A polynuclear metallo-organic cage material, a preparation method and application thereof

Abstract

The application provides a polynuclear metal organic cage material and a preparation method and application thereof, and the components of the polynuclear metal organic cage material include a metal cluster, a calix[4]arene ligand and a carboxylic acid ligand; the metal ions in the metal cluster include two or more than two kinds. The polynuclear metal organic cage material can not only combine the required enzyme activity as required, but also can synergistically enhance the corresponding enzyme activity by introducing multiple metals with adjustable types and contents in the metal organic cage with a clear structure. The nano-enzyme based on the polynuclear metal organic cage has the characteristics of stable and relatively clear structure, diverse and adjustable enzyme activity, and overcomes the problems of the existing nano-enzyme, such as unclear structure, difficult explanation of structure-activity relationship, difficult quality control in large-scale preparation and single enzyme activity, and provides a new development direction and alternative material for the development of the nano-enzyme, and provides a possible solution for biological medicine, especially inflammation treatment.

Description

Technical Field

[0001] This invention belongs to the field of anti-inflammatory drugs, specifically relating to a multinuclear metal-organic cage material, its preparation method, and its application. Background Technology

[0002] Inflammation is the body's defense mechanism, capable of detecting and eliminating harmful exogenous substances. Inflammation is associated with numerous diseases, including autoimmune diseases, infectious diseases, and chronic degenerative diseases, which are among the leading causes of human death. Reactive oxygen species (ROS) are the weapons used by immune cells to clear exogenous substances during inflammation and are also upstream signaling molecules of inflammation, closely related to its occurrence, development, and resolution. However, excessive ROS, while clearing exogenous substances, can also damage the body's own cells and tissues, leading to excessive inflammation. Therefore, clearing excessive ROS is crucial for human health and is a major pathway to alleviating inflammation. The body primarily utilizes antioxidant enzymes to clear ROS, including superoxide dismutase (SOD) and catalase (CAT). These natural enzymes are characterized by high activity, high specificity, and well-defined structures. However, the unstable structure of natural enzymes makes them difficult to prepare, prone to inactivation, costly, and difficult to scale up for large-scale production and long-term storage, hindering their clinical application. Therefore, the pharmaceutical field urgently needs to develop antioxidant systems that combine the activity and structural stability of natural enzymes.

[0003] Nanozymes have emerged, combining the physical, chemical, and biological properties of nanomaterials with the catalytic activity of natural enzymes. They possess advantages such as structural stability, multifunctionality, low cost, recyclability, and ease of large-scale production and storage. After nearly a decade of development, various nanozymes with different structures have been developed and applied to research on the treatment of various diseases, demonstrating excellent therapeutic potential.

[0004] However, existing nanozyme systems face many developmental bottlenecks:

[0005] 1) The structure of nanozymes is unclear and quality control is difficult, making it hard to elucidate the structure-activity relationship, which also poses challenges to mass production and clinical translation;

[0006] 2) The lack of standardized procedures for evaluating the catalytic activity of nanozymes makes it difficult to compare the catalytic activities of different nanozymes.

[0007] 3) The activity of nanozymes is often relatively singular, which limits their therapeutic effect;

[0008] 4) The biosafety of nanozymes is still unclear, bringing uncertainty and risks to their clinical use. Therefore, developing nanozymes with well-defined structures, multiple enzyme activities, and good biocompatibility is an inevitable development goal in this field. Summary of the Invention

[0009] In view of the characteristics of nanozymes having unclear structures and limited enzyme activities, this invention provides a multinuclear metal-organic cage material, its preparation method and application, providing an alternative material for inflammation treatment.

[0010] This invention employs a well-defined nanostructure system and introduces multiple metals to form multinuclear nanozymes, achieving diverse enzyme activities. Furthermore, it enhances the corresponding enzyme activities through the synergistic effect between different metals within the same metal cluster, achieving multiple antioxidant activities. The catalytic activity is optimized by adjusting the metal type and content within the multinuclear nanozyme through the type and amount of metals used. Through research and evaluation, the metal-organic cage is deemed an ideal system that meets the above requirements.

