Metallosupramolecular Complexes Research Articles

Metallo-supramolecular complexes enantioselectively target monkeypox virus RNA G-quadruplex and bolster immune responses against MPXV

Abstract Mpox viruses (MPXV) has emerged as a formidable orthopoxvirus, posing an immense challenge to global public health. Understanding the regulatory mechanisms of MPXV infection, replication and immune evasion will benefit the development of novel antiviral strategies. Despite the involvement of G-quadruplexes (G4s) in modulating infection and replication processes of multiple viruses, their roles in MPXV life cycle remain largely unknown. Here, we found a highly conservative and stable G4 in MPXV, which acts as a positive regulatory element for viral immunodominant protein expression. Furthermore, by screening 42 optically pure chiral metal complexes, we identified the Λ enantiomer of a pair of chiral helical compounds can selectively target mRNA G4 and enhance expression of the 39-kDa core protein encoded by the MPXV A5L gene. Mechanistically, RNA G4-specific helicase DHX36 inhibits A5L protein expression by unwinding G4. In contrast, MH3 Λ enhanced mRNA stability by specifically targeting G4 structures and subsequently increased protein expression. Furthermore, given the pivotal role of the 39-kDa core protein in activating immune responses and facilitating virion maturation, modulation of MPXV G4 folding by MH3 Λ exhibited inhibitory effects on MPXV replication through enhancing immune response. Our findings underscore the critical involvement of G4 in MPXV life cycle and offer potential avenues for developing antiviral drugs targeting G4.

Pd(II), Pt(II) metallosupramolecular complexes as Single-Site Co-Catalyst for photocatalytic H2 evolution

Pd(II), Pt(II) metallosupramolecular complexes as Single-Site Co-Catalyst for photocatalytic H2 evolution

Post-coordination photoinitiated macromolecular thiol-ene coupling reaction for construction of metallo-supramolecular complexes of ABCL2-type miktoarm star copolymers and self-assembly of the complexes in water

In this paper, we focus on investigating synthesis of metallo-supramolecular architectures of ABCL2-type miktoarm star copolymers PCL(-b-PDPA)-b-[(Tpyp)2-b-PMPC] (A, PCL; B, PDPA; C, PMPC; L, Tpyp) with ruthenium(II) (Ru(II)) ions and exploring self-assembly behavior of the complexes in water. Direct coordination of PCL(-b-PDPA)-b-[(Tpyp)2-b-PMPC] to Ru(II) ions and post-coordination photoinitiated macromolecular thiol-ene coupling reaction strategies were explored to construct Ru(II) coordination complexes, respectively. The result indicates that the post-coordination coupling reaction was more suitable strategy for constructing this kind of coordination complexes, which may avoid a larger steric hindrance generated from the coexistence of the three arms of PCL(-b-PDPA)-b-[(Tpyp)2-b-PMPC] leading to the disadvantageous influence on the formation of the bis(terpyridine)-Ru(II) complex. It should be mentioned that, however, although a photoinitiated macromolecular thiol-ene radical coupling reaction is facile, so far to achieve complete reaction of the target groups (i.e., alkene groups) has remained a challenge. Therefore, herein a post-coordination thiol-ene coupling reaction was explored carefully and an appropriate condition for the complete reaction of the alkene groups was given. Interestingly, the Ru(II) coordination complexes could self-assemble to form 2D platelets. This should be attributed to the unique metallo-supramolecular architecture. It is expected that the exploration can provide strategies for construction of complicated and exquisite metallo-supramolecular architectures and novel self-assemblies.

Adduct Ions as Diagnostic Probes of Metallosupramolecular Complexes Using Ion Mobility Mass Spectrometry

Following electrospray ionization, it is common for analytes to enter the gas phase accompanied by a charge-carrying ion, and in most cases, this addition is required to enable detection in the mass spectrometer. These small charge carriers may not be influential in solution but can markedly tune the analyte properties in the gas phase. Therefore, measuring their relative influence on the target molecule can assist our understanding of the structure and stability of the analyte. As the formed adducts are usually distinguishable by their mass, differences in the behavior of the analyte resulting from these added species (e.g., structure, stability, and conformational dynamics) can be easily extracted. Here, we use ion mobility mass spectrometry, supported by density functional theory, to investigate how charge carriers (H+, Na+, K+, and Cs+) as well as water influence the disassembly, stability, and conformational landscape of the homometallic ring [Cr8F8(O2CtBu)16] and the heterometallic rotaxanes [NH2RR'][Cr7MF8(O2CtBu)16], where M = MnII, FeII, CoII, NiII, CuII, ZnII, and CdII. The results yield new insights on their disassembly mechanisms and support previously reported trends in cavity size and transition metal properties, demonstrating the potential of adduct ion studies for characterizing metallosupramolecular complexes in general.

