Developing Metal-Binding Isosteres of 8-Hydroxyquinoline as Metalloenzyme Inhibitor Scaffolds.

The use of metal-binding pharmacophores (MBPs) in fragment-based drug discovery has proven effective for targeted metalloenzyme drug development. However, MBPs can still suffer from pharmacokinetic liabilities. Bioisostere replacement is an effective strategy utilized by medicinal chemists to navigate these issues during the drug development process. The quinoline pharmacophore and its bioisosteres, such as quinazoline, are important building blocks in the design of new therapeutics. More relevant to metalloenzyme inhibition, 8-hydroxyquinoline (8-HQ) and its derivatives can serve as MBPs for metalloenzyme inhibition. In this report, 8-HQ isosteres are designed and the coordination chemistry of the resulting metal-binding isosteres (MBIs) is explored using a bioinorganic model complex. In addition, the physicochemical properties and metalloenzyme inhibition activity of these MBIs were investigated to establish drug-like profiles. This report provides a new group of 8-HQ-derived MBIs that can serve as novel scaffolds for metalloenzyme inhibitor development with tunable, and potentially improved, physicochemical properties.

MOF-Polymer Hybrid Materials: From Simple Composites to Tailored Architectures.

Metal-organic frameworks (MOFs) are inherently crystalline, brittle porous solids. Conversely, polymers are flexible, malleable, and processable solids that are used for a broad range of commonly used technologies. The stark differences between the nature of MOFs and polymers has motivated efforts to hybridize crystalline MOFs and flexible polymers to produce composites that retain the desired properties of these disparate materials. Importantly, studies have shown that MOFs can be used to influence polymer structure, and polymers can be used to modulate MOF growth and characteristics. In this Review, we highlight the development and recent advances in the synthesis of MOF-polymer mixed-matrix membranes (MMMs) and applications of these MMMs in gas and liquid separations and purifications, including aqueous applications such as dye removal, toxic heavy metal sequestration, and desalination. Other elegant ways of synthesizing MOF-polymer hybrid materials, such as grafting polymers to and from MOFs, polymerization of polymers within MOFs, using polymers to template MOFs, and the bottom-up synthesis of polyMOFs and polyMOPs are also discussed. This review highlights recent papers in the advancement of MOF-polymer hybrid materials, as well as seminal reports that significantly advanced the field.

Green MIP-202(Zr) Catalyst: Degradation and Thermally Robust Biomimetic Sensing of Nerve Agents.

Rapid and robust sensing of nerve agent (NA) threats is necessary for real-time field detection to facilitate timely countermeasures. Unlike conventional phosphotriesterases employed for biocatalytic NA detection, this work describes the use of a new, green, thermally stable, and biocompatible zirconium metal-organic framework (Zr-MOF) catalyst, MIP-202(Zr). The biomimetic Zr-MOF-based catalytic NA recognition layer was coupled with a solid-contact fluoride ion-selective electrode (F-ISE) transducer, for potentiometric detection of diisopropylfluorophosphate (DFP), a F-containing G-type NA simulant. Catalytic DFP degradation by MIP-202(Zr) was evaluated and compared to the established UiO-66-NH2 catalyst. The efficient catalytic DFP degradation with MIP-202(Zr) at near-neutral pH was validated by 31P NMR and FT-IR spectroscopy and potentiometric F-ISE and pH-ISE measurements. Activation of MIP-202(Zr) using Soxhlet extraction improved the DFP conversion rate and afforded a 2.64-fold improvement in total percent conversion over UiO-66-NH2. The exceptional thermal and storage stability of the MIP-202/F-ISE sensor paves the way toward remote/wearable field detection of G-type NAs in real-world environments. Overall, the green, sustainable, highly scalable, and biocompatible nature of MIP-202(Zr) suggests the unexploited scope of such MOF catalysts for on-body sensing applications toward rapid on-site detection and detoxification of NA threats.

Evaluating Metal-Ligand Interactions of Metal-Binding Isosteres Using Model Complexes.