[0011] To further realize the synergistic effect of different metals within metal clusters, we selected metal-organic cages (MOCs) with an M4O cluster structure. MOCs possess atomically precise structures, being uniform, discrete, and ultra-small nanopolyhedra constructed through coordination bonds between metal ions or clusters and organic ligands. Combining the advantages of organic and inorganic technologies, MOCs exhibit precise and stable structures, tunable composition and size, nanoscale cavities and dimensions, ease of synthesis and modification, and excellent biocompatibility. They are widely used in the biomedical field, such as in imaging, sensing, and tumor therapy. For example, palladium-pyridine-based MOCs possess photooxidase activity, generating ROS to exert antibacterial properties.

[0012] This type of MOC has an octahedral structure, with six vertices occupied by calix[4]arenes, and eight faces or 12 edges composed of tricarboxylic acid ligands or dicarboxylic acid ligands. The carboxylic acid sites and the phenolic oxygen of the calix[4]arenes are respectively bound to the cluster M4O. This type of MOC has 24 metal sites, which can be isomorphically replaced to enrich the types of metals and thus achieve the diversity of enzyme activities. The interaction of different metals in the tetrametallic cluster will further enhance the enzyme activity.

[0013] Leveraging the structural characteristics of MOCs and the catalytic activity of metal sites, we aim to develop MOC nanozymes with diverse enzymatic activities, thereby establishing a nanozyme system with well-defined structures and varied activities. To achieve multiple enzymatic activities and optimize composition and performance, we plan to introduce various metals into MOCs to construct MOC nanozymes containing multiple metals.

[0014] There are three main strategies for introducing multiple metals into metal-organic cages (MOCs): metallization ligand strategy, heteronuclear cluster strategy, and isomorphic substitution strategy. Metallized ligands, when re-coordinated with other metals, result in multi-metal MOCs with well-defined structures, but their composition and properties are difficult to control, and there is virtually no interaction between different metals. The heteronuclear cluster strategy utilizes multi-metal clusters coordinated with ligands to obtain heteronuclear MOCs, which have well-defined structures and interactions between different metals, but their composition and properties are also difficult to control. Isomorphic substitution refers to the ability of different metals to equivalently occupy metal sites in the MOC, resulting in a reduced degree of structural definition. Therefore, this invention introduces multiple metals of adjustable types and amounts into a well-defined metal-organic cage, which not only allows for the combination of desired enzyme activities but also synergistically enhances the corresponding enzyme activities.

[0015] The technical solution provided by this invention is as follows:

[0016] <First Aspect>

[0017] A multinuclear metal-organic cage material, the components of which include metal clusters, calix[4] aromatic ligands, and carboxylic acid ligands; the metal ions in the metal clusters include two or more types.

[0018] The metal cluster is an M4O metal cluster;

[0019] The carboxylic acid ligands include dicarboxylic acid ligands or tricarboxylic acid ligands.

[0020] The dicarboxylic acid ligand is selected from 1,4-terephthalic acid, 4,4'-biphenyl dicarboxylic acid, and 2,2'-bipyridine-5,5'-dicarboxylic acid;

[0021] The tricarboxylic acid ligand is selected from 1,3,5-benzenetricarboxylic acid, 1,3,5-tris(4-carboxyphenyl)benzene, 2,4,6-tris(4-carboxyphenyl)-1,3,5-triazine, and 4,4'4"-triphenylamine tricarboxylic acid.

[0022] The polynuclear metal-organic cage material includes (M4O)6 (calix[4]arene)6 (dicarboxylic acid ligand). 12 Or (M4O)6(calix[4]aromatic)6(tricarboxylic acid ligand)8; of which 24 metal ions include two or more.

