Dual Responsive Regulation of Host–Guest Complexation in Aqueous Media to Control Partial Release of the Host

The regulation of the concentration of a wide range of small molecules is ubiquitous in biological systems because it enables them to adapt to the continuous changes in the environmental conditions. Herein, we report an aqueous synthetic system that provides an orchestrated, temperature and pH controlled regulation of the complexation between the cyclobis(paraquat-p-phenylene) host ( BBox ) and a 1,5-dialkyloxynaphthalene ( DNP ) guest attached to a well-defined dual responsive copolymer composed of N-isopropylacrylamide as thermoresponsive monomer and acrylic acid as pH-responsive monomer. Controlled, partial release of the BBox , enabling control over its concentration, is based on the tunable partial collapse of the copolymer. This colored supramolecular assembly is one of the first synthetic systems providing control over the concentration of a small molecule, providing great potential as both T and pH chromic materials and as a basis to develop more complex systems with molecular communication.     

Guest-Selective Recognition in a Flexible Bipyridinium-Based Framework in a Reversible Crystal-to-Crystal Fashion

A flexible bipyridinium-linker-based porous host framework with electron-accepting pore surface, namely, [Zn₂( L )(pmc)_1.5] ⋅ 12 H₂O ( 1 ; L⋅ Cl₂=1,1′-[1,4-phenylene-bis(methylene)]bis(4,4′-bipyridinium) dichloride, H₄pmc=pyromellitic acid) exhibits recognition of phenol and aromatic amine guests based on adsorbent–adsorbate charge-transfer interactions. Significantly, the resultant guest-encapsulated complexes 1@Guests can all be characterized by single-crystal X-ray diffraction. The host framework undergoes a reversible single crystal-to-single crystal transformation in response to the inclusion of different guests with flexible torsional motions of the hexagonal ring and the trapezoid-shaped bipyridinium groups. Such recognition can be visibly monitored and detected by obvious color changes. The host framework could also be recovered, and this suggested that guest sorption/desorption is reversible and that the host framework could be reused in potential applications. This work may provide an effective way to develop porous materials with special emphasis on applications involving guest recognition.     

Synthesis and Binding of Mannose-Specific Synthetic Carbohydrate Receptors

Synthetic carbohydrate receptors (SCRs) that selectively recognize cell-surface glycans could be used for detection, drug delivery, or as therapeutics. Here we report the synthesis of seven new C_2h symmetric tetrapodal SCRs. The structures of these SCRs possess a conserved biaryl core, and they vary in the four heterocyclic binding groups that are linked to the biaryl core via secondary amines. Supramolecular association between these SCRs and five biologically relevant C¹-O-octyloxy glycans, α/β-glucoside ( α/β-Glc ), α/β-mannoside ( α/β-Man ), and β-galactoside ( β-Gal ), was studied by mass spectrometry, ¹H NMR titrations, and molecular modeling. These studies revealed that selectivity can be achieved in these tetrapodal SCRs by varying the heterocyclic binding group. We found that SCR017 (3-pyrrole), SCR021 (3-pyridine), and SCR022 (2-phenol) bind only to β-Glc. SCR019 (3-indole) binds only to β-Man. SCR020 (2-pyridine) binds β-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and β-Gal with a preference to the former. The glycan guests bound within their SCR hosts in one of three supramolecular geometries: center-parallel, center-perpendicular, and off-center. Many host–guest combinations formed higher stoichiometry complexes, 2:1 glycan⋅SCR or 1:2 glycan⋅SCR , where the former are driven by positive allosteric cooperativity induced by glycan–glycan contacts.     

Dramatic Enhancement of Binding Affinities Between Foldamer-Based Receptors and Anions by Intra-Receptor π-Stacking

As a synthetic model for intra-protein interactions that reinforce binding affinities between proteins and ligands, the energetic interplay of binding and folding was investigated using foldamer-based receptors capable of adopting helical structures. The receptors were designed to have identical hydrogen-bonding sites for anion binding but different aryl appendages that simply provide additional π-stacking within the helical backbones without direct interactions with the bound anions. In particular, the presence of electron-deficient aryl appendages led to dramatic enhancements in the association constant between the receptor and chloride or nitrate ions, by up to three orders of magnitude. Extended stacking within the receptor contributes to the stabilization of the entire folding structure of complexes, thereby enhancing binding affinities.     

