Drug Delivery by Controlling a Supramolecular Host–Guest Assembly with a Reversible Photoswitch

The reversibly switchable trans‐chalcone/flavylium photochromic system was successfully coupled to the complexation equilibrium of a drug‐cucurbit[7]uril host–guest assembly. Hence, the phototriggered release of memantine under illumination at 366 nm was observed. The process can be partially reverted through a thermally activated back reaction.     

Effect of Methyl,Hydroxyl, and Chloro Substituents in Position 3 of 3′,4′,7‐Trihydroxyflavylium: Stability,Kinetics, and Thermodynamics

The effect of methyl, hydroxyl, and chloride substituents in position 3 of the 3′,4′,7‐trihydroxyflavylium core structure was studied. The stability, relative energy of each of chemical species (thermodynamics), and their rates of interconversion (kinetics) are very dependent on these substituents. By comparing the mole fraction distribution at equilibrium of the three multistate systems with the parent 3′,4′,7‐trihydroxyflavylium, introduction of a methyl substituent in position 3 increases the mole fraction of hemiketal at the expense of the trans‐chalcone and increases the hydration rate very significantly; a hydroxyl substituent in position 3 gives rise to a degradation process, as observed in anthocyanidins. In the case of 3‐chloro‐3′,4′,7‐trihydroxyflavylium, a dramatic increase of the flavylium cation acidity was observed and a photochromic system can be operated upon irradiation of the respective trans‐chalcone in 1 m HCl. According to the photochromic response of 3,3′,4′,7‐tetrahydroxyflavylium and 3′,4′,7‐trihydroxyflavylium, some requirements for a good photochromic performance are discussed.     

Light- and pH-regulated Water-soluble Pseudorotaxanes Comprising a Cucurbit[7]uril and a Flavylium-based Axle

A linear double pyridinium-terminated thread comprising a central chalcone moiety is shown to provide two independent binding sites with similar affinity for cucurbit[7]uril (CB7) macrocycles in water as judged from NMR, UV-Visible and fluorescence spectroscopies. Association results in [2] and [3]pseudorotaxanes, which are both pH and photosensitive. Switching from the neutral chalcone to the cationic flavylium form upon irradiation at 365 nm under acidic conditions provided an enhanced CB7 association (K_1:1 increases from 1.2×10⁵ M⁻¹ to 1.5×10⁸ M⁻¹), limiting spontaneous on-thread cucurbituril shuttling. This co-conformational change in the [2]pseudorotaxane is reversible in the dark with k_obs=4.1×10⁻⁴ s⁻¹. Threading the flavylium moiety into CB7 leads to a dramatic increase in the fluorescence quantum yield, from 0.29 in the free axle to 0.97 in the [2]pseudorotaxane and 1.0 in the [3]pseudorotaxane.     

Formation of a leuco Spirolactone from 4‐(2‐Carboxyphenyl)‐7‐diethylamino‐4′‐dimethylamino‐1‐benzopyrylium: Design of a Phase‐Change Thermochromic System Based on a Flavylium Dye

A phase‐change thermochromic system was designed through the reversible transformation of the 4‐substituted flavylium dye 4‐(2‐carboxyphenyl)‐7‐diethylamino‐4′‐dimethylamino‐1‐benzopyrylium into its leuco form, in the presence of a developer (ethyldiisopropylamine) and a suitable solvent (e.g., acetonitrile, n‐pentadecanonitrile). The leuco form of the flavylium‐based dye is a spirolactone species whose ring opens at low temperature (below the solvent melting point) to form the blue flavylium cation. Decarboxylation of the lactone to give 4‐phenyl‐7‐diethylamino‐4′‐dimethylamino‐1‐benzopyrylium was observed upon irradiation of the system with UV light, erasing the thermochromic effect.     