[0023] The (M4O)6 (calix[4]arene)6 (dicarboxylic acid ligand) 12 It includes 6 M4O metal clusters, 6 calix[4] aromatic ligands, and 12 dicarboxylic acid ligands;

[0024] The (M4O)6(calix[4]aromatic)6(tricarboxylic acid ligand)8 comprises 6 M4O metal clusters; 6 calix[4]aromatic ligands; and 8 tricarboxylic acid ligands.

[0025] The metal ions are selected from alkaline earth metals or transition metals;

[0026] The alkaline earth metals include one or more of magnesium, calcium, strontium, and barium;

[0027] The transition metals include one or more of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, and zinc.

[0028] The calix[4] ligands include 4-tert-butylsulfonylcalix[4] arsenide and / or 4-sulfonylsulfonylcalix[4] arsenide.

[0029] As one embodiment of the present invention, the polynuclear metal-organic cage material includes (M4O)6 (calix[4]arene)6 (dicarboxylic acid ligand). 12 Or (M4O)6(calix[4]aromatic)6(tricarboxylic acid ligand)8; wherein the 24 metal ions M include two or more.

[0030] The (M4O)6 (calix[4]arene)6 (dicarboxylic acid ligand) 12 It includes 6 M4O metal clusters, 6 calix[4] aromatic ligands, and 12 dicarboxylic acid ligands;

[0031] The (M4O)6(calix[4]aromatic)6(tricarboxylic acid ligand)8 comprises 6 M4O metal clusters; 6 calix[4]aromatic ligands; and 8 tricarboxylic acid ligands.

[0032] The dicarboxylic acid ligand is selected from 1,4-terephthalic acid, 4,4'-biphenyl dicarboxylic acid, and 2,2'-bipyridine-5,5'-dicarboxylic acid;

[0033] The tricarboxylic acid ligand is selected from 1,3,5-benzenetricarboxylic acid, 1,3,5-tris(4-carboxyphenyl)benzene, 2,4,6-tris(4-carboxyphenyl)-1,3,5-triazine, and 4,4'4"-triphenylamine tricarboxylic acid.

[0034] The calix[4] ligands include 4-tert-butylsulfonylcalix[4] arsenide and / or 4-sulfonylsulfonylcalix[4] arsenide.

[0035] The metal ions are selected from alkaline earth metals or transition metals;

[0036] The alkaline earth metals include one or more of magnesium, calcium, strontium, and barium;

[0037] The transition metals include one or more of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, and zinc.

[0038] <Second aspect>

[0039] This invention also provides a method for preparing a multinuclear metal-organic cage material, comprising the following steps:

[0040] Step 1: Mix the metal salt, carboxylic acid ligand, and calix[4] aromatic ligand, and dissolve them in an organic solvent to form solution A; the metal salt contains two or more metal ions;

[0041] Step 2: Perform a thermal reaction on solution A, then cool it.

[0042] Step 3: Separate and dry the crystals from the product of Step 2 to obtain the multinuclear metal-organic cage material.

[0043] In step one, the metal salt includes divalent or trivalent metal salts.

[0044] In step one, the calix[4] aryl ligand includes sulfonylcalix[4] aryl.

[0045] The sulfonyl calix[4] aromatics include 4-tert-butylsulfonyl calix[4] aromatics or 4-sulfonyl calix[4] aromatics.

[0046] In step one, the carboxylic acid ligand includes dicarboxylic acid ligands or tricarboxylic acid ligands.

[0047] The dicarboxylic acid ligand is selected from 1,4-terephthalic acid, 4,4'-biphenyl dicarboxylic acid, and 2,2'-bipyridine-5,5'-dicarboxylic acid;

[0048] The tricarboxylic acid ligand is selected from 1,3,5-benzenetricarboxylic acid, 1,3,5-tris(4-carboxyphenyl)benzene, 2,4,6-tris(4-carboxyphenyl)-1,3,5-triazine, and 4,4'4"-triphenylamine tricarboxylic acid.

[0049] In step one, the organic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, and n-butanol.

[0050] In one embodiment of the present invention, in step one, the organic solvent includes N,N-dimethylformamide and methanol; the volume ratio of N,N-dimethylformamide to methanol is 5-30:1.

