Supramolecular Binding Research Articles

Host–guest complexation of APP+ with cucurbit[7]uril. Theoretical and experimental studies on the supramolecular inhibition of its cytotoxicity on SERT

The supramolecular binding behavior of APP+ and CB[7] in aqueous solution was studied by different techniques. APP+ showed cytotoxicity towards HEK293 cells expressing hSERT. This cytotoxicity was inhibited by the treatment of the cells with CB[7].

Confining the Inner Space of Strained Carbon Nanorings

AbstractStrained aromatic macrocycles based on cycloparaphenylenes (CPPs) are the shortest repeating units of armchair single-walled carbon nanotubes. Since the development of several new synthetic methodologies for accessing these structures, their properties have been extensively studied. Besides the fundamental interest in these novel molecular scaffolds, their application in the field of materials science is an ongoing topic of research. Most of the reported CPP-type macrocycles display strong binding toward fullerenes, due to the perfect match between the convex and concave π-surfaces of fullerenes and CPPs, respectively. Highly functionalized CPP derivatives capable of supramolecular binding with other molecules are rarely reported. The synthesis of highly functionalized [n]cyclo-2,7-pyrenylenes leads to CPP-type macrocycles with a defined cavity capable of binding non-fullerene guests with high association constants.

Host-Guest Systems on the Surface of Functionalized Superparamagnetic Iron Oxide Nanoparticles (SPIONs) Utilizing Hamilton Receptors and Cyanurate Derivative Molecules.

The study of hydrogen bonding interactions at the level of functionalized nanoparticles remains highly challenging and poorly explored area. In this work, superparamagnetic iron oxide nanoparticles (SPIONs) were orthogonally functionalized using receptors bearing multiple hydrogen bonding motifs. Pristine SPIONs were modified by wet chemical processes with Hamilton receptors (hosts), or cyanurate‐guest molecules linked to phosphonic acid moieties for monolayer functionalization. The modified surfaces were fully characterized and the number of attached ligands on the surface were determined. The host‐guest interactions on the interface of modified SPIONs were investigated by using UV‐Vis spectroscopic titrations. Functionalized SPIONs demonstrated two to three magnitudes stronger binding affinities as compared to the related molecular interactions in solution due to synergistic effects on complex surface environment. Higher supramolecular binding ratios of host‐guest interactions on the modified surface were emerged. These studies provide fundamental insights into supramolecular complexations on the surface at solid‐liquid interface systems with applications in engineered nanomaterials, nano‐sensing devices, and drug delivery systems.

Switching the Mechanism of NADH Photooxidation by Supramolecular Interactions.

A series of three Ru(II) polypyridine complexes was investigated for the selective photocatalytic oxidation of NAD(P)H to NAD(P)+ in water. A combination of (time‐resolved) spectroscopic studies and photocatalysis experiments revealed that ligand design can be used to control the mechanism of the photooxidation: For prototypical Ru(II) complexes a 1O2 pathway was found. Rudppz ([(tbbpy)2Ru(dppz)]Cl2, tbbpy=4,4'‐di‐tert‐butyl‐2,2'‐bipyridine, dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine), instead, initiated the cofactor oxidation by electron transfer from NAD(P)H enabled by supramolecular binding between substrate and catalyst. Expulsion of the photoproduct NAD(P)+ from the supramolecular binding site in Rudppz allowed very efficient turnover. Therefore, Rudppz permits repetitive selective assembly and oxidative conversion of reduced naturally occurring nicotinamides by recognizing the redox state of the cofactor under formation of H2O2 as additional product. This photocatalytic process can fuel discontinuous photobiocatalysis.