Investigation of Host–Guest Compounds of Cucurbit[n=5–8]uril with Some Ortho Aminopyridines and Bispyridine

Host–guest complexes of cucurbit[n=5–8]uril and some examples of ortho substituted pyridines or aminopyridines were examined by ¹H NMR spectroscopy. Portal binding of two ortho aminopyridine free bases, by cucurbit[5]uril, was observed in ¹H NMR spectra. Combined cavity and portal binding in cucurbit[6]uril were observed for both the free base 2-aminomethylpyridine, ampy, the HCl salt, ampy·1HCl, and the salt of 2,2′-bispyridine, bpy·1HCl. Two novel complexes were formed with cucurbit[6]uril. The free base ampyas a dual occupant, formed a 2:1 complex, and bpy·1HCl formed a stable asymmetric 1:1 complex. Only portal binding of 2,6-bisaminomethylpyridine and its salts was observed for cucurbit[6]uril. Fast exchange of the free base and pyridineammonium salts was observed for cucurbit[7-8]uril.This revised version was published online in July 2005 with a corrected issue number.     

Modulation of Excited‐State Proton Transfer of 2‐(2′‐Hydroxyphenyl)benzimidazole in a Macrocyclic Cucurbit[7]uril Host Cavity: Dual Emission Behavior and pKa Shift

The effect of the macrocyclic host, cucurbit[7]uril (CB7), on the photophysical properties of the 2‐(2′‐hydroxyphenyl)benzimidazole (HPBI) dye have been investigated in aqueous solution by using ground‐state absorption and steady‐state and time‐resolved fluorescence measurements. All three prototropic forms of the dye (cationic, neutral, and anionic) form inclusion complexes with CB7, with the largest binding constant found for the cationic form (K≈2.4×10⁶ M ^?1). At pH≈4, the appearance of a blue emission band upon excitation of the HPBI cation in the presence of CB7 indicates that encapsulation into the CB7 cavity retards the deprotonation process of the excited cation, and hence reduces its subsequent conversion to the keto form. Excitation of the neutral form (pH≈8.5), however, leads to an increase in the keto form fluorescence, indicating an enhanced excited‐state intramolecular proton‐transfer process for the encapsulated dye. In both the ground and excited states, the two pK_a values of the HPBI dye show upward shifts in the presence of CB7. The prototropic equilibrium of the CB7‐complexed dye is represented by a six‐state model, and the pH‐dependent changes in the binding constants have been analyzed accordingly. It has been observed that the calculated pK_a values using this six‐state model match well with the values obtained experimentally. The changes in the pK_a values in the presence of CB7 have been corroborated with the modulation of the proton‐transfer process of the dye within the host cavity.     

Side‐chain polypseudorotaxanes by threading cucurbit[7]uril onto poly‐N‐n‐butyl‐N′‐(4‐vinylbenzyl)‐4,4′‐bipyridinium bromide chloride: Synthesis,characterization, and properties

A novel side‐chain polypseudorotaxanes P4VBVBu/CB[7] was synthesized from poly‐N‐n‐butyl‐N′‐(4‐vinylbenzyl)‐4,4′‐bipyridinium bromide chloride (P4VBVBu) and cucurbit [7]uril (CB[7]) in water by simple stirring at room temperature. CB[7] beads are localized on viologen units in side chains of polypseudorotaxanes as shown by ¹H NMR, IR, XRD, and UV–vis studies, and it is considered that the hydrophobic and charge‐dipole interactions are the driving forces. TGA data show that thermal stability of the polypseudorotaxanes increases with the adding of CB[7] threaded. DLS data show that P4VBVBu and CB[7] could form polypseudorotaxanes, and the average hydrodynamic radius of the polypseudorotaxanes increases with increasing the concentration of CB[7]. The typical cyclic voltammograms indicate that the oxidation reduction characteristic of P4VBVBu is remarkably affected by the addition of CB[7] because of the formation of polypseudorotaxanes and the shielding effects of CB[7] threaded on the viologen units of polypseudorotaxanes. With the increase of the concentration of KBr or K₂SO₄, the formation of the polypseudorotaxanes was inhibited due to the shielding effects of both Br^? or SO to viologen ion and K⁺ to CB[7] by UV–vis. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2135–2142, 2010     

Supramolecular Polymerization Promoted and Controlled through Self‐Sorting

A new method in which supramolecular polymerization is promoted and controlled through self‐sorting is reported. The bifunctional monomer containing p‐phenylene and naphthalene moieties was prepared. Supramolecular polymerization is promoted by selective recognition between the p‐phenylene group and cucurbit[7]uril (CB[7]), and 2:1 complexation of the naphthalene groups with cucurbit[8]uril (CB[8]). The process can be controlled by tuning the CB[7] content. This development will enrich the field of supramolecular polymers with important advances towards the realization of molecular‐weight and structural control.     