Bioisosteres are a useful approach to address pharmacokinetic liabilities and improve drug-like properties. Specific to developing metalloenzyme inhibitors, metal-binding pharmacophores (MBPs) have been combined with bioisosteres, to produce metal-binding isosteres (MBIs) as alternative scaffolds for use in fragment-based drug discovery (FBDD). Picolinic acid MBIs have been reported and evaluated for their metal-binding ability, pharmacokinetic properties, and enzyme inhibitory activity. However, their structural, electronic, and spectroscopic properties with metal ions other than Zn(II) have not been reported, which might reveal similarities and differences between MBIs and the parent MBPs. To this end, [M(TPA)(MBI)]+ (M = Ni(II) and Co(II), TPA = tris(2-pyridylmethyl)amine) is presented as a bioinorganic model system for investigating picolinic acid, four heterocyclic MBIs, and 2,2'-bipyridine. These complexes were characterized by X-ray crystallography as well as NMR, IR, and UV-vis spectroscopies, and their magnetic moments were accessed. In addition, [(TpPh,Me)Co(MBI)] (TpPh,Me = hydrotris(3,5-phenylmethylpyrazolyl)borate) was used as a second model compound, and the limitations and attributes of the two model systems are discussed. These results demonstrate that bioinorganic model complexes are versatile tools for metalloenzyme inhibitor design and can provide insights into the broader use of MBIs.

ReI Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS-CoV-2 Main Cysteine Protease.

Since its outbreak, the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has impacted the quality of life and cost hundreds-of-thousands of lives worldwide. Based on its global spread and mortality, there is an urgent need for novel treatments which can combat this disease. To date, the 3-chymotrypsin-like protease (3CLpro ), which is also known as the main protease, is considered among the most important pharmacological targets. The vast majority of investigated 3CLpro inhibitors are organic, non-covalent binders. Herein, the use of inorganic, coordinate covalent binders is proposed that can attenuate the activity of the protease. ReI tricarbonyl complexes were identified that demonstrate coordinate covalent enzymatic inhibition of 3CLpro . Preliminary studies indicate the selective inhibition of 3CLpro over several human proteases. This study presents the first example of metal complexes as inhibitors for the 3CLpro cysteine protease.

An Exceptionally Stable Metal-Organic Framework Constructed from Chelate-Based Metal-Organic Polyhedra.

We report the rational design and synthesis of a water-stable metal-organic framework (MOF), Fe-HAF-1, constructed from supramolecular, Fe3+-hydroxamate-based polyhedra with mononuclear metal nodes. Owing to its chelate-based construction, Fe-HAF-1 displays exceptional chemical stability in organic and aqueous solvents over a wide pH range (pH 1-14), including in the presence of 5 M NaOH. Despite the charge neutrality of the Fe3+-tris(hydroxamate) centers, Fe-HAF-1 crystals are negatively charged above pH 4. This unexpected property is attributed to the formation of defects during crystallization that results in uncoordinated hydroxamate ligands or hydroxide-coordinated Fe centers. The anionic nature of Fe-HAF-1 crystals enables selective adsorption of positively charged ions in aqueous solution, resulting in efficient separation of organic dyes and other charged species in a size-selective fashion. Fe-HAF-1 presents a new addition to a small group of chelate-based MOFs and provides a rare framework whose 3D connectivity is exclusively formed by metal-hydroxamate coordination.

Rational Design of a Uranyl Metal-Organic Framework for the Capture and Colorimetric Detection of Organic Dyes.

A new uranyl containing metal-organic framework, RPL-1: [(UO2)2(C28H18O8)] . H2O (RPL for Radiochemical Processing Laboratory), was prepared, structurally characterized, and the solid-state photoluminescence properties explored. Single crystal X-ray diffraction data reveals the structure of RPL-1 consists of two crystallographically unique three dimensional, interpenetrating nets with a 4,3-connected tbo topology. Each net contains large pores with an average width of 22.8 Šand is formed from monomeric, hexagonal bipyramidal uranyl nodes that are linked via 1,2,4,5-tetrakis(4-carboxyphenyl)benzene (TCPB) ligands. The thermal and photophysical properties of RPL-1 were investigated using thermogravimetric analysis and absorbance, fluorescence, and lifetime spectroscopies. The material displays excellent thermal stability and temperature dependent uranyl and TCPB luminescence. The framework is stable in aqueous media and due to the large void space (constituting 76 % of the unit cell by volume) can sequester organic dyes, the uptake of which induces a visible change to the color of the material.

Spray-Coating of Catalytically Active MOF-Polythiourea through Postsynthetic Polymerization.

