pH-dependent binding of guests in the cavity of a polyhedral coordination cage: reversible uptake and release of drug molecules

A range of organic molecules with acidic or basic groups exhibit strong pH-dependent binding inside the cavity of a polyhedral coordination cage. Guest binding in aqueous solution is dominated by a hydrophobic contribution which is compensated by stronger solvation when the guests become cationic (by protonation) or anionic (by deprotonation). The Parkinson''s drug 1-amino-adamantane (‘amantadine’) binds with an association constant of 10⁴ M^–1 in the neutral form (pH greater than 11), but the stability of the complex is reduced by three orders of magnitude when the guest is protonated at lower pH. Monitoring the uptake of the guests into the cage cavity was facilitated by the large upfield shift for the ¹H NMR signals of bound guests due to the paramagnetism of the host. Although the association constants are generally lower, guests of biological significance such as aspirin and nicotine show similar behaviour, with a substantial difference between neutral (strongly binding) and charged (weakly binding) forms, irrespective of the sign of the charged species. pH-dependent binding was observed for a range of guests with different functional groups (primary and tertiary amines, pyridine, imidazole and carboxylic acids), so that the pH-swing can be tuned anywhere in the range of 3.5–11. The structure of the adamantane-1-carboxylic acid complex was determined by X-ray crystallography: the oxygen atoms of the guest form CH···O hydrogen bonds with one of two equivalent pockets on the internal surface of the host. Reversible uptake and release of guests as a function of pH offers interesting possibilities in any application where controlled release of a molecule following an external stimulus is required.     

Reversible reduction drives anion ejection and C60 binding within an FeII4L6 cage

Fe^II₄L₆ tetrahedral cage 1 was prepared from a redox-active dicationic naphthalenediimide (NDI) ligand. The +20 charge of the cage makes it a good host for anionic guests, with no binding observed for neutral aromatic molecules. Following reduction by Cp₂Co, the cage released anionic guests; subsequent oxidation by AgNTf₂ led to re-uptake of anions. In its reduced form, however, 1 was observed to bind neutral C₆₀. The fullerene guest was subsequently ejected following cage re-oxidation. The guest release process was found to be facilitated by anion-mediated transport from organic to aqueous solution. Cage 1 thus employs electron transfer as a stimulus to control the uptake and release of both neutral and charged guests, through distinct pathways.

Fe^II₄L₆ cage 1 binds anionic guests but not neutral guests. In its reduced form, the cage can bind neutral C₆₀. Reduction and oxidation of the cage could thus be used as a stimulus to control the uptake and release of both neutral and charged guests.     

Cucurbit[7]uril Inclusion Complexes with Benzimidazole Derivatives: A Computational Study

Molecular dynamics (MD) simulations were carried out to study the host–guest complexation in aqueous solution between cucurbit[7]uril (CB7) and the neutral and protonated forms of benzimidazole derivatives. Complexation occurs via encapsulation of the hydrophobic part (benzene ring) of the guest within the CB7 hydrophobic cavity, and the interactions of the amine group(s) of the imidazole ring of the guest with the CB7 carbonyl portals. The molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method is used to estimate the host–guest Gibbs energy of binding. The results indicate that CB7 binds the protonated form more strongly than the neutral one, and that the dominant contribution to the Gibbs energy of complexation for the neutral and protonated guests is associated, respectively, with the host–guest van der Waals and electrostatic interactions. Quantum chemical calculations using dispersion-corrected density functional theory (DFT) are used to calculate the binding affinities and to predict the pK_a values of the free and complexed guests. The calculated pK_a values for the free guests reveal excellent agreement with the experimental values, while for the complexed guests, general trends are obtained.     

Specific adsorption of cesium on silica-titania

The amphoteric nature of hydrous silica-titania gel and its sorption behaviour towards cesium were studied. In NaNO₃ solution, the point of zero change (pH_pzc) of the gel was found to be 4.22 by pH-titration. The fraction of protonated, deprotonated and neutral surface hydroxyl groups as a function of pH have been computed. Sorption of cesium increased with the increase of pH, reached maximum at a pH of 7 followed by a plateau. Significant uptake of cesium was observed even when the pH was less than pH_pzc. Nearly 70% sorption was observed at pH_pzc. The free energy of specific adsorption was found to be –18.7 kJ·mol^–1.     