The Host – Guest Interaction Between Cucurbit[7]uril and Ferrocenemonocarboxylic Acid for Electrochemically Catalytic Determination of Glucose

A simple and sensitive method for glucose determination was described based on the host‐guest inclusive complex of cucurbit[7]uril and ferrocenemonocarboxylic acid. In this work, the mixture of cucurbit[7]uril and graphene oxide, ferrocenemonocarboxylic acid as electron transfer mediator and glucose oxidase as catalytic material were modified successively on the electrode. Under the optimized conditions, a linear response between current intensity and glucose concentrations over a range of 0.1–10 mM was obtained with a relatively low detection limit (27 µM, S/N=3). Meanwhile, this method exhibited high selectivity in the interference investigation, and the reliability and applicability in human serum samples analysis.     

Cucurbit[7]uril Complexation Drives Thermal trans–cis‐Azobenzene Isomerization and Enables Colorimetric Amine Detection

Complexation of yellow diaminoazobenzenes 1 and 3 inside cucurbit[7]uril (CB[7]) results in the formation of purple‐colored CB[7] ? cis‐ 1? 2 H⁺ and CB[7] ? cis‐ 3? 2 H⁺ complexes, respectively. The high binding affinity and selectivity displayed by CB[7] toward 1 and 3 pays the >10 kcal mol^?1 thermodynamic cost for this isomerization. We investigated the behavior of these complexes as a function of pH and observed large pK_a shifts and high pH responsiveness, which are characteristic of cucurbit[n]uril molecular containers. The remarkable yellow to purple color change was utilized in the construction of an indicator displacement assay for biologically active amines 4 – 10 . This indicator displacement assay is capable of quantifying the pseudoephedrine ( 5 ) content in Sudafed tablets over the 5–350 μM range.     

Cucurbit[7]uril as a Supramolecular Artificial Enzyme for Diels–Alder Reactions

The ability to mimic the activity of natural enzymes using supramolecular constructs (artificial enzymes) is a vibrant scientific research field. Herein, we demonstrate that cucurbit[7]uril (CB[7]) can catalyse Diels–Alder reactions for a number of substituted and unreactive N ‐allyl‐2‐furfurylamines under biomimetic conditions, without the need for protecting groups, yielding powerful synthons in previously unreported mild conditions. CB[7] rearranges the substrate in a highly reactive conformation and shields it from the aqueous environment, thereby mimicking the mode of action of a natural Diels–Alderase. These findings can be directly applied to the phenomenon of product inhibition observed in natural Diels–Alderase enzymes, and pave the way toward the development of novel, supramolecular‐based green catalysts.     

Synthesis of nitrogen‐containing heterocycles 9. Preparation and carbon‐carbon bond cleavage of spiro[cycloalkane[1′,2′,4′]‐triazolo[1′,5′‐a][1′,3′,5′]triazine] derivatives and related compounds

Diaminomethylenehydrazones of cyclic ketones 1–5 reacted with ethyl N‐cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1′,2′,4′]triazolo[1′,5′,‐a][1′,3′‐5′]triazine] derivatives 7–12 in moderate to high yields. Ring‐opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2‐alkyl‐5‐amino[1,2,4]triazolotriazines 13–16. Diaminomethylenehydrazones 17–19, of hindered acyclic ketones, gave 2‐methyl‐7‐methylthio[1,2,4]‐triazolo[1,5‐a][1,3,5]triazines 21–23 by the reaction with II as the main products with apparent loss of 2‐methylpropane from the potential precursor, 2‐tert‐butyl‐2‐methyl‐7‐methylthio[1,2,4]triazolo[1,5‐a]‐[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one‐step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed.     