A UiO-66-NCS MOF was formed by postsynthetic modification of UiO-66-NH2 . The UiO-66-NCS MOFs displays a circa 20-fold increase in activity against the chemical warfare agent simulant dimethyl-4-nitrophenyl phosphate (DMNP) compared to UiO-66-NH2 , making it the most active MOF materials using a validated high-throughput screening. The -NCS functional groups provide reactive handles for postsynthetic polymerization of the MOFs into functional materials. These MOFs can be tethered to amine-terminated polypropylene polymers (Jeffamines) through a facile room-temperature synthesis with no byproducts. The MOFs are then crosslinked into a MOF-polythiourea (MOF-PTU) composite material, maintaining the catalytic properties of the MOF and the flexibility of the polymer. This MOF-PTU hybrid material was spray-coated onto Nyco textile fibers, displaying excellent adhesion to the fiber surface. The spray-coated fibers were screened for the degradation of DMNP and showed durable catalytic reactivity.

Self-Assembly of Metal-Organic Framework (MOF) Nanoparticle Monolayers and Free-Standing Multilayers.

We report the first self-assembled porous monolayer and free-standing multilayer films composed of metal-organic framework (MOF) nanoparticles. Self-assembled MOF monolayers (SAMMs) were assembled at a liquid-air interface to produce films that are 87 wt % (89 vol %) MOF. Monolayer self-assembly was aided by growing a layer of poly(methyl methacrylate) (PMMA) on the particle surface using a histamine anchor. SAMMs could be stacked to obtain MOF multilayers, including alternating MOF/polymer heterostructures. SAMMs were coated on silicon microparticles, and a MOF film constructed of only five stacked layers could be manipulated as a free-standing, opalescent film. These monolayers are a significant advancement for obtaining highly functional porous membranes and coatings.

Tunable Metal Oxide Frameworks via Coordination Assembly of Preyssler-Type Molecular Clusters.

We present the synthesis of metal oxide frameworks composed of [NaP5W30O110]14- assembled with Mn, Fe, Co, Ni, Cu, or Zn bridging metal ions. X-ray diffraction shows that the frameworks adopt the same assembly regardless of bridging metal ion. Furthermore, our synthesis allows for the assembly of isostructural frameworks with mixed-metal ion bridges, or with clusters that have been doped with Mo, providing a high degree of compositional diversity. This consistent assembly enables investigation into the role of the building blocks in the properties of the metal oxide frameworks. The presence of bridging metal ions leads to increased conductivity compared to unbridged frameworks, and frameworks bridged with Fe have the highest conductivity. Additionally, Mo-doping can be used to enhance the conductivities of the frameworks. Similar structures can be obtained from clusters in which the central Na+ has been replaced with Bi3+ or Sm3+. Overall, the optical and electronic properties are tunable via choice of bridging metal ion and cluster building block and reveal emergent properties in these cluster-based frameworks. These results demonstrate the promise of using polyoxometalate clusters as building blocks for tunable complex metal oxide materials with emergent properties.

A Thorium Metal-Organic Framework with Outstanding Thermal and Chemical Stability.

A new thorium metal-organic framework (MOF), Th(OBA)2 , where OBA is 4,4'-oxybis(benzoic) acid, has been synthesized hydrothermally in the presence of a range of nitrogen-donor coordination modulators. This Th-MOF, described herein as GWMOF-13, has been characterized by single-crystal and powder X-ray diffraction, as well as through a range of techniques including gas sorption, thermogravimetric analysis (TGA), solid-state UV/Vis and luminescence spectroscopy. Single-crystal X-ray diffraction analysis of GWMOF-13 reveals an interesting, high symmetry (cubic Ia 3 ‾ d) structure, which yields a novel srs-a topology. Most notably, TGA analysis of GWMOF-13 reveals framework stability to 525 °C, matching the thermal stability benchmarks of the UiO-66 series MOFs and zeolitic imidazolate frameworks (ZIFs), and setting a new standard for thermal stability in f-block based MOFs.

Nylon-MOF Composites through Postsynthetic Polymerization.

Hybridization of metal-organic frameworks (MOFs) and polymers into composites yields materials that display the exceptional properties of MOFs with the robustness of polymers. However, the realization of MOF-polymer composites requires efficient dispersion and interactions of MOF particles with polymer matrices, which remains a significant challenge. Herein, we report a simple, scalable, bench-top approach to covalently tethered nylon-MOF polymer composite materials through an interfacial polymerization technique. The copolymerization of a modified UiO-66-NH2 MOF with a growing polyamide fiber (PA-66) during an interfacial polymerization gave hybrid materials with up to around 29 weight percent MOF. The covalent hybrid material demonstrated nearly an order of magnitude higher catalytic activity for the breakdown of a chemical warfare simulant (dimethyl-4-nitrophenyl phosphate, DMNP) compared to MOFs that are non-covalently, physically entrapped in nylon, thus highlighting the importance of MOF-polymer hybridization.