A Modular Phosphorylated Glycoluril-Derived Molecular Tweezer for Potent Binding of Aliphatic Diamines

A molecular tweezer based on a glycoluril-derived framework bearing four phosphate groups was synthesized and shown to be capable of binding organic amines in aqueous solution. This work reports the K_a values for 30 complexes of this molecular tweezer and amine guests, determined by means of ¹H NMR titrations. Both the hydrophobic cavity and the phosphate groups contribute to the binding. Bulkier molecules and molecules bearing negatively charged groups like carboxylates in amino acids bind less tightly due to a steric clash and coulombic repulsion. The narrow cavity and the strong ionic interactions of the phosphate groups with ammonium guests favor binding of aliphatic diamines. These binding properties clearly distinguish this system from structurally related molecular clips and tweezers.     

Constructing Adaptive Photosensitizers via Supramolecular Modification Based on Pillararene Host–Guest Interactions

In order to promote the development of photodynamic therapy (PDT), undesired side effects like low tumor specificity and the “always-on” phenomenon should be avoided. An effective solution is to construct an adaptive photosensitizer that can be activated to generate reactive oxygen species (ROS) in the tumor microenvironment. Herein, we design and synthesize a supramolecular switch based on a host–guest complex containing a water-soluble pillar[5]arene ( WP5 ) and an AIEgen photosensitizer ( G ). The formation of the host–guest complex WP5 ⊃ G quenches the fluorescence and inhibits ROS generation of G . Benefitting from the pH-responsiveness of WP5 , the binding site between G and WP5 changes in an acidic environment through a shuttle movement. Consequently, fluorescence and ROS generation of the host–guest complex can be switched on at pH 5.0. This work offers a new paradigm for the construction of adaptive photosensitizers by using a supramolecular method.     

Cambiarenes: Single-Step Synthesis and Selective Zwitterion Binding of a Clip-Shaped Macrocycle with a Redox-Active Core

A novel macrocyclic host molecule was synthesized that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, it is redox-active. Host–guest binding involving the clip-shaped cavity indicates selective binding of pyridine N-oxides based on the electron density of and steric bulk around the anionic oxygen.     

An Operative Electrostatic Slipping Mechanism along Macrocycle Flexibility Accelerates Guest Sliding during pseudo-Rotaxane Formation

A pseudo-rotaxane is a host−guest complex composed of a linear molecule encircled by a macrocyclic ring. These complexes can be assembled by sliding the host over the guest terminal groups. If there is a close match between the molecular volume of the flanking groups on the guest and the cavity size of the macrocycle, the slipping might occur slowly or even become completely hindered. We have previously shown that it is possible to overcome the restraints imposed by steric effects on the sliding process by integrating electrostatic attractive interactions during the slipping step. In this work, we extend our electrostatically assisted slipping approach (EASA) to a new host−guest system featuring a flexible macrocyclic ring and a series of asymmetric guests containing a cyclic tertiary ammonium group. Compelling evidence for pseudo-rotaxane formation is presented, along with thermodynamic and kinetic data. Experimental results suggests that the higher conformational flexibility of 24-crown-8 significantly increases the sliding rate, compared with the more rigid dibenzo-24-crown-8, without affecting complex stability. Furthermore, by combining the EASA and macrocycle flexibility, we were capable to slip a large eight-membered cyclic group across the 24-crown-8 annulus, setting a new limit on the ring molecular size that can pass through a 24-membered crown ether.     

