents decorating the rim of the pillararene controls binding affinities towards organic guest encapsulations within the cavity and dictates metal-ion binding properties through the formation of favorable S-M2+ coordination bonds outside the cavity, as determined by 1 H NMR and fluorescence spectroscopic experiments. Addition of a dinitrile guest containing a bis-triazole benzene spacer (btn) induced formation of pseudorotaxane host-guest complexes. Fluorescence emission signals from these discrete macrocycles were significantly attenuated in the presence of either Hg2+ or Cu2+ in solution. Analogous titrations utilizing the corresponding pseudorotaxanes alter the binding selectivity and improve fluorescence sensing sensitivity. In addition, preliminary liquid-liquid extraction studies indicate that the macrocycles facilitate the transfer of Cu2+ from the aqueous to the organic phase in comparison to extraction without pillar[5]arene ligands.

Trianglimine-Mediated Selective Sieving of Cis Isomer from the Mixture of Dihaloethenes: A Combined Molecular Dynamics and DFT Investigation.

The manufacture of alkenyl halides on a larger scale often results in the formation of a mixture of isomers, each having individual significant applications while their separation from each other is a strenuous task. Since most of the conventional distillation techniques are known to be intricate, energy consuming and expensive, the quest for an alternative separation strategies is still continuing. In this context, the recently reported trianglimine macrocycle - a new class of intrinsically porous material, is promising in discerning cis isomer from a mixture of cis and trans dichloroethene. Herein, an attempt has been made to apprehend the host-guest inclusion phenomenon accountable for the selectivity of cis over the trans isomers of 1,2-dihaloethene (F, Cl and Br) using molecular dynamics simulation and density functional calculations at ω-B97xd/6-311G+(d,p) level of theory. The average binding energy of selected snapshots has been calculated at different loadings, temperatures and pressures from molecular dynamics simulation. Our results show that trianglimine can stabilise the cis isomers of the dihaloethenes inside its cavity forming complexes with high interaction energies and the rationale behind the recyclability of the host molecule has been clarified. The outcomes of the calculations bring out the potential utility of this new host architecture to produce highly pure value added chemicals in industries.

Selective Molecular Recognition and Indicator Displacement Sensing of Neurotransmitters in Cellular Environments.

Flexible, water-soluble hosts are capable of selective molecular recognition in cellular environments and can detect neurotransmitters such as choline in cells. Both cationic and anionic water-soluble self-folded deep cavitands can recognize suitable styrylpyridinium dyes in cellular interiors. The dyes selectively accumulate in nucleotide-rich regions of the cell nucleus and cytoplasm. The hosts bind the dyes and promote their relocation to the outer cell membrane: the lipophilic cavitands predominantly reside in membrane environments but are still capable of binding suitable targets in other cellular organelles. Incubating the cells with structurally similar biomarkers such as choline, cholamine, betaine, or butyrylcholine illustrates the selective recognition. Choline and butyrylcholine can be bound by the hosts, but minimal binding is seen with betaine or cholamine. Varying the dye allows control of the optical detection method, and both "turn-on" sensing and "turn-off" sensing are possible.

A Review on Cyclodextrins/Estrogens Inclusion Complexes.

This review focuses on the methods of preparation and biological, physiochemical, and theoretical analysis of the inclusion complexes formed between estrogens and cyclodextrins (CDs). Because estrogens have a low polarity, they can interact with some cyclodextrins' hydrophobic cavities to create inclusion complexes, if their geometric properties are compatible. For the last forty years, estrogen-CD complexes have been widely applied in several fields for various objectives. For example, CDs have been used as estrogen solubilizers and absorption boosters in pharmaceutical formulations, as well as in chromatographic and electrophoretic procedures for their separation and quantification. Other applications include the removal of the endocrine disruptors from environmental materials, the preparation of the samples for mass spectrometric analysis, or solid-phase extractions based on complex formation with CDs. The aim of this review is to gather the most important outcomes from the works related to this topic, presenting the results of synthesis, in silico, in vitro, and in vivo analysis.

Noncovalent Modulation of Chemoselectivity in the Gas Phase Leads to a Switchover in Reaction Type from Heterolytic to Homolytic to Electrocyclic Cleavage.