Defect-controlled softness, diffusive permeability, and mesh-topology of metallo-supramolecular hydrogels.

Hydrogels are polymer networks swollen in water; they are suitable materials for biomedical applications such as tissue engineering and drug delivery. In the latter, the controlled diffusion of small diffusants inside the network is essential, as it determines the release mechanism of the drug. In general, the diffusion inside a polymer network is controlled by its mesh-size. Here, we actively control the diffusivity and also the softness of metallo-supramolecular hydrogels via the network mesh-topology by introducing connectivity defects. A model polymer network is realized based on a 4-arm poly(ethylene glycol) (pEG) where each arm is capped with terpyridine moieties that are capable of forming metallo-supramolecular complexes with zinc ions. In this model network, we insert 8-arm pEG macromolecules that are functionalized with terpyridine at different ratios to create connectivity defects. With an increasing amount of 8-arm pEG, the polymer network forms more loops, as quantified by double quantum-NMR. This doped network shows an enhanced self-diffusivity of the building block molecules within the network, as examined by fluorescence recovery after photobleaching, and a higher softness, as investigated by oscillatory shear rheology. With these findings, we show that it is possible to tune the diffusivity and softness of hydrogels with defects in a rational fashion.

Development of metallosupramolecular phosphatases based on the combinatorial self-assembly of metal complexes and organic building blocks for the catalytic hydrolysis of phosphate monoesters

The phosphorylation and dephosphorylation of proteins and other intracellular molecules are important reactions in living systems and are generally controlled by the action of kinases and phosphatases. The design and synthesis of artificial mimics of natural enzymes are important research subjects in bioorganic and bioinorganic chemistry. A supramolecular strategy based on the three-dimensional self-assembly of molecular building blocks would be useful for the construction of artificial supramolecular complexes. The main focus of this review is on artificial mimics of natural phosphatases that contain dimetallic cores in their active sites. Previous examples of artificial mimics of alkaline phosphatases (AP) constructed covalently are initially presented, then followed by a description of artificial metallosupramolecular complexes formed by the combinatorial self-assembly of different bis(Zn2+-cyclen) complexes containing 2,2′-bipyridyl (bpy) linker (cyclen = 1,4,7,10-tetraazacyclododecane), cyanuric acid or barbital (Bar) units, and Cu2+ ion in single or two-phase solvent systems. It is now thought that the appropriate combination of the various building blocks and solvent systems (single- and two-phase solvent systems) can strongly assist in developing the artificial systems that accelerate and catalyze the hydrolysis of a phosphate monoester, mono(p-nitrophenyl) phosphate (MNP). Such approaches would be useful in terms of understanding the mechanism of action of naturally occurring enzymes and to develop biologically active, bioorthogonal, and versatile supramolecular catalysts.

Catecholate‐Based Helicates

Catechol is a bidentate ligand for metal coordination which is well suited for the formation of helicates and related metallosupramolecular complexes. The development of the self‐assembly and stereochemistry of helicates based on catechol ligands in the last 25 years is discussed. Unsaturated, heteronuclear and hierarchical helicates as well as molecular switches based on catecholate helicates are covered.

Metallo-supramolecular complexes from mPEG/PDPA diblock copolymers and their self-assembled strip nanosheets.

Herein we designed and synthesized mPEG/PDPA copolymers containing two 4-([2,2′:6′,2′′-terpyridin]-4′-yl) phenyl (Tpyp) groups at the junction point of the two blocks (mPEG(-b-Tpyp)2-b-PDPAx, x = 23, 33, and 44). Interestingly, after a hierarchical pattern from the coordination of mPEG(-b-Tpyp)2-b-PDPAx with Ru(ii) ions followed by the self-assembly in water, 2D strip nanosheets with a monomolecular layer were obtained. In contrast, mPEG(-b-Tpyp)2-b-PDPAx without coordination self-assembled into spherical micelles in the similar condition. The formation of the rigid and charged ⋯Tpyp-Ru(ii)⋯ chain, the brush-shaped polymer architecture and the presence of the hexafluorophosphate (PF6−) counterions should be responsible for the unique self-assembly behavior of the metallo-supramolecular complexes. It is expected that the hierarchical self-assembly pattern can provide a new strategy for preparation of self-assemblies with different morphologies.