Thiourea Organocatalysts as Emerging Chiral Pollutants: En Route to Porphyrin-Based (Chir)Optical Sensing

Environmental pollution with chiral organic compounds is an emerging problem requiring innovative sensing methods. Amino-functionalized thioureas, such as 2-(dimethylamino)cyclohexyl-(3,5-bis(trifluoromethyl)phenyl)thiourea (Takemoto’s catalyst), are widely used organocatalysts with virtually unknown environmental safety data. Ecotoxicity studies based on the Vibrio fischeri luminescence inhibition test reveal significant toxicity of Takemoto’s catalyst (EC50 = 7.9 mg/L) and its NH2-substituted analog (EC50 = 7.2–7.4 mg/L). The observed toxic effect was pronounced by the influence of the trifluoromethyl moiety. En route to the porphyrin-based chemosensing of Takemoto-type thioureas, their supramolecular binding to a series of zinc porphyrins was studied with UV-Vis and circular dichroism (CD) spectroscopy, computational analysis and single crystal X-ray diffraction. The association constant values generally increased with the increasing electron-withdrawing properties of the porphyrins and electron-donating ability of the thioureas, a result of the predominant Zn⋯N cation–dipole (Lewis acid–base) interaction. The binding event induced a CD signal in the Soret band region of the porphyrin hosts—a crucial property for chirality sensing of Takemoto-type thioureas.

Nanoparticles exploring the macroscopic world

Nanoparticles exploring the macroscopic world

Supramolecular engineering of hydrogels for drug delivery.

Supramolecular binding motifs are increasingly employed in the design of biomaterials. The ability to rationally engineer specific yet reversible associations into polymer networks with supramolecular chemistry enables injectable or sprayable hydrogels that can be applied via minimally invasive administration. In this review, we highlight two main areas where supramolecular binding motifs are being used in the design of drug delivery systems: engineering network mechanics and tailoring drug-material affinity. Throughout, we highlight many of the established and emerging chemistries or binding motifs that are useful for the design of supramolecular hydrogels for drug delivery applications.

Multivalency Pattern Recognition to Sort Colloidal Assemblies.

Multivalent interaction is an important principle for self-assembly and has been widely used to assemble colloids. However, surface binding partners are statistically distributed, which falls short of the interaction possibilities arising from geometrically controlled multivalency patterns as seen in viruses. Herein, the precision provided by 3D DNA origami is exploited to introduce multivalency pattern recognition via designing geometrically precise interaction patterns at patches of patchy nanocylinders. This gives rise to self-sorting of colloidal assemblies despite having the same type and number of supramolecular binding motifs-solely based on the pattern located on a 20× 20 nm2 cross-section. The degree of sorting can be modulated by the geometric overlap of patterns and homo; mixed and alternating supracolloidal polymerizations are demonstrated. Multivalency patterns are able to provide an additional information layer to organize soft matter, important towards engineering of biological responses and functional materials design.

Local potential energy density model (LPE): Applications and limitations to quantify intra/intermolecular interactions

In our previous work, we developed the local potential energy density model, LPE, based on the electrostatic force and QTAIM topological data with a high linearity with the supramolecular binding energy, SME, for the classical hydrogen bonds. In this work, we extended the investigation to other inter/intramolecular interactions. The LPE presented a high linearity with SME when excluding interactions of an ion with π-bonded groups or polar molecule. Due to this linearity, it is possible to obtain the SME of nearly all inter/intramolecular interaction from LPE values. The energy decomposition analysis from SAPT-DFT and LMOEDA showed that dispersion and electrostatic components are important to LPE, while polarization component impairs it. The LPE cannot be used for ions interacting with dipole or dipole or ion interacting with π-bonded systems). In addition, the absolute difference between the numerical values of LPE and SME is very small as in the case of our previous work.

Synthesis and spectral characterization of the first fluorescein-tagged iron(ii) clathrochelates, their supramolecular interactions with globular proteins, and cellular uptake.