In the gas phase, thermal activation of supramolecular assemblies such as host-guest complexes leads commonly to noncovalent dissociation into the individual components. Chemical reactions, for example of encapsulated guest molecules, are only found in exceptional cases. As observed by mass spectrometry, when 1-amino-methyl-2,3-diazabicyclo[2.2.2]oct-2-ene (DBOA) is complexed by the macrocycle ß-cyclodextrin, its protonated complex undergoes collision-induced dissociation into its components, the conventional reaction pathway. Inside the macrocyclic cavity of cucurbit[7]uril (CB7), a competitive chemical reaction of monoprotonated DBOA takes place upon thermal activation, namely a stepwise homolytic covalent bond cleavage with the elimination of N2 , while the doubly protonated CB7⋅DBOA complex undergoes an inner-phase elimination of ethylene, a concerted, electrocyclic ring-opening reaction. These chemical reaction pathways stand in contrast to the gas-phase chemistry of uncomplexed monoprotonated DBOA, for which an elimination of NH3 predominates upon collision-induced activation, as a heterolytic bond cleavage reaction. The combined results, which can be rationalized in terms of organic-chemical reaction mechanisms and density-function theoretical calculations, demonstrate that chemical reactions in the gas phase can be steered chemoselectively through noncovalent interactions.

Noncovalent PEGylation of protein and peptide therapeutics.

Clinical applications of protein therapeutics-an advanced generation of drugs characterized by high biological specificity-are rapidly expanding. However, their development is often impeded by unfavorable pharmacokinetic profiles and largely relies on the use of drug delivery systems to prolong their in vivo half-life and suppress undesirable immunogenicity. Although a commercially established PEGylation technology based on protein conjugation with poly(ethylene glycol) (PEG)-protective steric shield resolves some of the challenges, the search for alternatives continues. Noncovalent PEGylation, which mainly relies on multivalent (cooperative) interactions and high affinity (host-guest) complexes formed between protein and PEG offers a number of potential advantages. Among them are dynamic or reversible protection of the protein with minimal loss of biological activity, drastically lower manufacturing costs, "mix-and-match" formulations approaches, and expanded scope of PEGylation targets. While a great number of innovative chemical approaches have been proposed in recent years, the ability to effectively control the stability of noncovalently assembled protein-PEG complexes under physiological conditions presents a serious challenge for the commercial development of the technology. In an attempt to identify critical factors affecting pharmacological behavior of noncovalently linked complexes, this Review follows a hierarchical analysis of various experimental techniques and resulting supramolecular architectures. The importance of in vivo administration routes, degradation patterns of PEGylating agents, and a multitude of potential exchange reactions with constituents of physiological compartments are highlighted. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Cooperative Supramolecular Polymerization of Triphenylamine bis-Urea Macrocycles.

Herein, we probe the hydrogen bond-driven self-assembly of a triphenylamine (TPA) bis-urea macrocycle in the presence and absence of guests. Comprised of methylene urea-bridged TPAs with exterior tridodecyloxy benzene solubilizing groups, the macrocycle exhibits concentration-dependent aggregate formation in THF and H2 O/THF mixtures as characterized by 1 H NMR and DOSY experiments. Its assembly processes were further probed by temperature-dependent UV/Vis and fluorescence spectroscopy. Upon heating, UV/Vis spectra exhibit a hypsochromic shift in the λmax , while fluorescence spectra show an increase in emission intensity. Conversely, the protected macrocycle that lacks hydrogen bond donors demonstrates no significant change. Thermodynamic analysis indicates a cooperative self-assembly pathway with distinct nucleation and elongation regimes. The morphology and structure of the aggregate were elucidated by dynamic light scattering, atomic force microscopy, scanning and transmission electron microscopy. Variable temperature emission spectra were utilized to monitor the impact of guests, such as diphenylacetylene, that can be bound in the columnar channels. The findings suggest that the elongation of assemblies is influenced by the presence of these guests. In comparison, diphenyl sulfoxide, likely functioning as a chain stopper, limited the assembly size. These studies suggest that judicious selection of (co)monomers may modulate the function and utility of these supramolecular systems.

Pillararenes as Promising Carriers for Drug Delivery.

Since their discovery in 2008 by N. Ogoshi and co-authors, pillararenes (PAs) have become popular hosts for molecular recognition and supramolecular chemistry, as well as other practical applications. The most useful property of these fascinating macrocycles is their ability to accommodate reversibly guest molecules of various kinds, including drugs or drug-like molecules, in their highly ordered rigid cavity. The last two features of pillararenes are widely used in various pillararene-based molecular devices and machines, stimuli-responsive supramolecular/host-guest systems, porous/nonporous materials, organic-inorganic hybrid systems, catalysis, and, finally, drug delivery systems. In this review, the most representative and important results on using pillararenes for drug delivery systems for the last decade are presented.