[0051] In step one, the metal salt is one of the nitrates, chlorides, or acetates of alkaline earth metals or transition metals, including their hydrated forms.

[0052] The alkaline earth metals include one or more of magnesium, calcium, strontium, and barium;

[0053] The transition metals include one or more of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, and zinc.

[0054] In solution A, the molar ratio of the total amount of metal salt to the calix[4] aromatic ligand is 2-10:1.

[0055] In solution A, the molar ratio of the total amount of metal salt to the carboxylic acid contained in the polybasic acid ligand is 0.2-10:1.

[0056] In step two, solution A is placed on a metal bath and heated to react at a temperature of 90-140℃ for 2-36 hours.

[0057] In step three, separation and drying can be achieved by directly removing the solvent and air-drying, or by centrifugal washing and vacuum drying.

[0058] <Third aspect>

[0059] The application of the multinuclear metal-organic cage material in anti-inflammatory applications is also within the scope of protection of this invention.

[0060] The present invention has the following beneficial effects:

[0061] 1. The multinuclear metal-organic cage structure provided by this invention has a well-defined structure, strong regulation, good stability, strong antioxidant capacity, low cytotoxicity, and good biocompatibility. It can reduce ROS levels at inflammatory sites and promote the study of structure-activity relationships of nanozymes.

[0062] 2. This invention can obtain multinuclear metal-organic cages through a simple solvothermal method, which can be prepared in large quantities and in a controllable manner, and can greatly promote the clinical translation of nanozymes.

[0063] 3. Due to the different coordination conditions and activities of different metals, the introduction of multiple elements cannot necessarily satisfy the construction of polynuclear metal-organic cages, nor can they all achieve the function of eliminating reactive oxygen species. Through a large number of experiments, this invention has successfully introduced multiple metal elements, such as magnesium, manganese, iron, cobalt, nickel, and zinc, into metal-organic cages with well-defined structures; it has high structural stability and component adjustability; in particular, the cobalt-nickel system has a good reactive oxygen species scavenging ability. Attached Figure Description

[0064] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0065] Figure 1 A schematic diagram of constructing a multinucleated MOC using 4-tert-butylsulfonylcalix[4]arene and pyromellitic acid as an example;

[0066] Figure 2 Optical photographs of polynuclear metal-organic cage crystals prepared from different metal combinations;

[0067] Figure 3 XRD pattern of a representative polynuclear metal-organic cage crystal;

[0068] Figure 4The mass spectrum of a representative polynuclear metal-organic cage;

[0069] Figure 5 To evaluate the superoxide dismutase-like activity of multinucleated metal-organic cages using the NBT method;

[0070] Figure 6 To assess the catalase-like activity of multinucleated metal-organic cages using the oxygen release method. Detailed Implementation

[0071] The present invention will be described in detail below with reference to embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several adjustments and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0072] Figure 1 This is a schematic diagram of constructing a multinucleated MOC using 4-tert-butylsulfonylcalix[4]arene and pyromellitic acid as an example.

[0073] Example 1

[0074] A method for preparing a binuclear metal-organic cage (MOC-BTC-CoNi) includes the following steps:

[0075] Step 1: Weigh out cobalt chloride, nickel chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon respectively, and place them in a 2ml sample bottle; wherein, cobalt chloride 0.025mmol, nickel chloride 0.025mmol, 1,3,5-benzenetricarboxylic acid 0.03mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01mmol.

[0076] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0077] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0078] Step 4: Remove the supernatant from the sample vial and allow the obtained crystals to air dry naturally in a ventilated area to obtain the binuclear metal-organic cage MOC-BTC-CoNi. Figure 2 Crystal optical photographs, Figure 3 XRD in Figure 4 The mass spectrometry results all showed that it was successfully prepared.

