Coordination Cages Research Articles

Investigating the Cell Entry Mechanism, Disassembly, and Toxicity of the Nanocage PCC-1: Insights into Its Potential as a Drug Delivery Vehicle.

The porous coordination cage PCC-1 represents a new platform potentially useful for the cellular delivery of drugs with poor cell permeability and solubility. PCC-1 is a metal-organic polyhedron constructed from zinc metal ions and organic ligands through coordination bonds. PCC-1 possesses an internal cavity that is suitable for drug encapsulation. To better understand the biocompatibility of PCC-1 with human cells, the cell entry mechanism, disassembly, and toxicity of the nanocage were investigated. PCC-1 localizes in the nuclei and cytoplasm within minutes upon incubation with cells, independent of endocytosis and cargo, suggesting direct plasma membrane translocation of the nanocage carrying its guest in its internal cavity. Furthermore, the rates of cell entry correlate to extracellular concentrations, indicating that PCC-1 is likely diffusing passively through the membrane despite its relatively large size. Once inside cells, PCC-1 disintegrates into zinc metal ions and ligands over a period of several hours, each component being cleared from cells within 1 day. PCC-1 is relatively safe for cells at low micromolar concentrations but becomes inhibitory to cell proliferation and toxic above a concentration or incubation time threshold. However, cells surviving these conditions can return to homeostasis 3-5 days after exposure. Overall, these findings demonstrate that PCC-1 enters live cells by crossing biological membranes spontaneously. This should prove useful to deliver drugs that lack this capacity on their own, provided that the dosage and exposure time are controlled to avoid toxicity.

Synthesis, structure, and thermal stability of new one-dimensional rubidium coordination supramolecular compound

New one-dimensional rubidium dipicolinate hydrate, Rb(Hpdc)(H2pdc)·2H2O, Rb-pdc (H2pdc = pyridine-2,6-dicarboxylic acid) has been grown via hydrothermal method. Single crystal X‐ray diffraction indicates that Rb-pdc reveal a zigzag chain structure, and is composed of RbO7N2 polyhedra, 2,6-pdc ligand, and H2O. Rb-pdc crystallizes in the triclinic space group P1¯ (No.2) with unit cell of a = 6.9050(4) Å, b = 10.9237(7) Å, c = 11.3319(7) Å, α = 94.014(2)°, β = 90.591(2) , γ = 99.6870(10)°, V = 840.28(9) Å3, Z = 2. The observed Rb–O and Rb–N bond distances are 2.904(4)–3.545(4) Å and 3.112(3)–3.159(4) Å, respectively. H-bonds incorporate the chains in Rb-pdc into a 2D (along [1,0,0] direction) network topology. Thermogravimetric analysis (TGA) and powder X-ray diffraction measured at different temperatures show that Rb-pdc exhibits three steps of weight losses, and Rb2O as the final thermal decomposition product is demonstrated. Also, elemental analysis (EA) and infrared (IR) spectrum are performed to identify the chemical composition and characterized bonding.

Abstract A027: A photoactivatable microtubule-targeting rigidin prodrug

Abstract Analogues of marine alkaloid rigidins have been found to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was “caged” by coordination of its thioether group to a photosensitive ruthenium polypyridyl complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell lines monolayers, 3D lung cancer tumor spheroids (A549), and in a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O2) but also, remarkably, in hypoxic conditions (1% O2). In vivo, light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the efficacy of a ruthenium-based photocaged compounds in a tumor xenograft. In subsequent unpublished work, we fine-tuned the excited states in this complex by adding an amide functional group on the ruthenium cage. By doing so, a new caged complex was obtained that was activated by red light (instead of green light). We demonstrated the red light activation of this compound in solution and in vitro. This result demonstrates that functionalization of ruthenium cage with electron-withdrawing groups can radically enhance their photochemical properties, which is essential for this method development (red light penetrates better into tissues than green light). We will present our results of in vivo testing of this caged compound activated by tumor penetrable red light, where significant tumor reduction is seen in mice xenografted with subcutaneous human uveal melanoma liver metastatic cells. Citation Format: Alexander Kornienko, Sylvestre Bonnet. A photoactivatable microtubule-targeting rigidin prodrug [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A027.