Manipulating Host-Guest Charge Transfer of a Water-Soluble Double-Cavity Cyclophane for NIR-II Photothermal Therapy.

Water-soluble small organic photothermal agents (PTAs) over NIR-II biowindow (1000-1350 nm) are highly desirable, but the rarity greatly limits their applications. Based on a water-soluble double-cavity cyclophane GBox-44+ , we report a class of host-guest charge transfer (CT) complexes as structurally uniform PTAs for NIR-II photothermal therapy. As a result of its high electron-deficiency, GBox-44+ can bind different electron-rich planar guests with a 1 : 2 host/guest stoichiometry to readily tune the CT absorption band that extends to the NIR-II region. When using a diaminofluorene guest substituted with an oligoethylene glycol chain, the host-guest system realized both good biocompatibility and enhanced photothermal conversion at 1064 nm, and was then exploited as a high-efficiency NIR-II PTA for cancer cell and bacterial ablation. This work broadens the potential applications of host-guest cyclophane systems and provides a new access to bio-friendly NIR-II photoabsorbers with well-defined structures.

Ultrasensitive hydrogel grating detector for real-time continuous-flow detection of trace threat Pb2.

Ultrasensitive real-time detection of trace Pb2+ in continuous flow is vital to effectively and timely eliminate the potential hazards to ecosystem health and sustainability. This work reports on a micro-structured smart hydrogel grating with ultra-sensitivity, high selectivity, good transparency and mechanical property for real-time detection of Pb2+ in continuous flow. The hydrogel grating possesses uniform surface relief microstructures with periodic nano-height ridges made of poly(acrylamide-co-benzo-18-crown-6-acrylamide) networks that crosslinked by tetra-arm star poly(ethylene glycol)acrylamide. The hydrogel grating with good optical transparency and mechanical property can change its height via selective host-guest complexation with Pb2+ to output a changed diffraction efficiency. Meanwhile, the periodic nano-ridges with large specific area benefit the contact with Pb2+ for fast Pb2+-induced height change. Thus, with such rationally designed molecular structures and surface relief microstructures, the hydrogel grating integrated in a glass-based mini-chip allows real-time detection of Pb2+ in continuous flow with ultra-sensitivity and high selectivity. The hydrogel grating detector can achieve ultralow detection limit (10-9 M Pb2+), fast response (2 min), and selective detection of Pb2+ from dozens of interfering ions even with high concentrations. This high-performance hydrogel grating detector is general and can be extended to detect many analytes due to the wide choice of responsive hydrogels, thus opening new areas for creating advanced smart detectors in analytical science.

Circularly polarized luminescence in molecular recognition systems: Recent achievements.

Circularly polarized luminescence (CPL) dyes are recognized to be new generation materials and have been actively developed. Molecular recognition systems provide nice approaches to novel CPL materials, such as stimuli-responsive switches and chemical sensing materials. CPL may be induced simply by mixing chiral or achiral, luminescent or nonluminescent host and guest; there are several combinations. Molecular recognition can potentially save time and effort to construct well-ordered chiral structures with noncovalent attractive interactions as compared with the multi-step synthesis of covalently bonded dyes. It is a challenging subject to engage molecular recognition events with CPL, and it is important and interesting to see how it is achieved. In fact, simple molecular recognition systems can even enable the fine adjustment of CPL performance and detailed conformational/configurational analysis of the excited state. Here we overview the recent achievements of simple host-guest complexes capable of exhibiting CPL, summarizing concisely the host/guest structures, CPL intensities, and characteristics.

Modulation of redox reactivity of resazurin through host-guest complexation with Cucurbit[n]uril (n = 7, 8).

Resazurin (Alamar Blue, RZ) is a widely utilized fluorescent probe for biological sensing, whose fluorescent intensity can be modulated by changing its redox states; thereby, electrochemical reactivity of RZ is of significance when designing a sensing assay. Herein, we report novel two-way electrochemical reactivity modulation of RZ using host-guest complexation with rigid molecular containers cucurbit[n]uril (CBn, n = 7, 8). The complexation between CBn and RZ is confirmed by 1H NMR measurements and supported by computational simulation, and the binding constants are determined via UV-vis titration. Notably, the voltametric data highlights that the redox reactivity of RZ can be activated or deactivated upon encapsulation by CB8 or CB7, respectively. This two-way reactivity modulation is hypothesized to be mediated by the difference in cavity volume that favors or hinders the approach of water molecules to the encapsulated reaction center during the reduction process. Despite the similar cavity size to CB, molecular containers such as cyclodextrins (CDs) exhibit considerably weaker modulation effects. Our approach can potentially be applied to other redox processes that involve proton transfer, and open new possibilities in supramolecular electrochemistry.