[0079] Example 2

[0080] A method for preparing a trinuclear metal-organic cage (MOC-BTC-MgMnZn) includes the following steps:

[0081] Step 1: Weigh magnesium chloride, manganese chloride, zinc chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon respectively, and place them in a 2ml sample bottle; wherein, magnesium chloride 0.017mmol, zinc chloride 0.017mmol, manganese chloride 0.017mmol, 1,3,5-benzenetricarboxylic acid 0.03mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01mmol.

[0082] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0083] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0084] Step 4: Remove the supernatant from the sample vial and allow the obtained crystals to air dry naturally in a ventilated area to obtain the trinuclear metal-organic cage MOC-BTC-MgMnZn. Figure 2 The optical photographs of the crystal show that it was successfully prepared.

[0085] Example 3

[0086] A method for preparing a trinuclear metal-organic cage (MOC-BTC-MgCoZn) includes the following steps:

[0087] Step 1: Weigh out a fixed amount of magnesium chloride, cobalt chloride, zinc chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.017 mmol, zinc chloride 0.017 mmol, cobalt chloride 0.017 mmol, 1,3,5-benzenetricarboxylic acid 0.03 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol.

[0088] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0089] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0090] Step 4: Remove the supernatant from the sample vial and allow the obtained crystals to air dry naturally in a ventilated area to obtain the trinuclear metal-organic cage MOC-BTC-MgCoZn. Figure 2 The optical photographs of the crystal show that it was successfully prepared.

[0091] Example 4

[0092] A method for preparing a tetranuclear metal-organic cage (MOC-BTC-MgMnCoZn) includes the following steps:

[0093] Step 1: Weigh out a fixed amount of magnesium chloride, manganese chloride, zinc chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.0125 mmol, zinc chloride 0.0125 mmol, manganese chloride 0.0125 mmol, cobalt chloride 0.0125 mmol, 1,3,5-benzenetricarboxylic acid 0.03 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol.

[0094] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0095] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0096] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain a tetranuclear metal-organic cage MOC-BTC-MgMnCoZn. Figure 2 The optical photographs of the crystal show that it was successfully prepared.

[0097] Example 5

[0098] A method for preparing a pentanuclear metal-organic cage (MOC-BTC-MgMnCoNiZn-1) includes the following steps:

[0099] Step 1: Weigh out a fixed amount of magnesium chloride, zinc chloride, manganese chloride, cobalt chloride, nickel chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.01 mmol, zinc chloride 0.01 mmol, manganese chloride 0.01 mmol, cobalt chloride 0.01 mmol, nickel chloride 0.01 mmol, 1,3,5-benzenetricarboxylic acid 0.03 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol.

[0100] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0101] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0102] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain the pentanuclear metal-organic cage MOC-BTC-MgMnCoNiZn-1. Figure 2 Crystal optical photographs, Figure 3 Powder X-ray diffraction pattern Figure 4 Mass spectrometry data showed that it was successfully prepared.

[0103] Example 6

[0104] A method for preparing a pentanuclear metal-organic cage (MOC-BTC-MgMnCoNiZn-2) includes the following steps:

[0105] Step 1: Weigh out the amounts of magnesium chloride, zinc chloride, manganese chloride, cobalt chloride, nickel chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbons respectively, and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.003 mmol, manganese chloride 0.006 mmol, cobalt chloride 0.01 mmol, nickel chloride 0.013 mmol, zinc chloride 0.017 mmol, 1,3,5-benzenetricarboxylic acid 0.03 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol.

[0106] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0107] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0108] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain the pentanuclear metal-organic cage MOC-BTC-MgMnCoNiZn-2. Figure 2 The optical photographs of the crystal show that it was successfully prepared.

[0109] Example 7

[0110] A method for preparing a binuclear metal-organic cage (MOC-PTA-MgZn) includes the following steps:

[0111] Step 1: Weigh out a fixed amount of magnesium chloride, zinc chloride, 1,4-terephthalic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.02 mmol, zinc chloride 0.02 mmol, 1,4-terephthalic acid 0.02 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol.

[0112] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0113] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0114] Step 4: Remove the supernatant from the sample vial and allow the obtained crystals to air dry naturally in a ventilated area to obtain the binuclear metal-organic cage MOC-PTA-MgZn.