A fluorescein-tagged iron(ii) cage complex was obtained in a moderate total yield using a two-step synthetic procedure starting from its propargylamine-containing clathrochelate precursor. An 11-fold decrease in fluorescence quantum yield is observed in passing from the given fluorescein-based dye to its clathrochelate derivative. An excitation energy transfer from the terminal fluorescent group of the macrobicyclic molecule to its quasiaromatic highly π-conjugated clathrochelate framework can explain this effect. The kinetics of the hydrolysis of the acetyl groups of acetylated fluorescein azide and its clathrochelate derivative in the presence of one equivalent of BSA evidenced no strong supramolecular host–guest interactions between BSA and the tested compounds. Study of a chemical stability of the deacetylated iron(ii) clathrochelate suggested the formation of a supramolecular 1 : 1 BSA–clathrochelate assembly. Moreover, an addition of BSA or HSA to its solution caused the appearance of strong clathrochelate-based ICD outputs. The fluorescence emission anisotropy studies also evidenced the supramolecular binding of the fluorescein-tagged iron(ii) clathrochelate to the BSA macromolecule, leading to a high increase in this type of anisotropy. Subcellular uptake of the fluorescein-tagged molecules was visualized using fluorescence microscopy and showed its distribution to be mainly in the cytosol without entering the nucleus or accumulating in any other organelle. An X-rayed crystal of the above propargylamide macrobicyclic precursor with a reactive terminal C Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> C bond contains the clathrochelate molecules of two types, A and B. The encapsulated iron(ii) ion in these molecules is situated in the center of its FeN6-coordination polyhedron, the geometry of which is intermediate between a trigonal prism (TP) and a trigonal antiprism (TAP). The Fe–N distances vary from 1.8754(6) to 1.9286(4) Å and the heights h of their distorted TP–TAP polyhedra are very similar (2.30 and 2.31 Å); their values of φ are equal to 25.3 and 26.6°. In this crystal, the molecules of types A and B participate in different types of hydrogen bonding, giving H-bonded clathrochelate tetramers through their carboxylic and amide groups, respectively; these tetramers are connected to H-bonded chains.

PEGylated sequence-controlled macromolecules using supramolecular binding to target the Taspase1/Importin α interaction.

A novel strategy to inhibit the oncologically relevant protease Taspase1 is explored by developing PEGylated macromolecular ligands presenting the supramolecular binding motif guanidiniocarbonylpyrrole (GCP). Taspase1 requires interaction of its nuclear localization signal (NLS) with import receptor Importin α. We show the synthesis and effective interference of PEGylated multivalent macromolecular ligands with Taspase1-Importin α-complex formation.

Crystallizable Supramolecular Polymers: Binding Motif and Processing Matter

A systematic investigation of the influence of the binding motif and the processing history on the formation, crystallization, and mechanical properties of supramolecular polymers (SMPs) with a crystallizable core is reported. Telechelic, low-molecular-weight poly(butylene adipate) (PBA, 2700 g mol–1) was end-functionalized with either quadruple hydrogen-bonding 2-ureido-4[1H]pyrimidinone (UPy) motifs or 2,6-bis(1′-methylbenzimidazolyl)pyridine (Mebip) ligands. The UPy-based macromonomer spontaneously self-assembles into an SMP, whereas the Mebip-terminated building block was chain-extended by complex formation with a stoichiometric amount of Zn(NTf2)2. We show that the morphology and the properties of the SMPs are strongly affected by the nature of the supramolecular binding motif and also the processing parameters. In the case of the UPy-functionalized SMP, all processing conditions led to microphase segregation of the supramolecular binding motifs and the PBA cores. When this material was solution-cast or compression-molded, the crystallization of dimerized UPy stacks occurred first and stifled the PBA crystallization. This afforded flexible materials with storage moduli E′ of 72–92 MPa and a tensile strength (σmax) of 3.6 MPa (all at 25 °C). When UPy-functionalized PBA was rapidly quenched from the melt, both microphases crystallized readily, and this led to much stiffer materials, with E′ = 673 MPa and σmax = 5 MPa. No phase segregation was observed for the metallosupramolecular polymer. In this case, all processes investigated afforded materials with a crystalline PBA phase, but crystallization from the melt was, at least at ambient temperature, very slow. This material displays an E′ of 645–913 MPa and a σmax of 6.0–7.6 MPa, which represents a significant improvement over a low-molecular-weight PBA reference.