Adsorption of -histidine on copper surface as evidenced by surface-enhanced Raman scattering spectroscopy

The adsorption of -histidine on a copper electrode from H₂O- and D₂O-based solutions is studied by means of surface-enhanced Raman scattering (SERS) spectroscopy. Different adsorption states of histidine are observed depending upon pH, potential, and the presence of the SO²⁻₄ and Cl⁻ ions. In acidic solutions of pH 1.2 the imidazole ring of the adsorbed histidine remains protonated and is not involved in the chemical coordination with the surface. The SO²⁻₄ and Cl⁻ ions compete with histidine for the adsorption sites. In solutions of pH 3.1 three different adsorption states of histidine are observed depending on the potential. Histidine adsorbs with the protonated imidazole ring oriented mainly perpendicularly to the surface at potentials more positive than −0.2 V. Transformation of that adsorption state occurs at more negative potentials. As this takes place, histidine adsorbs through the α-NH₂ group and the neutral imidazole ring. The Cl⁻ ions cause the protonation and detachment of the α-NH₂ group from the surface and the formation of the ion pair NH⁺₃ … Cl⁻ can be observed. In the neutral solution of pH 7.0 histidine adsorbs through the deprotonated nitrogen atom of the imidazole ring and the α-COO⁻ group at E ≥ −0.2 V. However, this adsorption state is transformed into the adsorption state in which the α-NH₂ group and/or neutral imidazole ring participate in the anchoring of histidine to the surface, once the potential becomes more negative. In alkaline solutions of pH 11.9 histidine is adsorbed on the copper surface through the neutral imidazole ring.     

Simulation of pH-Dependent Conformational Transitions in Membrane Proteins: The CLC-ec1 Cl−/H+ Antiporter

Intracellular transport of chloride by members of the CLC transporter family involves a coupled exchange between a Cl⁻ anion and a proton (H⁺), which makes the transport function dependent on ambient pH. Transport activity peaks at pH 4.5 and stalls at neutral pH. However, a structure of the WT protein at acidic pH is not available, making it difficult to assess the global conformational rearrangements that support a pH-dependent gating mechanism. To enable modeling of the CLC-ec1 dimer at acidic pH, we have applied molecular dynamics simulations (MD) featuring a new force field modification scheme—termed an Equilibrium constant pH approach (ECpH). The ECpH method utilizes linear interpolation between the force field parameters of protonated and deprotonated states of titratable residues to achieve a representation of pH-dependence in a narrow range of physiological pH values. Simulations of the CLC-ec1 dimer at neutral and acidic pH comparing ECpH-MD to canonical MD, in which the pH-dependent protonation is represented by a binary scheme, substantiates the better agreement of the conformational changes and the final model with experimental data from NMR, cross-link and AFM studies, and reveals structural elements that support the gate-opening at pH 4.5, including the key glutamates Glu_in and Glu_ex.     

Orthogonal binding and displacement of different guest types using a coordination cage host with cavity-based and surface-based binding sites

The octanuclear Co(ii) cubic coordination cage system H (or HW if it bears external water-solubilising substituents) has two types of binding site for guests. These are (i) the partially-enclosed central cavity where neutral hydrophobic organic species can bind, and (ii) the six ''portals'' in the centres of each of the faces of the cubic cage where anions bind via formation of a network of CH⋯X hydrogen bonds between the anion and CH units on the positively-charged cage surface, as demonstrated by a set of crystal structures. The near-orthogonality of these guest binding modes provides the basis for an unusual dual-probe fluorescence displacement assay in which either a cavity-bound fluorophore (4-methyl-7-amino-coumarin, MAC; λ_em = 440 nm), or a surface-bound anionic fluorophore (fluorescein, FLU; λ_em = 515 nm), is displaced and has its emission ‘switched on’ according to whether the analyte under investigation is cavity-binding, surface binding, or a combination of both. A completely orthogonal system is demonstrated based using a Hw/MAC/FLU combination: addition of the anionic analyte ascorbate displaced solely FLU from the cage surface, increasing the 515 nm (green) emission component, whereas addition of a neutral hydrophobic guest such as cyclooctanone displaced solely MAC from the cage central cavity, increasing the 440 nm (blue) emission component. Addition of chloride results in some release of both components, and an intermediate colour change, as chloride is a rare example of a guest that shows both surface-binding and cavity-binding behaviour. Thus we have a colourimetric response based on differing contributions from blue and green emission components in which the specific colour change signals the binding mode of the analyte. Addition of a fixed red emission component from the complex [Ru(bipy)₃]²⁺ (Ru) provides a baseline colour shift of the overall colour of the luminescence closer to neutral, meaning that different types of guest binding result in different colour changes which are easily distinguishable by eye.