Reversible Shape‐Morphing and Fluorescence‐Switching in Supramolecular Nanomaterials Consisting of Amphiphilic Cyanostilbene and Cucurbit[7]uril

We demonstrate a reversible shape‐morphing with concurrent fluorescence switching in the nanomaterials which are complexed with cucurbit[7]uril (CB[7]) in water. The cyanostilbene derivative alone forms ribbon‐like two‐dimensional (2D) nanocrystals with bright yellow excimeric emission in water (λ_em=540 nm, Φ_F=42 %). Upon CB[7] addition, however, the ribbon‐like 2D nanocrystals immediately transform to spherical nanoparticles with significant fluorescence quenching and blue‐shifting (λ_em=490 nm, Φ_F=1 %) through the supramolecular complexation of the cyanostilbene and CB[7]. Based on this reversible fluorescence switching and shape morphing, we could demonstrate a novel strategy of turn‐on fluorescence sensing of spermine and also monitoring of lysine decarboxylase activity.     

Synthesis,structure and some reactions of 4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]‐quinazolines]

2′‐Substituted 5′,6′,7′,8′‐tetrahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 3a‐d were synthesized by condensation of 3‐substituted 5‐amino‐1,2,4‐triazoles 1a‐d with 2‐cyclohexylidene cyclohexanone 2 in DMF. The compounds 3 were hydrogenated with sodium borohydride in ethanol to give 2′‐substituted cis‐4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 4a‐d in high yields. The reactions of alkylation, acylation and sulfonylation of the compounds 4 were studied. The structure of the synthesized compounds was determined on the basis of NMR measurements including HSQC, HMBC, NOESY techniques and confirmed by the X‐ray analysis of 6 and 11b . The described synthetic protocols provide rapid access to novel and diversely substituted hydrogenated [1,2,4]triazolo[5,1‐b]quinazolines.     

Cucurbit[7]uril as a Tool in the Green Synthesis of Gold Nanoparticles

A simple, green, one‐pot synthesis of gold nanoparticles was achieved through the reaction of an aqueous mixture of potassium tetrachloroaurate(III) and the macrocycle cucurbit[7]uril in the presence of sodium hydroxide at room temperature without introducing any kind of traditional reducing agents and/or external energy. The as‐prepared gold nanoparticles showed catalytic activity for the reduction reaction of 4‐nitrophenol in the presence of NaBH₄, which has been established by visual inspection and UV/Vis spectroscopy. This report is the first for the preparation of gold nanoparticles using cucurbit[7]uril in aqueous media through chemical reduction without employing conventional reducing agents and/or external energy.     

Synthesis and characterization of a symmetric bis(7-hydroxyflavylium) containing a methyl viologen bridge

A symmetric bis(flavylium) constituted by two 7-hydroxyflavylium moieties linked by a methylviologen bridge was synthesized. The thermodynamic and kinetics of the network of chemical reactions involving bis(flavylium) and the model compound 7-hydroxy-4'-methylflavylium was completely characterized by means of direct and reverse pH jumps (stopped flow) and flash photolysis. Both compounds follow the usual pH-dependent network of chemical reactions of flavylium derivatives. The equilibrium species of the model compound are the flavylium cation (acidic species) and the trans-chalcone (basic species) with an apparent pK'(a)=2.85. In the case of the bis(flavylium) it was possible to characterize by (1)H NMR spectroscopy three species with different degrees of isomerization: all flavylium, flavylium-trans-chalcone, and all trans-chalcone. Representation of the time-dependent mole fraction distribution of these three forms after a pH jump from equilibrated solutions of all-flavylium cation (lower pH values) to higher pH values, shows that formation of trans-chalcone is not completely stochastic (two independent isomerizations), the isomerization of one flavylium showing a small influence on the isomerization of the other. The radical of the methyl viologen bridge is formed upon reduction of the bis(trans-chalcone) with dithionite. The system is reversible after addition of an oxidant in spite of the occurrence of some decomposition.     