Sensing of a Protein’s Structure Using the Induced Circular Dichroism Spectra by the Monocarboxyphenylsulfide Iron(II) Clathrochelates as Optical Reporters

CD testing of a supramolecular binding of three constitutional isomers (ortho-, meta-, and para-substituted) of an inherently CD-silent monomethinemonocarboxyphenylsulfide iron(II) clathrochelate to globular proteins (serum albumins BSA and HSA, lysozyme and β-lactoglobulin) was performed. This type of isomerism is found to strongly affect an induced CD-activity of these clathrochelates upon their binding to protein. To study an effect of the additional ribbed functionalization on protein’s sensing properties, the CD outputs of clathrochelate analogs with biorelevant morpholine group were studied. Such a functionalization is found to substantially affect the protein’s CD-sensing properties; this is explained by a formation of hydrogen bonds between this substituent and aminoacid residues of a protein binding site, thus affecting and altering an arrangement of the corresponding clathrochelate–protein assembly. Molecular docking calculations were performed for structural modeling of the BSA–clathrochelate assemblies and to estimate an energy of these supramolecular processes.

Protein-encapsulated chlorophyll a molecules for biological solar cells

This paper reports a novel design of an artificial pigment-protein complex, created by supramolecular binding of chlorophyll a (Chl a) in the hydrophobic cavity of single-ring mutant of bacterial GroEL (SR). The results show that Chl a molecules assembled in SR nano-ring retain their native structure, and an increase of loading amount (up to ~26 pigment molecules per protein nano-ring) with the equilibrium concentration of Chl a upon dialysis has been observed. It is further seen that the nanoscale organization of Chl a in SR leads to a significant quenching of Chl a fluorescence, especially at high loadings. Moreover, the photostability of Chl a encapsulated in SR is significantly enhanced in comparison with free Chl a, as evidenced by an up to 6-fold increase of its half-life time. Both the interaction of Chl a with SR and the interaction between Chl a molecules contribute to photostability. Finally, it is shown that the Chl a-SR complex has good photoreduction activity as well as photoelectrochemical activity under visible light illumination. The maximum photoelectric conversion efficiency of the Chl a-SR-sensitized solar cells is around 1.09%. The strategy presented herein is believed to be instrumental in the design of effective photoenergy conversion materials.

Secoisolariciresinol diglucoside protects against cadmium-induced oxidative stress-mediated renal toxicity in rats

BackgroundCadmium is a well known environmental pollutant and strong toxic heavy metal, that causes oxidative damage to various organs of the body, including the kidney. Cadmium (II) chloride (CdCl2) is a water-soluble crystalline form, which exhibits a higher affinity with chlorides at the target site. The current study examined the protective effects of Secoisolariciresinol diglucoside (SDG), a principal lignan extracted from flaxseeds against CdCl2-induced renal toxicity in rats. MethodsTwenty four healthy male Wistar rats with four groups of six animals each were used in the study. Group-1- Control was administered with saline. Group-2 –was treated with SDG; Group-3 with CdCl2 alone, and Group-4 were treated with CdCl2 plus SDG. The effect of Cd on kidney was assessed in terms of various parameters like lipid peroxidation, production of Nitric oxide (NO) and Myeloperoxidase (MPO), and kidney function markers like uric acid, urea, and creatinine. The levels of antioxidant molecules like glutathione content and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were also measured, apart from histopathological studies. ResultsThe animals that received CdCl2, exhibited changes in the concentration of Cd in the kidney. The levels of kidney function markers like uric acid, urea, and creatinine were found to be abnormal in serum, and also there was a drastic decrease in the levels of glutathione content and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. The treatment of SDG significantly decreased (p < 0.05) the levels of NO and MPO in the animals treated with CdCl2 plus SDG when compared to the animal group treated with CdCl2 alone. The treatment of SDG before CdCl2 injection exhibited significant changes in the activity of the antioxidant enzymes, which was evidenced by the restoration in their activities, when compared to CdCl2 alone treated group (p < 0.05), as observed in the results of histopathology. ConclusionsThe findings of the present investigation suggested that SDG exhibited anti-oxidant, anti-apoptotic and renoprotective properties. Thus, SDG may act as a supramolecular binding component and naturally occurring metal chelating agent for metal cations like Cd2+. Therefore, flaxseed lignan-SDG can be used as a therapeutic agent against nephrotoxicity caused by cadmium. However, detailed future studies are needed to know the underlying mechanism of action of SDG against the Cd and other heavy metals induced nephrotoxicity.