Selectivity, synthesis, crystal structure and biological activity of the anion-coordination phenanthrolinium tartratogermanate

Novel supramolecular cation-anionic coordination compound (HPhen)4[(μ-O){Ge2(OH) (μ-Tart)2}2]·9H2O was synthesised and characterised by the X-ray, elemental, IR- and Hirshfeld surface analysis. It was established that original synthesis method and ability of 1,10-phenanthroline to be protonated promotes the formation of [(μ-O){Ge2(OH)(μ-Tart)2}2]4- anion. In this anion, dimeric fragments are connected by a bridging oxygen atom, and the coordination polyhedra around the germanium atoms adopt a distorted trigonal bipyramidal geometry. The cations HPhen+ serve as effective building blocks, strengthening the overall structure through classical hydrogen bonding and additional π-π stacking interactions. Biological screening of (HPhen)4[(μ-O){Ge2(OH) (μ-Tart)2}2]·9H2O demonstrated its remarkable enzyme-effector and antimicrobial activity. The compounds' efficacy can be attributed to the synergistic effects of the independent cations and anions, as well as the ability of protonated 1,10-phenanthroline to inhibit metal ions in enzymes and form stacking interactions with specific protein components. These characteristics make such compounds highly effective and promising antibacterial agents that minimize the risk of developing bacterial resistance.

Chemical Site-Differentiation of Calix[4]arenes through Enforced Conformations by Confinement in a Cage.

Desymmetrization of a symmetric skeleton enables late-stage functionalization of molecules. However, reagent-controlled desymmetrization by site-selective reactions of symmetric molecules remains a difficult synthetic strategy. Here, we found that complete confinement of a symmetric molecule within a coordination cage can desymmetrize the guest conformation, making it possible to site-selectively activate or protect the otherwise equivalent reaction sites of calix[4]arene derivatives. Multistep, one-cage reactions also demonstrated the transformation of an AAAA-type calix[4]arene into a lower symmetry ABAC-type one.

Catalytic Inhibition of Base-Mediated Reactivity by a Self-Assembled Metal-Ligand Host.

Spacious M4 L6 tetrahedra can act as catalytic inhibitors for base-mediated reactions. Upon adding only 5 % of a self-assembled Fe4 L6 cage complex, the conversion of the conjugate addition between ethylcyanoacetate and β-nitrostyrene catalyzed by proton sponge can be reduced from 83 % after 75 mins at ambient temperature to <1 % under identical conditions. The mechanism of the catalytic inhibition is unusual: the octacationic Fe4 L6 cage increases the acidity of exogenous water in the acetonitrile reaction solvent by favorably binding the conjugate acid of the basic catalyst. The inhibition only occurs for Fe4 L6 hosts with spacious internal cavities: minimal inhibition is seen with smaller tetrahedra or Fe2 L3 helicates. The surprising tendency of the cationic cage to preferentially bind protonated, cationic ammonium guests is quantified via the comprehensive modeling of spectrophotometric titration datasets.

Controlling the Assembly of PdII/Bianthryl‐Based Monomeric and Dimeric Interlocked Cages by Steric Effects