High catalytic activity and selectivity in hydrosilylation of new Pt(II) metallosupramolecular complexes based on ambidentate ligands

Two new air- and water-stable Pt(II) metallosupramolecular complexes based on ambidentate ligands have been designed, synthesized and fully characterized. The structure of complexes has been determined by various analytical techniques including NMR spectroscopy and TOF-MS. Additionally, the single crystal structure of 2 was determined by X-ray diffraction. The catalytic activity of these complexes in hydrosilylation has been investigated, establishing that both have similar high activity and selectivity within a broad scope of structurally distinct olefins and hydrosilanes.

Construction of Metallosupramolecular Coordination Complexes: From Lanthanide Helicates to Octahedral Cages Showing Single-Molecule Magnet Behavior.

The construction of metallosupramolecular complexes toward interesting topological structures is a critical challenge for chemists. The fluctuation in the synthetic strategy, by keeping the same metal-ligand combination, has proved a very significant approach to construct metallosupramolecular architectures. Herein, by varying the reaction conditions four new DyIII-supramolecular complexes based on a flexible dihydrazone ligand H2L (H2L = bis(2-hydroxy-3-methoxybenzylidene)adipohydrazide) in cooperation with different anions and solvents having formulas [Dy4L4(μ2-N3)2](NO3)2·6CH3OH·2H2O (1), [Dy8L8(μ2-CH3OH)4]Cl8·6CH3OH·14H2O (2), [Dy12L12(μ2-OH)2(OH)6(CH3O)2](NO3)2·2CH3OH·14H2O (3), and [Dy12L12(μ2-OH)2(NO3)2(OH)3(CH3O)](NO3)4·22H2O (4), have been successfully synthesized and their crystal structures confirmed by single crystal X-ray diffraction studies. The structural study reveals that 1 and 2 have quadruple-stranded helicate and dual triple-stranded helicate supramolecular structures, respectively, while 3 and 4 display "octahedron" cagelike supramolecular structures. The magnetic studies reveal that complexes 1-3 exhibit slow magnetic relaxation behavior, while complex 4 displays a series of typical frequency-dependent relaxation signals at 0 Oe applied dc field which is a rare case in polynuclear 4f single-molecule magnet (SMM) family to date. Interestingly, the distinct magnetic dynamic behavior was noticed for nearly isoskeletal complexes 3 and 4, which can be attributed to the modification of the coordination environment around DyIII ions.

Selective Metal-Assisted Assembly of Mesocates or Helicates with Tristhiosemicarbazone Ligands.

The effect of the ligand and/or metal-related factors on the formation of tristhiosemicarbazone metallosupramolecular complexes has been studied in this work. The crystal structures of zinc(II) and lead(II) tristhiosemicarbazone mesocates and a hydrolyzed cadmium(II) helicate let us better rationalize some factors involved in the selective formation of helicates or mesocates.

Ion mobility–mass spectrometry of supramolecular complexes and assemblies

Despite their structural and functional differences, synthetic supramolecular assemblies share many similarities with biological assemblies, especially enzymes. The assemblies can be on the same length scale, and their structures and guest binding are typically governed by non-covalent interactions. Thus, only relatively weak interactions define the shape of a synthetic supramolecule or the secondary and tertiary structure of a protein, such that the resulting dynamism makes structure elucidation challenging. For biomolecules such as peptides, proteins, glycans and lipids this has often been tackled using ion mobility–mass spectrometry (IM-MS), whereby analyte ions are separated according to their gas-phase mobility and their mass-to-charge ratio. IM-MS is an established method in omics, separation sciences and small-molecule structural chemistry, but has only recently grown in popularity for the study of synthetic supramolecular assemblies in the gas phase. This Review describes IM-MS techniques and how they can help us understand the structures of molecular self-assemblies, host–guest complexes and metallosupramolecular complexes. Ion mobility–mass spectrometry (IM-MS) is a gas-phase method for structural characterization — a tool prevalent in biology but only recently finding applications in supramolecular chemistry. This Perspective describes how IM-MS techniques give us information about the structures of molecular self-assemblies, host–guest complexes and metallosupramolecular systems.

Multivalent Metallosupramolecular Assemblies as Effective DNA Binding Agents.

We report the implementation of coordination chemistry onto the generation of new types of metallosupramolecular complexes with laterally appended cationic moieties for DNA binding in buffered aqueous media. Utilization of an N,N,O-type coordination pocket along with an octahedral zinc(II) metal ion allowed us to obtain mono- and tetranuclear complexes in both solution and solid state, as confirmed by NMR spectroscopy and single-crystal X-ray diffraction, respectively. By using isothermal titration calorimetry and gel electrophoresis, multiply charged cationic assemblies were observed to effectively bind to DNA through multivalent electrostatic interactions. Furthermore, we observed a correlation between the multivalency of the compounds employed and the effectiveness of DNA binding.