Chiroptic behaviour of a chiral guest in an achiral cucurbit[7]uril host

The protonated forms of the chiral molecules (S)- and (R)-N-benzyl-1-(1-naphthyl)ethylamine (BNEAH⁺) form very stable 1:1 guest–host complexes with cucurbit[7]uril in aqueous solution. The stoichiometry and stability constants for the guest–host complexes were determined by ¹H NMR, UV–visible and circular dichroism spectroscopy and electrospray mass spectrometry. The molecular optical rotations of the guests increase in magnitude by about 5-fold upon formation of the {BNEAH·CB[7]}⁺ species. Energy minimized structures of the guests and guest–host complexes indicate changes in the dihedral angles about the stereogenic centre upon ion-dipole and H-bonding interactions between the ammonium hydrogens of the guest and the carbonyl groups of the cucurbituril portals. The increases in the optical rotations are discussed in terms of restricted rotations of the naphthyl groups and in preferential solvation of benzylamine in the cucurbit[7]uril cavity.     

Hydroxypyridinechromene and Pyridinechalcone: Two Coupled Photochromic Systems

Substitution of the phenyl group in 2‐hydroxychalcones by a 4‐pyridine unit dramatically changes the network of chemical reactions of this compound: trans‐chalcone‐type ( Ct ), cis‐chalcone‐type ( Cc ), and a hemiketal (hydroxy‐4‐pyridinechromene) ( B ) and their protonated forms are formed, but the presence of a flavylium‐type cation could not be detected even at very acidic pH values. Moreover, whereas in 2‐phenyl‐2‐benzopyrylium compounds B and Cc are generally elusive species whose kinetic processes in aqueous solutions occur on the sub‐second timescale, in the present compound these species equilibrate on a timescale four orders of magnitude lower. Complete characterization of the equilibrium and kinetics of the reaction network could thus be achieved by ¹H NMR spectroscopy and UV/Vis spectrophotometry. The network of chemical reactions exhibits cis–trans photoisomerization, as well as photochromism between the hemiketal and the chalcone‐type species. The irradiation of Ct in MeOH/H₂O (1:1) at 365 nm produces B almost quantitatively through two consecutive photochemical reactions: Ct → Cc photoisomerization followed by Cc → B photo ring closure with a global quantum yield of 0.02. On the other hand, irradiation of B at 254 nm leads to a photostationary state composed by 80 % Ct and 20 % B , with a quantum yield of 0.21.     

Three‐Component Reaction for Construction of Spiro[indoline‐3,7′‐thiazolo[3,2‐a]pyridines] and Spiro[benzo[4,5]thiazolo[3,2‐a]pyridine‐3,3′‐indolines]

The three‐component reaction of thiazole (benzothiazole), dialkyl but‐2‐ynedioate, and isatinylidene malononitriles in toluene at 110–120°C in a sealed tube afforded a mixture of cis/trans‐isomers of functionalized diastereoisomeric spiro[indoline‐3,7′‐thiazolo[3,2‐a]pyridines] and spiro[benzo[4,5]thiazolo[3,2‐a]pyridine‐3,3′‐indolines] in good yields. Both cis‐isomers and trans‐isomers were successfully separated out and fully characterized with spectroscopy and single crystal determination. Under similar conditions, the three‐component reaction containing 2‐(1,3‐dioxo‐1H‐inden‐2(3H)‐ylidene)malononitrile resulted in spiro[indene‐2,7′‐thiazolo[3,2‐a]pyridine] derivatives.     

An Efficient Synthesis of 1′,7′,8′,9′‐Tetrahydrospiro[indoline‐3,4′‐pyrazolo[3,4‐b]quinoline]‐2,5′(6′H)‐dione Derivatives in Aqueous Medium

An efficient and green reactions of isatins, 3‐amine‐1H‐pyrazole (5‐methyl‐1H‐pyrazol‐3‐amine) and 1,3‐diketone in aqueous medium for the synthesis of novel 1′,7′,8′,9′‐tetrahydrospiro[indoline‐3,4′‐pyrazolo[3,4‐b]quinoline]‐2,5′(6′H)‐dione derivatives were reported in this research. The advantages of this reaction are simple operation, mild‐reaction conditions, wide scope substrate, high yields, and friendly environment. The products were confirmed by IR, ¹H NMR, ¹³C NMR, and HRMS.