AbstractIn the energy landscape of coordination‐driven self‐assembly processes, the isolation of kinetically formed supramolecular cages has long been identified as a challenging task. This study reports a reliable strategy for the selective isolation of kinetically or thermodynamically preferred stable coordination cages, whose formation depends on the degree of steric protection offered by the exterior side chains. The combination of PdII ions with arc‐shaped 2,2′‐bianthryl‐based ligands that contain different numbers of methoxyethoxy side chains led to the quantitative formation of both kinetically favorable monomeric M2L4 cages and thermodynamically favorable dimeric (M2L4)2 interlocked cages. These assemblies were structurally fully characterized via NMR spectroscopy, mass spectrometry, and single‐crystal X‐ray diffraction analysis. Although the monomeric cages with fewer exterior side chains can reassemble into interlocked cages, the cages with more exterior substituents remain monomeric cages under similar conditions. A computational study revealed that this different behavior is mainly governed by the destabilization of the interlocking assemblies due to the steric repulsion among the side chains on the overcrowded exterior. Furthermore, the kinetically stabilized monomeric M2L4 cages exhibit permanent host abilities toward sulfonate guests, while the cages with lower steric protection undergo dimerization accompanied by guest release.

Distinct selectivity inside self-assembled coordination cages.

Supramolecular containers have long been applied to regulate organic reactions with distinct selectivity, owing to their diverse functions such as the ability to pose a guest molecule(s) with a certain orientation and conformation. In this review, we try to illustrate how self-assembled coordination cages could achieve this goal. Two representative cage hosts, namely, self-assembled Pd(II)-ligand octahedral coordination cages ([Pd6L4]12+) and self-assembled Ga(III)-ligand tetrahedral coordination cages ([Ga4L6]12-) are selected as the pilot hosts that this mini review covers. Representative works in this area are presented here in brief.

Quantifying the Effect of Guest Binding on Host Environment.

The environment around a host-guest complex is defined by intermolecular interactions between the complex, solvent molecules, and counterions. These interactions govern both the solubility of these complexes and the rates of reactions occurring within the host molecules and can be critical to catalytic and separation applications of host-guest systems. However, these interactions are challenging to detect using standard analytical chemistry techniques. Here, we quantify the hydration and ion pairing of a FeII4L4 coordination cage with a set of guest molecules having widely varying physicochemical properties. The impact of guest properties on host ion pairing and hydration was determined through microwave microfluidic measurements paired with principal component analysis (PCA). This analysis showed that introducing guest molecules into solution displaced counterions that were bound to the cage, and that the solvent solubility of the guest has the greatest impact on the solvent and ion-pairing dynamics surrounding the host. Specifically, we found that when we performed PCA of the measured equivalent circuit parameters and the solubility and dipole moment, we observed a high (>90%) explained variance for the first two principal components for each circuit parameter. We also observed that cage-counterion pairing is well-described by a single ion-pairing type, with a one-step reaction model independent of the type of cargo, and that the ion-pairing association constant is reduced for cargo with higher water solubility. Quantifying hydration and cage-counterion interactions is a critical step to building the next generation of design criteria for host-guest chemistries.

A cage-on-MOF strategy to coordinatively functionalize mesoporous MOFs for manipulating selectivity in adsorption and catalysis

Functionalizing porous materials with capping agents generates hybrid materials with enhanced properties, while the challenge is how to improve the selectivity and maintain the porosity of the parent framework. Herein, we developed a “Cage-on-MOF” strategy to tune the recognition and catalytic properties of MOFs without impairing their porosity. Two types of porous coordination cages (PCCs) of opposite charges containing secondary binding groups were developed to coordinatively functionalize two distinct porous MOFs, namely MOF@PCC nanocomposites. We demonstrated that the surface-capped PCCs can act as “modulators” to effectively tune the surface charge, stability, and adsorption behavior of different host MOF particles. More importantly, the MOF@PCCs can serve as selective heterogeneous catalysts for condensation reactions to achieve reversed product selectivity and excellent recyclability. This work sets the foundation for using molecular cages as porous surface-capping agents to functionalize and manipulate another porous material, without affecting the intrinsic properties of the parent framework.

Capture of Singlet Oxygen Modulates Host-Guest Behavior of Coordination Cages.