Orthogonal binding of neutral or anionic fluorophores to the cavity or surface, respectively, of a coordination cage host allows a dual-probe displacement assay which gives a different fluorescence colorimetric response according to where analyte species bind.     

Encapsulation of Metronidazole in Biocompatible Macrocycles and Structural Characterization of Its Nano Spray-Dried Nanostructured Composite

Due to the great potential of biocompatible cucurbit[7]uril (CB7) and 4-sulfonatocalix[4]arene (SCX4) macrocycles in drug delivery, the confinement of the pharmaceutically important metronidazole as an ionizable model drug has been systematically studied in these cavitands. Absorption and fluorescence spectroscopic measurements gave 1.9 × 10⁵ M⁻¹ and 1.0 × 10⁴ M⁻¹ as the association constants of the protonated metronidazole inclusion in CB7 and SCX4, whereas the unprotonated guests had values more than one order of magnitude lower, respectively. The preferential binding of the protonated metronidazole resulted in 1.91 pH unit pK_a diminution upon encapsulation in CB7, but the complexation with SCX4 led to a pK_a decrease of only 0.82 pH unit. The produced protonated metronidazole–SCX4 complex induced nanoparticle formation with protonated chitosan by supramolecular crosslinking of the polysaccharide chains. The properties of the aqueous nanoparticle solutions and the micron-sized solid composite produced therefrom by nano spray drying were unraveled. The results of the present work may find application in the rational design of tailor-made self-assembled drug carrier systems.     

Self-Assembly by Tridentate or Bidentate Ligand: Synthesis and Vapor Adsorption Properties of Cu(II), Zn(II), Hg(II) and Cd(II) Complexes Derived from a Bis(pyridylhydrazone) Compound

Four complexes, [Cu₄L₂(OCH₃)₂(CH₃OH)₂]·2H₂O (1), [Zn₂L₂Cl₄]·2H₂O·2CH₃OH (2), [Hg₂L₂Br₄]·4CH₃OH (3), and {[CdL₂Cl₂]·4H₂O·4CH₃OH}_n (4), have been synthesized and characterized from a bis(pyridylhydrazone) ligand (L) with copper(II), zinc(II), mercury(II) or cadmium(II), respectively. Complex 1 exists as a centrosymmetric tetranuclear dimer with L as deprotonated tridentate ligand. Complexes 2 and 3 exist as centrosymmetric metallamacrocycles with L as bidentate ligand. Complex 4 exists as a 1D looped-chain coordination polymer. The thermal stabilities and vapor adsorption properties of the four complexes were investigated as well.     

pH-responsive and switchable triplex-based DNA hydrogels

New methods for the preparation of reversible pH-responsive DNA hydrogels based on Hoogsteen triplex structures are described. One system consists of a hydrogel composed of duplex DNA units that bridge acrylamide chains at pH = 7.4 and undergoes dissolution at pH = 5.0 through the reconfiguration of one of the duplex bridging units into a protonated CG·C⁺ triplex structure. The second system consists of a hydrogel consisting of acrylamide chains crosslinked in the presence of an auxiliary strand by Hoogsteen TA·T triplex interaction at pH = 7.0. The hydrogel transforms into a liquid phase at pH = 10.0 due to the separation of the triplex bridging units. The two hydrogel systems undergo reversible and cyclic hydrogel/solution transitions by subjecting the systems to appropriate pH values. The anti-cancer drug, coralyne, binds specifically to the TA·T triplex-crosslinked hydrogel thereby increasing its stiffness. The pH-controlled release of the coralyne from the hydrogel is demonstrated.     