[0115] Example 8

[0116] A method for preparing a trinuclear metal-organic cage (MOC-BDC-MgMnZn) includes the following steps:

[0117] Step 1: Weigh out a fixed amount of magnesium chloride, manganese chloride, zinc chloride, 4,4'-biphenyldicarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.013 mmol, manganese chloride 0.013 mmol, zinc chloride 0.013 mmol, 4,4'-biphenyldicarboxylic acid 0.02 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol.

[0118] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0119] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0120] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain the trinuclear metal-organic cage MOC-BDC-MgMnZn.

[0121] Example 9

[0122] A method for preparing a tetranuclear metal-organic cage (MOC-BPDC-MgMnCoZn) includes the following steps:

[0123] Step 1: Weigh out the amounts of magnesium chloride, manganese chloride, cobalt chloride, zinc chloride, 2,2'-bipyridine-5,5'-dicarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon respectively, and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.01 mmol, manganese chloride 0.01 mmol, cobalt chloride 0.01 mmol, zinc chloride 0.01 mmol, 2,2'-bipyridine-5,5'-dicarboxylic acid 0.02 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol;

[0124] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0125] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0126] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain a tetranuclear metal-organic cage MOC-BPDC-MgMnCoZn.

[0127] Example 10

[0128] A method for preparing a pentanuclear metal-organic cage (MOC-BTB-MgMnCoNiZn) includes the following steps:

[0129] Step 1: Weigh out the following amounts of magnesium chloride, manganese chloride, cobalt chloride, nickel chloride, zinc chloride, 1,3,5-tris(4-carboxyphenyl)benzene and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbons respectively, and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.01 mmol, manganese chloride 0.01 mmol, cobalt chloride 0.01 mmol, nickel chloride 0.01 mmol, zinc chloride 0.01 mmol, 1,3,5-tris(4-carboxyphenyl)benzene 0.03 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol;

[0130] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0131] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0132] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain the pentanuclear metal-organic cage MOC-BTB-MgMnCoNiZn.

[0133] Example 11

[0134] A method for preparing a binuclear metal-organic cage (MOC-BTC-FeZn) includes the following steps:

[0135] Step 1: Weigh out a fixed amount of ferric chloride, zinc chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon and place them in a 2 ml sample bottle; wherein, ferric chloride 0.025 mmol, zinc chloride 0.025 mmol, 1,3,5-benzenetricarboxylic acid 0.03 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol.

[0136] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0137] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0138] Step 4: Remove the supernatant from the sample vial and allow the obtained crystals to air dry naturally in a ventilated area to obtain the binuclear metal-organic cage MOC-BTC-FeZn.

[0139] Example 12

[0140] A method for preparing a binuclear metal-organic cage (MOC-BTC-MgZn-SO3) includes the following steps:

[0141] Step 1: Weigh out a fixed amount of magnesium chloride, zinc chloride, 1,3,5-benzenetricarboxylic acid and 4-sulfonyl sulfonyl calix[4] aromatic hydrocarbon and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.025 mmol, zinc chloride 0.025 mmol, 1,3,5-benzenetricarboxylic acid 0.03 mmol and 4-sulfonyl sulfonyl calix[4] aromatic hydrocarbon 0.01 mmol.

[0142] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0143] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0144] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain the binuclear metal-organic cage MOC-BTC-MgZn-SO3.

[0145] Example 13

[0146] A method for preparing a hexanuclear metal-organic cage (MOC-BTC-MgMnFeCoNiZn) includes the following steps:

[0147] Step 1: Weigh out the following amounts of magnesium chloride, manganese chloride, cobalt chloride, nickel chloride, zinc chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon and place them in a 2 ml sample bottle; wherein, magnesium chloride 0.01 mmol, manganese chloride 0.01 mmol, ferric chloride 0.01 mmol, cobalt chloride 0.01 mmol, nickel chloride 0.01 mmol, zinc chloride 0.01 mmol, 1,3,5-benzenetricarboxylic acid 0.03 mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01 mmol;

[0148] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0149] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0150] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain the hexanuclear metal-organic cage MOC-BTC-MgMnFeCoNiZn.