Facile,high-yielding synthesis of deepened cavitands: a synthetic and theoretical study

A wide variety of 2-methyl-resorcinol-based deepened cavitands were synthesised from readily available reagents in a four-step procedure with overall yields of up to 62%. A systematic variation of the rim was carried out by building up a flexible upper aromatic wall on the rigid cavitand platform through CH₂, CH₂O and CH₂OCH₂ spacers. These aromatic walls were further extended by a Suzuki cross-coupling reaction. Full characterisation of the synthesised cavitands was carried out. The solid-state structure of tetrakis(phenoxymethyl)cavitand was determined by X-ray crystallography. Gas-phase theoretical calculations for this molecule predict the presence of weak T-shaped interactions between the upper phenyl rings. The host–guest complex formation ability of two deepened cavitand hosts towards 4-chloro-benzotrifluoride was proved by photoluminescence method.     

Highly Selective Binding and Inhibition of Pyr-His-Pro-NH2 (TRH) Function using a Polypyridinyl Macrocyclic Receptor with an Amphiphilic Cavity

Macrocycle, cyclo[4] [(1,3-(4,6)-dimethylbezene)[4](2,6-(3,5)-dimethylpyridine ( B4P4 ), shows highly selective binding affinity with protirelin (Pyr-His-Pro-NH₂; TRH) among the tested 26 drug or drug adductive substrates. The stable complexation in a 1:1 manner was fully characterized in solution, gas phase, and solid state study. Furthermore, B4P4 acts as an efficient TRH inhibitor even at [macrocycle]:[drug] <1:300, both in membrane transport and cellar incubation. The current work provides an unprecedented strategy for macrocycles to be efficiently used in drug target therapy.     

An Anionic Ring Locked into an Anionic Axle: A Metastable Rotaxane with Chemically Activated Electrostatic Stoppers

The use of the electrostatic stoppers concept in the field of mechanically interlocked molecules is reported; these stoppers are chemically sensitive end groups on a linear guest molecule that allows for the conversion of a pseudo-rotaxane species into a rotaxane complex by a change in the medium acidity. The chemical stimulus causes the appearance of negative charges on both ends of the linear component, passing from cationic to anionic, and causing a significant ring-to-axle electrostatic repulsion. This phenomenon has two different and simultaneous effects: 1) destabilizes the complex as a consequence of confining an anionic ring into an anionic axle, and 2) increases the dissociation energy barrier, thus impeding ring extrusion. This newly formed metastable rotaxane species is resistant to solvent and temperature effects and performs as a two-state degenerated molecular shuttle in solution.     

Redox-Guest-Induced Multimode Photoluminescence Switch for Sequential Logic Gates in a Photoactive Coordination Cage

Molecular or supramolecular level photoluminescence (PL) modulation combining chemical and photonic input/output signals together in an integrated system can provide potential high-density data memorizing and process functions intended for miniaturized devices and machines. Herein, a PL-responsive supramolecular coordination cage has been demonstrated for complex interactions with redox-active guests. PL signals of the cage can be switched and modulated by adding or retracting Fc derivatives or converting TTF into different oxidation states through chemical or photochemical pathways. As a result, reversible or stepwise PL responses are displayed by these host–guest systems because of the occurrence of photoinduced electron-transfer (PET) or fluorescence resonance energy transfer (FREnT) processes, providing unique nanodevice models bearing off/on logic gates or memristor-like sequential memory and Boolean operation functions.     

A Binary Bivalent Supramolecular Assembly Platform Based on Cucurbit[8]uril and Dimeric Adapter Protein 14-3-3

Interactions between proteins frequently involve recognition sequences based on multivalent binding events. Dimeric 14-3-3 adapter proteins are a prominent example and typically bind partner proteins in a phosphorylation-dependent mono- or bivalent manner. Herein we describe the development of a cucurbit[8]uril (Q8)-based supramolecular system, which in conjunction with the 14-3-3 protein dimer acts as a binary and bivalent protein assembly platform. We fused the phenylalanine–glycine–glycine (FGG) tripeptide motif to the N-terminus of the 14-3-3-binding epitope of the estrogen receptor α (ERα) for selective binding to Q8. Q8-induced dimerization of the ERα epitope augmented its affinity towards 14-3-3 through a binary bivalent binding mode. The crystal structure of the Q8-induced ternary complex revealed molecular insight into the multiple supramolecular interactions between the protein, the peptide, and Q8.     