Solid-State Structures and Photoluminescence of Lamellar Architectures of Cu(I) and Ag(I) Paddlewheel Clusters with Hydrogen-Bonded Polar Guests

Two hexanuclear paddlewheel-like clusters appending six carboxylic-acid pendants have been isolated with the inclusion of polar solvent guests: [Cu₆(Hmna)₆]·7DMF (1·7DMF) and [Ag₆(Hmna)₆]·8DMSO (2·8DMSO), where H₂mna = 2-mercaptonicotininc acid, DMF = N,N’-dimethylformamide, and DMSO = dimethyl sulfoxide. The solvated clusters, together with their fully desolvated forms 1 and 2, have been characterized by FTIR, UV–Vis diffuse reflectance spectroscopy, TG-DTA analysis, and DFT calculations. Crystal structures of two solvated clusters 1·7DMF and 2·8DMSO have been unambiguously determined by single-crystal X-ray diffraction analysis. Six carboxylic groups appended on the clusters trap solvent guests, DMF or DMSO, through H-bonds. As a result, alternately stacked lamellar architectures comprising of a paddlewheel cluster layer and H-bonded solvent layer are formed. Upon UV illumination (λ_ex = 365 nm), the solvated hexasilver(I) cluster 2·8DMSO gives intense greenish-yellow photoluminescence in the solid state (λ_PL = 545 nm, Φ_PL = 0.17 at 298 K), whereas the solvated hexacopper(I) cluster 1·7DMF displays PL in the near-IR region (λ_PL = 765 nm, Φ_PL = 0.38 at 298 K). Upon complete desolvation, a substantial bleach in the PL intensity (Φ_PL < 0.01) is observed. The desorption–sorption response was studied by the solid-state PL spectroscopy. Non-covalent interactions in the crystal including intermolecular H-bonds, CH⋯π interactions, and π⋯π stack were found to play decisive roles in the creation of the lamellar architectures, small-molecule trap-and-release behavior, and guest-induced luminescence enhancement.     

Lanthanide complexes of ethylenediaminotetramethylene-phosphonic acid

Ethylenediaminotetramethylenephosphonic acid (EDTMP, H₈L) was prepared and its complexes with some lanthanide ions (La, Eu, Gd and Sm) were isolated under various conditions. IR spectra and thermal stabilities of EDTMP and its complexes were studied. The experimental conditions of the preparation influence to the composition of the complexes were shown. In alkaline solution (pH=8) deprotonated (P(O)(O^–)₂), and in acidic solution (pH=3–4) deprotonated and partly protonated (P(O)(O^–)(OH)) and non-protonated (P(O)(OH)₂) phosphonic groups are present in the complexes. All the complexes contain coordinated water molecules. The complexes containing a protonated phosphonic group contain coordinated and hydrogen-bonded water molecules.This revised version was published online in November 2005 with corrections to the Cover Date.     

Selective separation of planar and non-planar hydrocarbons using an aqueous Pd6 interlocked cage

Polycyclic aromatic hydrocarbons (PAHs) find multiple applications ranging from fabric dyes to optoelectronic materials. Hydrogenation of PAHs is often employed for their purification or derivatization. However, separation of PAHs from their hydrogenated analogues is challenging because of their similar physical properties. An example of such is the separation of 9,10-dihydroanthracene from phenanthrene/anthracene which requires fractional distillation at high temperature (∼340 °C) to obtain pure anthracene/phenanthrene in coal industry. Herein we demonstrate a new approach for this separation at room temperature using a water-soluble interlocked cage (1) as extracting agent by host–guest chemistry. The cage was obtained by self-assembly of a triimidazole donor L·HNO₃ with cis-[(tmeda)Pd(NO₃)₂] (M) [tmeda = N,N,N′,N′-tetramethylethane-1,2-diamine]. 1 has a triply interlocked structure with an inner cavity capable of selectively binding planar aromatic guests.

We report here a triply interlocked cage with the ability to encapsulate planar guests in aqueous medium. This property was then employed to efficiently separate planar and non-planar aromatic hydrocarbons by aqueous extraction.     