The anthracene panels of two tetrahedral MII 4 L6 cages, where MII =CoII or FeII , were found to react with photogenerated singlet oxygen (1 O2 ) in a hetero-Diels-Alder reaction. ESI-MS analysis showed the cobalt(II) cages to undergo complete transformation of all anthracene panels into endoperoxides, whereas the iron(II) congeners underwent incomplete conversion. The reaction was found to be partially reversible in the case of the 1-FeII cage. The dioxygen-cage cycloadducts were found to bind a set of guest molecules more weakly than the parent cages, with affinity dropping by more than two orders of magnitude in some cases. The light-driven cycloaddition reaction between cage and 1 O2 thus served as a stimulus for guest release and reuptake.

Guest-induced structural transformation of a coordination cage

Guest-induced structural transformation of a coordination cage

Increasing the structural complexity of lantern-type coordination cages

Increasing the structural complexity of lantern-type coordination cages

Confinement inside MOFs Enables Guest-Modulated Spin Crossover of Otherwise Low-Spin Coordination Cages.

Confinement of discrete coordination cages within nanoporous lattices is an intriguing strategy to gain unusual properties and functions. We demonstrate here that the confinement of coordination cages within metal-organic frameworks (MOFs) allows the spin state of the cages to be regulated through multilevel host-guest interactions. In particular, the confined in situ self-assembly of an anionic FeII4L6 nanocage within the mesoporous cationic framework of MIL-101 leads to the ionic MOF with an unusual hierarchical host-guest structure. While the nanocage in solution and in the solid state has been known to be invariantly diamagnetic with low-spin FeII, FeII4L6@MIL-101 exhibits spin-crossover (SCO) behavior in response to temperature and release/uptake of water guest within the MOF. The distinct color change concomitant with water-induced SCO enables the use of the material for highly selective colorimetric sensing of humidity. Moreover, the spin state and the SCO behavior can be modulated also by inclusion of a guest into the hydrophobic cavity of the confined cage. This is an essential demonstration of the phenomenon that the confinement within porous solids enables an SCO-inactive cage to show modulable SCO behaviors, opening perspectives for developing functional supramolecular materials through hierarchical host-guest structures.

Dynamic Cages—Towards Nanostructured Smart Materials

AbstractThe interest in capsular assemblies such as dynamic organic and coordination cages has blossomed over the last decade. Given their chemical and structural variability, these systems have found applications in diverse fields of research, including energy conversion and storage, catalysis, separation, molecular recognition, and live‐cell imaging. In the exploration of the potential of these discrete architectures, they are increasingly being employed in the formation of more complex systems and smart materials. This Review highlights the most promising pathways to overcome common drawbacks of cage systems (stability, recovery) and discusses the most promising strategies for their hybridization with systems featuring various dimensionalities. Following the description of the most recent advances in the fabrication of zero to three‐dimensional cage‐based systems, this Review will provide the reader with the structure‐dependent relationship between the employed cages and the properties of the materials.

Dynamic Cages-Towards Nanostructured Smart Materials.

The interest in capsular assemblies such as dynamic organic and coordination cages has blossomed over the last decade. Given their chemical and structural variability, these systems have found applications in diverse fields of research, including energy conversion and storage, catalysis, separation, molecular recognition, and live-cell imaging. In the exploration of the potential of these discrete architectures, they are increasingly being employed in the formation of more complex systems and smart materials. This Review highlights the most promising pathways to overcome common drawbacks of cage systems (stability, recovery) and discusses the most promising strategies for their hybridization with systems featuring various dimensionalities. Following the description of the most recent advances in the fabrication of zero to three-dimensional cage-based systems, this Review will provide the reader with the structure-dependent relationship between the employed cages and the properties of the materials.

Programmable Monodisperse Glyco-Multivalency Using Self-Assembled Coordination Cages as Scaffolds.