Ultra-Tight Host-Guest Binding with Exceptionally Strong Positive Cooperativity.

Cooperativity plays a critical role in self-assembly and molecular recognition. A rigid aromatic oligoamide macrocycle with a cyclodirectional backbone binds with DABCO-based cationic guests in a 2 : 1 ratio in high affinities (Ktotal ≈1013  M-2 ) in the highly polar DMF. The host-guest binding also exhibits exceptionally strong positive cooperativity quantified by interaction factors α that are among the largest for synthetic host-guest systems. The unusually strong positive cooperativity, revealed by isothermal titration calorimetry (ITC) and fully corroborated by mass spectrometry, NMR and computational studies, is driven by guest-induced stacking of the macrocycles and stabilization from the alkyl end chains of the guests, interactions that appear upon binding the second macrocycle. With its tight binding driven by extraordinary positive cooperativity, this host-guest system provides a tunable platform for studying molecular interactions and for constructing stable supramolecular assemblies.

Highly Efficient and Selective Recognition of Dicyanoaurate(I) by a Bambusuril Macrocycle in Water.

Dicyanoaurate(I) anion, [Au(CN)2 ]- , plays a central role in the current industrial production of gold, as its extraction from crude ore samples represents the most money-consuming step. Herein, we present the strongest host-guest recognition of dicyanoaurate anion using the bambusuril receptor in water, a highly competitive solvent. The micromolar stability of such a complex facilitated the up to date most efficient supramolecular stripping of dicyanoaurate from activated carbon at ambient temperature. Thermodynamic characteristics of bambusuril binding with [Au(CN)2 ]- differing from binding of other inorganic chaotropic anions are rationalized, as well as the bambusuril selectivity for [Au(CN)2 ]- over [Ag(CN)2 ]- .

Cucurbit[7]uril-Encapsulation-Controlled Supramolecular Photoproduct and Radical Fluorescence Emission.

Herein, a host-guest interaction-controlled photoproduct created by using cucurbit[7]uril (Q[7])-based pseudorotaxane structures is reported. The assembly exhibited controlled behavior towards the reduction of the ethylene (C=C) bond in the tetrakis(pyridin-4-yl)ethylene (TPyE) guest molecule under UV light irradiation. This can be attributed to the Q[7] encapsulation masking the four pyridinium arms of the guest, which inhibits planarization of the TPyE core to form the cyclization product. In particular, the strong affinity of Q[7] for the butyl-substituted guest (TPyE-4C) led to an unusual radical fluorescence emission of the photoirradiation-triggered intermediate of the guest molecule being observed in aqueous solution. This work provides a valuable paradigm and new insight for macrocycle-based host-guest interactions in supramolecular catalysis and luminescent radical materials.

Current Status of Quantum Chemical Studies of Cyclodextrin Host-Guest Complexes.

This article aims to review the application of various quantum chemical methods (semi-empirical, density functional theory (DFT), second order Møller-Plesset perturbation theory (MP2)) in the studies of cyclodextrin host-guest complexes. The details of applied approaches such as functionals, basis sets, dispersion corrections or solvent treatment methods are analyzed, pointing to the best possible options for such theoretical studies. Apart from reviewing the ways that the computations are usually performed, the reasons for such studies are presented and discussed. The successful applications of theoretical calculations are not limited to the determination of stable conformations but also include the prediction of thermodynamic properties as well as UV-Vis, IR, and NMR spectra. It has been shown that quantum chemical calculations, when applied to the studies of CD complexes, can provide results unobtainable by any other methods, both experimental and computational.

Dynamic Interconversions of Single Molecules Probed by Recognition Tunneling at Cucurbit[7]uril-Functionalized Supramolecular Junctions.

We introduce a versatile recognition tunneling technique using doubly cucurbit[7]uril-functionalized electrodes to form supramolecular junctions that capture analytes dynamically by host-guest complexation. This results in characteristic changes in their single-molecule conductance. For structurally related drug molecules (camptothecin, sanguinarine, chelerythrine, and berberine) and mixtures thereof, we observed distinct current switching signals related to their intrinsic conductance properties as well as pH-dependent effects which can be traced back to their different states (protonated versus neutral). The conductance variation of a single molecule with pH shows a sigmoidal distribution, allowing us to extract a pKa value for reversible protonation, which is consistent with the reported macroscopic results. The new electronic method allows the characterization of unmodified drug molecules and showcases the transfer of dynamic supramolecular chemistry principles to single molecules.