Enrichment of Zinc and Iron Micronutrients in Lentil (Lens culinaris Medik.) through Biofortification

Biofortification of pulse crops with Zn and Fe is a viable approach to combat their widespread deficiencies in humans. Lentil (Lens culinaris Medik.) is a widely consumed edible crop possessing a high level of Zn and Fe micronutrients. Thus, the present study was conducted to examine the influence of foliar application of Zn and Fe on productivity, concentration, uptake and the economics of lentil cultivation (LL 931). For this, different treatment combinations of ZnSO₄·7H₂O (0.5%) and FeSO₄·7H₂O (0.5%), along with the recommended dose of fertilizer (RDF), were applied to the lentil. The results of study reported that the combined foliar application of ZnSO₄·7H₂O (0.5%) + FeSO₄·7H₂O (0.5%) at pre-flowering (S1) and pod formation (S2) stages was most effective in enhancing grain and straw yield, Zn and Fe concentration, and uptake. However, the outcome of this treatment was statistically on par with the results obtained under the treatment ZnSO₄·7H₂O (0.5%) + FeSO₄·7H₂O (0.5%) at S1 stage. A single spray of ZnSO₄·7H₂O (0.5%) + FeSO₄·7H₂O (0.5%) at S1 stage enhanced the grain and straw yield up to 39.6% and 51.8%, respectively. Similarly, Zn and Fe concentrations showed enhancement in grain (10.9% and 20.4%, respectively) and straw (27.5% and 27.6% respectively) of the lentil. The increase in Zn and Fe uptake by grain was 54.8% and 68.0%, respectively, whereas uptake by straw was 93.6% and 93.7%, respectively. Also the benefit:cost was the highest (1.96) with application of ZnSO₄·7H₂O (0.5%) + FeSO₄·7H₂O (0.5%) at S1 stage. Conclusively, the combined use of ZnSO₄·7H₂O (0.5%) + FeSO₄·7H₂O (0.5%) at S1 stage can contribute significantly towards yield, Zn and Fe concentration, as well as uptake and the economic returns of lentil to remediate the Zn and Fe deficiency.     

4,5-Dicyano-1,2,3-Triazole—A Promising Precursor for a New Family of Energetic Compounds and Its Nitrogen-Rich Derivatives: Synthesis and Crystal Structures

The nitrogen-rich compounds and intermediates with structure of monocyclic, bicyclic, and fused rings based on 1,2,3-triazole were synthesized and prepared by using a promising precursor named 4,5-dicyano-1,2,3-triazole, which was obtained by the cyclization reaction of diaminomaleonitrile. Their structure and configurational integrity were assessed by Fourier transform-infrared spectroscopy (FT-IR), mass spectrometry (MS), and elemental analysis (EA). Additionally, fourteen compounds were further confirmed by X-ray single crystal diffraction. Meanwhile, the physical properties of four selected compounds (3·H₂O, 6·H₂O, 10·H₂O, and 16) including thermal stability, detonation parameters, and sensitivity were also estimated. All these compounds could be considered to construct more abundant 1,2,3-triazole-based neutral energetic molecules, salts, and complex compounds, which need to continue study in the future in the field of energetic materials.     

Copper(II)-Mediated Iodination of 1-Nitroso-2-naphthol

The 3-Iodo-1-nitrosonaphthalene-2-ol (I-NON) was obtained by the copper(II)-mediated iodination of 1-nitroso-2-naphthol (NON). The suitable reactants and optimized reaction conditions, providing 94% NMR yield of I-NON, included the usage of Cu(OAc)₂·H₂O and 1:2:8 Cu^II/NON/I₂ molar ratio between the reactants. The obtained I-NON was characterized by elemental analyses (C, H, N), high-resolution ESI⁺-MS, ¹H and ¹³C{¹H} NMR, FTIR, UV-vis spectroscopy, TGA, and X-ray crystallography (XRD). The copper(II) complexes bearing deprotonated I-NON were prepared as follows: cis-[Cu(I-NON–H)(I-NON)](I₃) (1) was obtained by the reaction between Cu(NON-H)₂ and I₂ in CHCl₃/MeOH, while trans-[Cu(I-NON–H)₂] (2) was synthesized from I-NON and Cu(OAc)₂ in MeOH. Crystals of trans-[Cu(I-NON–H)₂(THF)₂] (3) and trans-[Cu(I-NON–H)₂(Py)₂] (4) were precipitated from solutions of 2 in CHCl₃/THF and Py/CHCl₃/MeOH mixtures, respectively. The structures of 1 and 3–4 were additionally verified by X-ray crystallography. The characteristic feature of the structures of 1 and 3 is the presence of intermolecular halogen bonds with the involvement of the iodine center of the metal-bound deprotonated I-NON. The nature of the I···I and I···O contacts in the structures of 1 and 3, correspondingly, were studied theoretically at the DFT (PBE0-D3BJ) level using the QTAIM, ESP, ELF, NBO, and IGM methods.     