The multivalent presentation of glycans leads to enhanced binding avidity to lectins due to the cluster glycoside effect. Most materials used as scaffolds for multivalent glycan arrays, such as polymers or nanoparticles, have intrinsic dispersity: meaning that in any sample, a range of valencies are presented and it is not possible to determine which fraction(s) are responsible for binding. The intrinsic dispersity of many multivalent glycan scaffolds also limits their reproducibility and predictability. Here we make use of the structurally programmable nature of self-assembled metal coordination cages, with polyhedral metal-ion cores supporting ligand arrays of predictable sizes, to assemble a 16-membered library of perfectly monodisperse glycoclusters displaying valencies from 2 to 24 through a careful choice of ligand/metal combinations. Mono- and trisaccharides are introduced into these clusters, showing that the synthetic route is tolerant of biologically relevant glycans, including sialic acids. The cluster series demonstrates increased binding to a range of lectins as the number of glycans increases. This strategy offers an alternative to current glycomaterials for control of the valency of three-dimensional (3-D) glycan arrays, and may find application across sensing, imaging, and basic biology.

A novel Ag3L2 coordination cage derived from a tripodal oxazoline ligand: synthesis, structure and catalysis

Coordination cages have attracted considerable attention recently due to the well-defined cavities and varied potential applications in different fields. In this work, a new tripodal oxazoline-based ligand with C3 symmetry, tris(4-(4,5-dihydrooxazol-2-yl)phenyl)amine (TOPA), was synthesized and employed to constitute coordination cage compounds. By the reaction of TOPA and AgPF6 at room temperature, a novel M3L2-type crystalline coordination cage complex was obtained with the formula of {[Ag3(TOPA)2]·(PF6)3}(1). In this complex, the adjacent two ligands coordinated with three Ag+ ions to form a coordination cage and these cages further generate the three-dimensional (3D) supramolecular networks through noncovalent interactions including hydrogen bond, C-H…π and F…Ag interactions. Moreover, cage complex 1 exhibited good catalytic performance in the cyclopropanation of styrene with methyl 2-diazo-2-(4-methoxyphenyl)acetate.

Triphenylamine-Functionalized Coordination Cage as a Supramolecular Fluorescence Sensor for Sequential Detection of Aluminum Ions and Nitrofurantoin.

Coordination cages with a well-defined nanocavity are a class of promising supramolecular materials for molecular recognition and sensing. However, their applications in sequential sensing of multiple types of pollutants are highly desirable yet extremely limiting and challenging. Herein, we demonstrate a convenient strategy to develop a supramolecular fluorescence sensor for sequentially detecting environmental pollutants of aluminum ions and nitrofurantoin. A coordination cage (Ni-NTB), adopting an octahedral structure with triphenylamine chromophores occupying on the faces, is weakly emissive in solution due to the intramolecular rotations of the phenyl rings. Ni-NTB exhibits sensitive and selective fluorescence "off-on-off" processes during consecutive sensing of Al3+ and nitrofurantoin, an antibacterial drug. These sequential detection processes are highly interference-tolerant and visually observable with the naked eye. Mechanism studies reveal that the fluorescence switch is controllable by tuning the degree of intramolecular rotations of the phenyl rings and the pathway of intermolecular charge transfer, which is associated with the host-guest interaction. Moreover, the fabrication of Ni-NTB on test strips enabled a quick naked-eye sequential sensing of Al3+ and nitrofurantoin in seconds. Hence, this novel supramolecular fluorescence "off-on-off" sensing platform provides a new approach to developing supramolecular functional materials for monitoring environmental pollution.

Caging the Hofmeister Effect by a Biomimetic Supramolecular Receptor.

The effect of anions on the solubility and function of proteins was recognized in 1888 and is now termed the Hofmeister effect. Numerous synthetic receptors are known that overcome the associated anion recognition bias. However, we are unaware of a synthetic host being used to overcome Hofmeister effect perturbations to natural proteins. Here, we report a protonated small molecule cage complex that acts as an exo-receptor and displays non-Hofmeister solubility behavior, with only the chloride complex remaining soluble in aqueous media. This cage allows for the activity of lysozyme to be retained under conditions where anion-induced precipitation would otherwise cause it to be lost. To our knowledge, this is the first time a synthetic anion receptor is used to overcome the Hofmeister effect in a biological system.