Covalent post-assembly modification in metallosupramolecular chemistry.

A growing variety of covalent reactions have been employed to achieve the post-assembly modification (PAM) of self-assembled metallosupramolecular complexes. Covalent PAM enables the late-stage derivatisation of pre-assembled parent complexes in a modular fashion, thus expanding the chemical space available for supramolecular synthesis. The oldest and most widespread implementation of covalent PAM is in metal-preorganised covalent synthesis. Recent work, however, has broadened the scope of covalent PAM to include: protocols for efficiently grafting new functionalities onto supramolecular architectures, reactions that permanently 'lock-down' metastable complexes, and covalent bond-forming stimuli that trigger controlled structural transformations between distinct supramolecular species. This review highlights key examples of each of these distinct kinds of covalent PAM in metallosupramolecular chemistry, before providing a perspective upon future challenges and opportunities.

Chiral metallohelices enantioselectively target hybrid human telomeric G-quadruplex DNA

The design and synthesis of metal complexes that can specifically target DNA secondary structure has attracted considerable attention. Chiral metallosupramolecular complexes (e.g. helicates) in particular display unique DNA-binding behavior, however until recently few examples which are both water-compatible and enantiomerically pure have been reported. Herein we report that one metallohelix enantiomer Δ1a, available from a diastereoselective synthesis with no need for resolution, can enantioselectively stabilize human telomeric hybrid G-quadruplex and strongly inhibit telomerase activity with IC50 of 600 nM. In contrast, no such a preference is observed for the mirror image complex Λ1a. More intriguingly, neither of the two enantiomers binds specifically to human telomeric antiparallel G-quadruplex. To the best of our knowledge, this is the first example of one pair of enantiomers with contrasting selectivity for human telomeric hybrid G-quadruplex. Further studies show that Δ1a can discriminate human telomeric G-quadruplex from other telomeric G-quadruplexes.

Self-assembly of highly luminescent heteronuclear coordination cages.

Exo-functionalized Pd2L4 cage compounds with attached Ru(ii) pyridine complexes were prepared via coordination-driven self-assembly. Unlike most of the previously reported palladium(ii) cages, one of these metallocages exhibits an exceptionally high quantum yield of 66%. The presented approach is promising to obtain luminescent coordination complexes for various applications.

Dicopper(II) metallacyclophanes as multifunctional magnetic devices: a joint experimental and computational study.

Metallosupramolecular complexes constitute an important advance in the emerging fields of molecular spintronics and quantum computation and a useful platform in the development of active components of spintronic circuits and quantum computers for applications in information processing and storage. The external control of chemical reactivity (electro- and photochemical) and physical properties (electronic and magnetic) in metallosupramolecular complexes is a current challenge in supramolecular coordination chemistry, which lies at the interface of several other supramolecular disciplines, including electro-, photo-, and magnetochemistry. The specific control of current flow or spin delocalization through a molecular assembly in response to one or many input signals leads to the concept of developing a molecule-based spintronics that can be viewed as a potential alternative to the classical molecule-based electronics. A great variety of factors can influence over these electronically or magnetically coupled, metallosupramolecular complexes in a reversible manner, electronic or photonic external stimuli being the most promising ones. The response ability of the metal centers and/or the organic bridging ligands to the application of an electric field or light irradiation, together with the geometrical features that allow the precise positioning in space of substituent groups, make these metal-organic systems particularly suitable to build highly integrated molecular spintronic circuits. In this Account, we describe the chemistry and physics of dinuclear copper(II) metallacyclophanes with oxamato-containing dinucleating ligands featuring redox- and photoactive aromatic spacers. Our recent works on dicopper(II) metallacyclophanes and earlier ones on related organic cyclophanes are now compared in a critical manner. Special focus is placed on the ligand design as well as in the combination of experimental and computational methods to demonstrate the multifunctionality nature of these metallosupramolecular complexes. This new class of oxamato-based dicopper(II) metallacyclophanes affords an excellent synthetic and theoretical set of models for both chemical and physical fundamental studies on redox- and photo-triggered, long-distance electron exchange phenomena, which are two major topics in molecular magnetism and molecular electronics. Apart from their use as ground tests for the fundamental research on the relative importance of the spin delocalization and spin polarization mechanisms of the electron exchange interaction through extended π-conjugated aromatic ligands in polymetallic complexes, oxamato-based dicopper(II) metallacyclophanes possessing spin-containing electro- and chromophores at the metal and/or the ligand counterparts emerge as potentially active (magnetic and electronic) molecular components to build a metal-based spintronic circuit. They are thus unique examples of multifunctional magnetic complexes to get single-molecule spintronic devices by controlling and allowing the spin communication, when serving as molecular magnetic couplers and wires, or by exhibiting bistable spin behavior, when acting as molecular magnetic rectifiers and switches. Oxamato-based dicopper(II) metallacyclophanes also emerge as potential candidates for the study of coherent electron transport through single molecules, both experimentally and theoretically. The results presented herein, which are a first step in the metallosupramolecular approach to molecular spintronics, intend to attract the attention of physicists and materials scientists with a large expertice in the manipulation and measurement of single-molecule electron transport properties, as well as in the processing and addressing of molecules on different supports.