Synthesis and Binding Properties of a Tren-Capped Hexahomotrioxacalix[3]arene

The straightforward synthesis of a new hexahomotrioxacalix[3]arene-based ligand capped by a tren subunit was developed and the binding properties of the corresponding zinc complex were explored by NMR spectroscopy. Similarly to the closely related calix[6]tren-based systems, the homooxacalixarene core ensures the mononuclearity of the zinc complex and the metal center displays a labile coordination site for exogenous guests. However, very different host–guest properties were observed: i) in CDCl₃, the zinc complex strongly binds a water molecule and is reluctant to recognize other neutral guests, ii) in CD₃CN, the exo-coordination of anions prevails. Thus, in strong contrast to the calix[6]tren-based systems, the coordination of neutral guests that thread through the small rim and fill the polyaromatic cavity was not observed. This unique behaviour is likely due to the fact that the 18-membered ethereal macrocycle is too small to let a molecule threading through it. This work illustrates the key role played by the second coordination sphere in the binding properties of metal complexes.     

M-Carboxylic Acid Induced Formation of New Coordination Polymers for Efficient Photocatalytic Degradation of Ciprofloxacin

Four new 2–3D materials were designed and synthesized by hydrothermal methods, namely, {[(L1·Cu·2H₂O) (4,4-bipy)_0.5] (β-Mo₈O₂₆)_0.5·H₂O} (1), {[(L1·Cu)₂·(4,4-bipy)] (Mo₅O₁₆)} (2), {Co(L1)₂}_n (3), and {[(L1)₂][β-Mo₈O₂₆]_0.5·5H₂O} (4). [L1=5-(4-aminopyridine) isophthalic acid]. The degradation of ciprofloxacin (CIP) in water by compounds 1–4 was studied under visible light. The experimental results show that compounds 1–4 have obvious photocatalytic degradation effect on CIP. In addition, for compound 1, the effects of temperature, pH, and adsorbent dosage on photocatalytic performance were also investigated. The stability of compound 1 was observed by a cycle experiment, indicating that there was no significant change after three cycles of CIP degradation.     

Pyridyl thioureas as switchable anion receptors

The binding selectivity of simple pyridyl thioureas in acetonitrile can be completely switched by protonation; hence the neutral thiourea binds acetate, but not chloride or bromide, whereas the protonated thiourea binds strongly to chloride or bromide, but is deprotonated by acetate.     

Optimization of S-Nitrosocaptopril Monohydrate Storage Conditions Based on Response Surface Method

From unstable crystals to relatively stable monohydrate crystals, many researchers have been working on S-nitrosocaptopril for more than two decades. S-nitrosocaptopril monohydrate (Cap-NO·H₂O) is a novel crystal form of S-nitrosocaptopril (Cap-NO), and is not only a nitric oxide (NO) donor, but also an angiotensin-converting enzyme inhibitor (ACEI). Yet, a method for long-term storage has never been reported. In order to determine the optimal storage conditions, Plackett–Burman (PB) design was performed to confirm the critical factors. Response surface methodology (RSM) was employed to determine the optimal Cap-NO·H₂O storage condition, based on the rough interval determined by the path of steepest ascent experiment. The optimized storage condition was denoted as nitrogen purity of 97%, temperature of −10 °C and 1.20 g deoxidizer. In this case, a final preservation rate of 97.91 ± 0.59% could be obtained. In specific storage conditions, Cap-NO·H₂O was found to be stable for at least 6 months in individual PE package, procreating a potentially applicable avenue.