[0151] Example 14

[0152] The difference between this embodiment and Embodiment 1 is that, in step one, the dosage is as follows:

[0153] 0.04 mmol of cobalt chloride, 0.01 mmol of nickel chloride, 0.03 mmol of 1,3,5-benzenetricarboxylic acid, and 0.01 mmol of 4-tert-butylsulfonylcalix[4]arene were used to obtain a binuclear metal-organic cage MOC-BTC-CoNi-2. Figure 4 Mass spectrometry data showed that it was successfully prepared.

[0154] Comparative Example 1

[0155] A method for preparing a mononuclear metal-organic cage (MOC-BTC-Co) includes the following steps:

[0156] Step 1: Weigh out cobalt chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon respectively, and place them in a 2ml sample bottle; wherein, cobalt chloride 0.05mmol, 1,3,5-benzenetricarboxylic acid 0.03mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01mmol.

[0157] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0158] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0159] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain a mononuclear metal-organic cage MOC-BTC-Co. Figure 2 Crystal optical photographs, Figure 3 Powder X-ray diffraction pattern Figure 4 Mass spectrometry data showed that it was successfully prepared.

[0160] Comparative Example 2

[0161] A method for preparing a mononuclear metal-organic cage (MOC-BTC-Ni) includes the following steps:

[0162] Step 1: Weigh out nickel chloride, 1,3,5-benzenetricarboxylic acid and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon respectively, and place them in a 2ml sample bottle; wherein, nickel chloride 0.05mmol, 1,3,5-benzenetricarboxylic acid 0.03mmol and 4-tert-butylsulfonylcalix[4] aromatic hydrocarbon 0.01mmol.

[0163] Step 2: Add DMF and methanol in a volume ratio of V:V = 20:1 to the sample vial containing the mixed drugs from Step 1, and dissolve by sonication to obtain a mixed solution; wherein the added DMF and methanol are 1 ml and 50 μL, respectively;

[0164] Step 3: Place the sample vial containing the mixed solution from Step 2 into a constant temperature metal bath equipped with a heating module, and react at 100°C for 24 hours. After the system cools to room temperature, remove the sample vial.

[0165] Step 4: Remove the supernatant from the sample vial, and allow the obtained crystals to air dry naturally in a ventilated area to obtain a mononuclear metal-organic cage MOC-BTC-Ni. Figure 2 Crystal optical photographs, Figure 4 Mass spectrometry data showed that it was successfully prepared.

[0166] Performance test examples

[0167] The performance of the polynuclear metal-organic cages prepared in Example 1 and Comparative Examples 1-2 was tested.

[0168] 1. Superoxide dismutase (SOD)-like activity.

[0169] The superoxide dismutase (SOD)-like activity of polynuclear metal-organic cages was determined using the nitroblue tetrazolium (NBT) method. Polynuclear metal-organic cages (2 mg / mL, 90 μL) were incubated with NBT (750 μmol / L, 0.5 mL), Met (130 mmol / L, 0.5 mL), EDTA-Na2 (100 μmol / L, 0.3 mL), riboflavin (20 μmol / L, 0.5 mL), and phosphate buffer solution (pH = 7.4) under constant UV irradiation for 60 s. SOD-like activity was measured using a UV-Vis spectrophotometer; lower absorbance indicated stronger SOD-like enzyme activity. Results are shown below. Figure 5 and Table 1:

[0170] Table 1. Evaluation of SOD-like enzyme activity in multinuclear metal-organic cages using the NBT method (absorbance at 120 seconds)