Biologically active [Pd2L4]4+quadruply-stranded helicates: stability and cytotoxicity

There is emerging interest in the anti-proliferative effects of metallosupramolecular systems due to the different size and shape of these metallo-architectures compared to traditional small molecule drugs. Palladium(II)-containing systems are the most abundant class of metallosupramolecular complexes, yet their biological activity has hardly been examined. Here a small series of [Pd2(L)4](BF4)4 quadruply-stranded, dipalladium(II) architectures were screened for their cytotoxic effects against three cancer cell lines and one non-malignant line. The helicates exhibited a range of cytotoxic properties, with the most cytotoxic complex [Pd2(hextrz)4](BF4)4 possessing low micromolar IC50 values against all of the cell lines tested, while the other helicates displayed moderate or no cytotoxicity. Against the MDA-MB-231 cell line, which is resistant to platinum-based drugs, [Pd2(hextrz)4](BF4)4 was 7-fold more active than cisplatin. Preliminary mechanistic studies indicate that the [Pd2(hextrz)4](BF4)4 helicate does not induce cell death in the same way as clinically used metal complexes such as cisplatin. Rather than interacting with DNA, the helicate appears to disrupt the cell membrane. These studies represent the first biological characterisation of quadruply-stranded helicate architectures, and provide insight into the design requirements for the development of biologically active and stable palladium(II)-containing metallosupramolecular architectures.

Metallo-supramolecular complexes mediated thermoplastic elastomeric block copolymer

Orthogonal multi-phase strategy has been applied to generate a novel type of thermoplastic elastomeric block copolymer which was obtained via anionic polymerization. Functional terpyridine groups which can potentially form metallo-supramolecular complexes with a variety of metal ions has been introduced to the polystyrene-b-polyisoprene (PS-PI) living chain ends through the termination reaction in an optimized condition. Iron(II), cobalt(II) and zinc(II) metal ions have been used to form metal-ligand complexes with the terpyridine end groups, which can phase separate from the polymer matrix to form hybrid clusters. The formation of metallo-supramolecular hybrid clusters have dramatic effects on the micro-phase separated structures of the PS-PI diblock copolymer, which have been characterized by transmission electron microscopy, small-angle X-ray scattering and atomic force microscopy. This type of hybrid material containing hard PS nanophase and metal-ligand clusters exhibit distinct mechanic properties such as increased modulus, higher yield strength and improved toughness, which is further discussed in light of nature of the metal-ligand bonds and the liability of the clusters. The utilization of metallo-supramolecular complex and its high tunability is potential to fabricate new types of supramolecular nanocomposite materials.

Chiral metallohelical complexes enantioselectively target amyloid β for treating Alzheimer's disease.

Stereochemistry is a very important issue for the pharmaceutical industry and can determine drug efficacy. The design and synthesis of small molecules, especially chiral molecules, which selectively target and inhibit amyloid-β (Aβ) aggregation, represent valid therapeutic strategies for treatment of Alzheimer's disease (AD). Herein we report that two triple-helical dinuclear metallosupramolecular complexes can act as a novel class of chiral amyloid-β inhibitors. Through targeting α/β-discordant stretches at the early steps of aggregation, these metal complexes can enantioselectively inhibit Aβ aggregation, which is demonstrated using fluorescent living cell-based screening and multiple biophysical and biochemical approaches. To the best of our knowledge, this is the first report of enantioselective inhibition of Aβ aggregation. Intriguingly, as a promising candidate for AD treatment, the chiral metal complex can cross the blood-brain barrier and have superoxide dismutase activity. It is well-known that chiral discrimination is important for understanding chiral drug action. Generally, one enantiomer is pharmaceutically active while the other is inactive or exerts severe side effects. Chiral discrimination should be important for AD treatment. Our work provides new insights into chiral inhibition of Aβ aggregation and opens a new avenue for design and screening of chiral agents as Aβ inhibitors against AD.