Local potential energy: A novel QTAIM tool to quantify the binding energy of classical hydrogen bonds

We developed the local potential energy, LPE, model based on the electrostatic force (the unique fundamental force for chemical bonds) whose equation uses QTAIM topological data. The effectiveness of the LPE was evaluated with other well-known methods (supramolecular binding enthapy, SAPT-DFT, LMOEDA and IQA) by analyzing the hydrogen bond energy for a set of organic and inorganic molecules. The LPE has the second highest linearity with the supramolecular binding enthalpy (R2 = 0.9808) and the highest precision (RMSD = 1.60 kcal mol−1). In addition, LPE has the advantage to give individual binding energy values when the complex has more than one hydrogen bond.

On-Surface Supramolecular Chemistry with Porphyrins and Phthalocyanines: An Architectural Concept Leading to Engineered Quantum-Functional Nanostructures

The availability of porphyrin and phthalocyanine functionalization and synthesis, ‘by design’, at the time when sub-molecular resolution imaging at surfaces came into action boosted the emergence of ‘On-Surface-Supramolecular Chemistry’. [1] It is instructive to compare supra-molecular binding motifs in the fluid phase with the corresponding or modified analogues found after assembly on surfaces. In some similarity to chemistry and coordination chemistry translating into the corresponding ‘on-surface’ sciences, there are many factors complicating the on-surface assembly and architecture. Examples are provided by the modified dimensionality and kinetics, the site-specific conformational flexure and chirality and the close to irreversible adsorption in the strong surface potential in absence of a solvent which may complicate the on-surface assembly and architecture. Further, porphyrins and phthalocyanines interact with the substrate by different, competitive interactions, i.e. via (1) the central metal atom and (2) the porphyrin pi-system in addition to (3) the functional side groups. Binary and ternary assemblies of porphyrins and other functional components make it possible to create a wealth of ‘phases’, i.e. different complex supramolecular architectures with interesting physical properties to explore and exploit.We analyze structure-function correlations for a broad spectrum of functionalized porphyrins and phthalocyanines in their propensity to create structures of increasing complexity and functionality, on surfaces, also for future quantum technology. Notably, the large delocalized electronic system of the porphyrins and their easy-to-replace central atom further extend the achievable range of architectures and functions. Thus, by their dance on the nose of the ‘devil’ [3], porphyrins and phthalocyanines justify the emergence of ‘on-surface supramolecular physics’ as reflected by ongoing and future research work.[1] N. Wintjes et al. Two-dimensional phase behavior of a bimolecular porphyrin system at the solid-vacuum interface, J. Am. Chem. Soc. 2010, 132, 21, 7306-7311; N. Wintjes et al., Supramolecular synthons on surfaces: Controlling dimensionality and periodicity of tetraarylporphyrin assemblies by the interplay of cyano and alkoxy substituents Chem. Eur. J. 2008, 14, 5794.[2] S. Nowakowska et al., Adsorbate-induced modification of the confining barriers in a quantum box array, ACS Nano 2018, 12, 768.[3] W. Pauli “God made the bulk; surfaces were invented by the devil.” Quoted, e.g. in the Preface of A. Zangwill, Physics at Surfaces, Cambridge University Press, 1988. ISBN 978-0-521-34752-5Fig. 1) Adsorbate-induced modification of the confining barriers in a quantum box array formed by a functionalized fluoro-bi-phenyl porphyrin on Ag(111). (Taken from [2]) Figure 1