Restricted Speciation and Supramolecular Assembly in the 5f Block.

Hybrid materials bearing elements from the 5f block display a rich diversity of coordination geometries, connectivities, and assembly motifs. Exemplary in this regard have been uranyl coordination polymers, which feature a wide range of secondary building units resulting from hydrolysis and oligomerization of the [UO2 ]2+ cation. An alternative approach to novel materials, however, suppresses hydrolysis and relies on non-covalent interactions (e.g. hydrogen or halogen bonding) to direct assembly of a more limited suite of species or building units. This may be achieved through the use of high-anion media to promote singular actinyl anions that are assembled with organic cations, or by way of functionalized chelating ligands that produce complexes suited for assembly through peripheral donor/acceptor sites. Presented in this Concept article is therefore an overview of our efforts in this arena. We highlight examples of each approach, share our thoughts regarding delineation of assembly criteria, and discuss the opportunities for exploring structure-property relationships in these systems.

How to Bend the Uranyl Cation via Crystal Engineering.

Bending the linear uranyl (UO22+) cation represents both a significant challenge and opportunity within the field of actinide hybrid materials. As part of related efforts to engage the nominally terminal oxo atoms of uranyl cation in noncovalent interactions, we synthesized a new uranyl complex, [UO2(C12H8N2)2(C7H2Cl3O2)2]·2H2O (complex 2), that featured both deviations from equatorial planarity and uranyl linearity from simple hydrothermal conditions. Based on this complex, we developed an approach to probe the nature and origin of uranyl bending within a family of hybrid materials, which was done via the synthesis of complexes 1-3 that display significant deviations from equatorial planarity and uranyl linearity (O-U-O bond angles between 162° and 164°) featuring 2,4,6-trihalobenzoic acid ligands (where Hal = F, Cl, and Br) and 1,10-phenanthroline, along with nine additional "nonbent" hybrid materials that either coformed with the "bent" complexes (4-6) or were prepared as part of complementary efforts to understand the mechanism(s) of uranyl bending (7-12). Complexes were characterized via single crystal X-ray diffraction and Raman, infrared (IR), and luminescence spectroscopy, as well as via quantum chemical calculations and density-based quantum theory of atoms in molecules (QTAIM) analysis. Looking comprehensively, these results are compared with the small library of bent uranyl complexes in the literature, and herein we computationally demonstrate the origin of uranyl bending and delineate the energetics behind this process.

Engaging the Terminal: Promoting Halogen Bonding Interactions with Uranyl Oxo Atoms.

Engaging the nominally terminal oxo atoms of the linear uranyl (UO22+ ) cation in non-covalent interactions represents both a significant challenge and opportunity within the field of actinide hybrid materials. An approach has been developed for promoting oxo atom participation in a range of non-covalent interactions, through judicious choice of electron donating equatorial ligands and appropriately polarizable halogen-donor atoms. As such, a family of uranyl hybrid materials was generated based on a combination of 2,5-dihalobenzoic acid and aromatic, chelating N-donor ligands. Delineation of criteria for oxo participation in halogen bonding interactions has been achieved by preparing materials containing 2,5-dichloro- (25diClBA) and 2,5-dibromobenzoic acid (25diBrBA) coupled with 2,2'-bipyridine (bipy) (1 and 2), 1,10-phenanthroline (phen) (3-5), 2,2':6',2''-terpyridine (terpy) (6-8), or 4'-chloro-2,2':6',2''-terpyridine (Cl-terpy) (9-10), which have been characterized through single crystal X-ray diffraction, Raman, Infrared (IR), and luminescence spectroscopy, as well as through density functional calculations of electrostatic potentials. Looking comprehensively, these results are compared with recently published analogues featuring 2,5-diiodobenzoic acid which indicate that although inclusion of a capping ligand in the uranyl first coordination sphere is important, it is the polarizability of the selected halogen atom that ultimately drives halogen bonding interactions with the uranyl oxo atoms.

Syntheses, Structures, and Comparisons of Heterometallic Uranyl Iodobenzoates with Monovalent Cations.