Urea Derivatives as Functional Molecules: Supramolecular Capsules,Supramolecular Polymers,Supramolecular Gels,Artificial Hosts,and Catalysts

Urea, which has both hydrogen bond acceptor and donor moieties, is an ideal structure for a supramolecular synthon. Various supramolecules having ureido group(s) have been widely developed. This article summarizes recent developments of urea derivatives that exhibit various functions: i) supramolecular capsules that form discrete urea–urea intermolecular hydrogen bonds, ii) supramolecular polymers that form continuous urea–urea intermolecular hydrogen bonds, iii) supramolecular gels that form continuous urea–urea intermolecular hydrogen bonds, iv) artificial host molecules based on the molecular recognition ability of the ureido group, and v) catalytic reactions developed by utilizing the molecular recognition ability of the ureido group.     

Dynamic Combinatorial Chemistry: A New Methodology Comes of Age

Dynamic combinatorial chemistry (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromolecular targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodynamic equilibrium. However, upon addition of a macromolecular host which can bind and stabilize certain components of the library, the equilibrium composition changes and induces an evolution-like selection and enrichment of high-affinity ligands. A valuable application of this so-called target-directed DCC (tdDCC) is the identification of potent ligands for pharmacologically relevant targets. Over time, the term tdDCC has been applied to describe a number of different experimental setups, leading to some ambiguity concerning its definition. This article systematically classifies known procedures for tdDCC and related approaches, with a special focus on the methods used for analysis and evaluation of experiments.     

Tuning the Outcome of Enzyme-Mediated Dynamic Cyclodextrin Libraries to Enhance Template Effects

Enzyme-mediated dynamic combinatorial chemistry combines the concept of thermodynamically controlled covalent self-assembly with the inherent biological relevance of enzymatic transformations. A system of interconverting cyclodextrins has been explored, in which the glycosidic linkage is rendered dynamic by the action of cyclodextrin glucanotransferase (CGTase). External factors, such as pH, temperature, solvent, and salinity are reported to modulate the composition of the dynamic cyclodextrin library. Dynamic libraries of cyclodextrins (CDs) could be obtained in wide ranges of pH (5.0–9.0), temperature (5–37 °C), and salinity (up to 7.5 m NaNO₃), and with high organic solvent content (50 % by volume of ethanol), showing that enzyme-mediated dynamic systems can be robust and not limited to physiological conditions. Furthermore, it is demonstrated how strategic choice of reaction conditions can enhance template effects, in this case, to achieve highly selective production of α-CD, an otherwise challenging target due to competition from the structurally similar β-CD.     

Pillar[5]-bis-thiacrown: An Adaptive Tricyclic Host Selectively Recognizing an Organic Guest by Dimetalation

Some biological receptors change their shapes and rigidity by metalation to recognize substrates precisely via adaptive guest binding process. Herein we present a semi-flexible tricyclic host molecule whose conformation is rigidified by dimetalation to uptake organic guests selectively. Considering two metal binding sites and an empty space between them, pillar[5]-bis-thiacrown (L) was synthesized. The tricyclic host L forms a disilver(I) complex [Ag₂L(NO₃)₂], with an Ag⋅⋅⋅Ag separation of 9.976 Å. Binding studies based on ¹H NMR including 2D NOESY and DOSY experiments towards α,ω-dicyanoalkanes [CN(CH₂)_nCN, n=2–6, shortly C2–C6] demonstrated that the dimetalated L, Ag₂L preferentially recognizes C2 over other guests than that of free L. Furthermore, the dimetalated the host only uptakes C2 in the presence of other guests. Crystal structures support the idea that the space between two silver(I) centers plays a decisive role on the selective guest binding forming an Ag-C2-Ag@L arrangement via the length-selective recognition. This work demonstrates the chemical example of the adaptive guest binding and presents a new perspective on the metallosupramolecules of pillararenes.