Physicochemical and in vitro cytotoxicity studies of inclusion complex between gemcitabine and cucurbit[7]uril host.

Gemcitabine, a cytostatic drug from the pyrimidine antimetabolite group, exhibits limited storage stability and numerous side effects during therapy. One of the strategies to improve the effectiveness of therapy with such drugs is the use of supramolecular nano-containers, including dendrimers and macrocyclic compounds. The ability of gemcitabine to attach a proton in an aqueous environment necessitates the search for a carrier that is well-tolerated by an organism and capable of supramolecular binding of a ligand (drug) in a cationic form. In the current study a promising strategy was tested for using cucurbituril Q7 to bind gemcitabine cations for its efficient intracellular delivery on three selected cancer cell lines (MOLT4, THP-1 and U937). Based on physicochemical studies (equilibrium dialysis, UV and 1H NMR titrations, DOSY 1H NMR measurements, DSC calorimetry) and cytotoxicity tests on cells with a free and blocked hENT1 transporter, the conclusion was drawn about the binding and penetration of the cucurbituril-drug complex into cancer cells.

Smart Glycopolymeric Nanoparticles for Multivalent Lectin Binding and Stimuli-Controlled Guest Release.

The synthesis and self-assembly of a polymer featuring a self-complementary supramolecular binding motif guanidiniocarbonyl pyrrole carboxylate zwitterion (GCP-zwitterion) bearing lactose moieties are reported. The GCP-zwitterion acts as a cross-linker to facilitate self-assembly of the polymeric chain into nanoparticles (NPs) at neutral pH in an aqueous medium. The formation of polymeric NPs can be controlled by addition of external stimuli (acid or base), which disfavors self-assembly of the GCP-zwitterion because of protonation or deprotonation of the GCP units in the polymer chain. The small-sized (<40 nm) NPs have a hydrophobic cavity and accessible lactose units on the outer shell for multivalent lectin binding. The multivalent interaction between NPs and the lectin peanut agglutinin was confirmed by agglutination experiments. In addition, the stimuli-responsive property of NPs was exploited for the uptake and release of a hydrophobic guest Nile red. Furthermore, the selectivity toward different cell lines (HEK 296T, HeLa, and Hep2G) was tested, and a cellular uptake of cargo-loaded NPs was found for Hep2G cells bearing the lactose-specific asialogylcoprotein receptor, whereas all other cells showed no NP interaction.

Supracolloidal Self-Assembly of Divalent Janus 3D DNA Origami via Programmable Multivalent Host/Guest Interactions.

We introduce divalent 3D DNA origami cuboids as truly monodisperse colloids and harness their ability for precision functionalization with defined patches and defined numbers of supramolecular binding motifs. We demonstrate that even adamantane/β‐cyclodextrin host/guest inclusion complexes of moderate association strength can induce efficient supracolloidal fibrillization at high dilution of the 3D DNA Origami as a result of cooperative multivalency. We show details on the assembly of Janus and non‐Janus 3D DNA origami into supracolloidal homo‐ and heterofibrils with respect to multivalency effects, electrostatic screening, and stoichiometry. We believe that the merger of 3D DNA origami with colloidal self‐assembly and supramolecular motifs provides new synergies at the interface of these disciplines to better understand multivalency effects, to promote structural complexity, and add non‐DNA assembling and switching mechanisms to DNA nanoscience.