The syntheses and crystal structures of six new heterometallic compounds containing the UO22+ cation, o-, m-, and p-iodobenzoic acid ligands, and Tl+, Rb+, and Cs+ cations which adopt the role of both charge balancing cation and secondary metal center are described, as are the luminescent properties for Tl+ containing compounds 1, 4, and 6. The structures of compounds 1-3 are isomorphous and contain uranyl monomers bound by o-iodobenzoic acid ligands with Tl+, Rb+, and Cs+ cations acting as secondary metal centers. Compounds 4 and 5 are also isomorphous and feature m-iodobenzoic acid ligands bound to the uranyl cation along with Tl+ and Rb+ cations. Compound 6 is unique in this series as it is assembled from a dimeric uranyl unit and features p-iodobenzoic acid ligands and Tl+ cations which function as charge balancing secondary metal centers. Single crystal X-ray diffraction analysis of these materials suggests that the secondary metal cations are incorporated based on the size of their ionic radius (Tl+ < Rb+ < Cs+), which is directly related to the size of the "pocket" observed in 1-6. Further, Voronoi-Dirichlet tessellation and Hirshfeld surface analysis were used to probe the coordination environment of the secondary metal centers as part of ongoing efforts to develop metrics for determining the coordination number of secondary metal cations in similar systems.

Correction: 19F-Tagged metal binding pharmacophores for NMR screening of metalloenzymes.

Correction for '19F-Tagged metal binding pharmacophores for NMR screening of metalloenzymes' by Kathleen E. Prosser et al., Chem. Commun., 2021, 57, 4934-4937, DOI: 10.1039/D1CC01231B.

Salicylate metal-binding isosteres as fragments for metalloenzyme inhibition.

Metalloenzyme inhibitors typically share a common need to possess a metal-binding pharmacophore (MBP) for binding the active site metal ions. However, MBPs can suffer from physicochemical liabilities, impeding the pharmacological properties and drug-likeliness of inhibitors. To circumvent this, problematic features of the MBP can be identified and exchanged with isosteric replacements. Herein, the carboxylic and hydroxyl group of the salicylic acid MBP were replaced and a total of 27 salicylate metal-binding isosteres (MBIs) synthesized. Of these 27 MBIs, at least 12 represent previously unreported compounds, and the metal-binding abilities of >20 of the MBIs have not been previously reported. These salicylate MBIs were examined for their metal-binding features in model complexes, physicochemical properties, and biological activity. It was observed that salicylate MBIs can demonstrate a range of attractive physicochemical properties and bind to the metal in a variety of expected and unexpected binding modes. The biological activity of these novel MBIs was evaluated by measuring inhibition against two Zn2+-dependent metalloenzymes, human glyoxalase 1 (GLO1) and matrix metalloproteinase 3 (MMP-3), as well as a dinuclear Mn2+-dependent metalloenzyme, influenza H1N1 N-terminal endonuclease (PAN). It was observed that salicylate MBIs could maintain or improve enzyme inhibition and selectivity. To probe salicylate MBIs as fragments for fragment-based drug discovery (FBDD), an MBI that showed good inhibitory activity against GLO1 was derivatized and a rudimentary structure-activity relationship was developed. The resulting elaborated fragments showed GLO1 inhibition with low micromolar activity.

Metal-hydrogen-pi-bonded organic frameworks.

We report the synthesis and characterization of a new series of permanently porous, three-dimensional metal-organic frameworks (MOFs), M-HAF-2 (M = Fe, Ga, or In), constructed from tetratopic, hydroxamate-based, chelating linkers. The structure of M-HAF-2 was determined by three-dimensional electron diffraction (3D ED), revealing a unique interpenetrated hcb-a net topology. This unusual topology is enabled by the presence of free hydroxamic acid groups, which lead to the formation of a diverse network of cooperative interactions comprising metal-hydroxamate coordination interactions at single metal nodes, staggered π-π interactions between linkers, and H-bonding interactions between metal-coordinated and free hydroxamate groups. Such extensive, multimodal interconnectivity is reminiscent of the complex, noncovalent interaction networks of proteins and endows M-HAF-2 frameworks with high thermal and chemical stability and allows them to readily undergo postsynthetic metal ion exchange (PSE) between trivalent metal ions. We demonstrate that M-HAF-2 can serve as versatile porous materials for ionic separations, aided by one-dimensional channels lined by continuously π-stacked aromatic groups and H-bonding hydroxamate functionalities. As an addition to the small group of hydroxamic acid-based MOFs, M-HAF-2 represents a structural merger between MOFs and hydrogen-bonded organic frameworks (HOFs) and illustrates the utility of non-canonical metal-coordinating functionalities in the discovery of new bonding and topological patterns in reticular materials.