[0171] Metal-organic cage material absorbance Example 1 MOC-BTC-CoNi 0.32 Example 2 MOC-BTC-MgMnZn 0.40 Example 3 MOC-BTC-MgCoZn 0.36 Example 4 MOC-BTC-MgMnCoZn 0.37 Example 5 MOC-BTC-MgMnCoNiZn-1 0.35 Example 6 MOC-BTC-MgMnCoNiZn-2 0.36 Example 7 MOC-PTA-MgZn 0.38 Example 8 MOC-BDC-MgMnZn 0.40 Example 9 MOC-BPDC-MgMnCoZn 0.35 Example 10 MOC-BTB-MgMnCoNiZn 0.38 Example 11 MOC-BTC-FeZn 0.40 Example 12 MOC-BTC-MgZn-SO3 0.40 Example 13 MOC-BTC-MgMnFeCoNiZn 0.39 Example 14 MOC-BTC-CoNi-2 0.39 Comparative Example 1 MOC-BTC-Co 0.42 Comparative Example 2 MOC-BTC-Ni 0.45 Comparison No metal organic cage material added 0.58

[0172] 2. Assay for catalase-like (CAT) activity:

[0173] The catalase-like activity of multinuclear metal-organic cages was determined using a dissolved oxygen analyzer. Specifically, 200 μL of 30% H₂O₂ solution was added to 14.94 mL of water, followed by 100 μL of the multinuclear molecular cage sample (2 mg / mL). The increase in oxygen release from the solution over 0 to 5 minutes was recorded; a higher value indicated higher CAT-like activity in the corresponding material. Results are shown below. Figure 6 And Table 2:

[0174] Table 2. Evaluation of CAT-like enzyme activity in multinuclear metal-organic cages using the oxygen release method (release amount at 240 seconds).

[0175] Metal-organic cage material Oxygen release (unit: mg / L) Example 1 MOC-BTC-CoNi 8.5 Example 2 MOC-BTC-MgMnZn 4.5 Example 3 MOC-BTC-MgCoZn 5.6 Example 4 MOC-BTC-MgMnCoZn 4.8 Example 5 MOC-BTC-MgMnCoNiZn-1 4.6 Example 6 MOC-BTC-MgMnCoNiZn-2 4.7 Example 7 MOC-PTA-MgZn 4.2 Example 8 MOC-BDC-MgMnZn 4.5 Example 9 MOC-BPDC-MgMnCoZn 5.0 Example 10 MOC-BTB-MgMnCoNiZn 5.2 Example 11 MOC-BTC-FeZn 4.0 Example 12 MOC-BTC-MgZn-SO3 4.7 Example 13 MOC-BTC-MgMnFeCoNiZn 5.5 Example 14 MOC-BTC-CoNi-2 5.8 Comparative Example 1 MOC-BTC-Co 3.8 Comparative Example 2 MOC-BTC-Ni 4.3 Comparison No metal organic cage material added 2.5

[0176] The results show that:

[0177] The MOC-BTC-CoNi prepared in Example 1 has advantages over MOC-BTC-Co in Comparative Example 1 and MOC-BTC-Ni in Comparative Example 2 in terms of both SOD-like and CAT-like enzyme activities.

[0178] Compared with Example 14, when the amount of cobalt chloride was increased and the amount of nickel chloride was decreased, the activities of SOD-like enzymes and CAT-like enzymes in the prepared polynuclear metal organic cages decreased. This indicates that the metal content in the polynuclear MOC has a certain influence on its activity and its enzyme activity can be regulated according to different needs.

[0179] Compared with Example 4 (MOC-BTC-MgMnCoZn), the addition of the metal element Mn in Example 3 (MOC-BTC-MgCoZn) hardly affected the SOD-like enzyme activity, but the CAT-like enzyme activity decreased. This is because different metals have different catalytic activities, and adding metals will affect the content of other metals and thus their activity.

[0180] Comparing the two pentanuclear MOCs with different metal contents in Examples 5 and 6, it is further shown that the metal content also affects their activity.

[0181] Compared with the two tetranuclear MOCs in Example 4 and Example 9, their activities are very similar, indicating that the type and content of metal have a greater impact on their activity, while the carboxylic acid ligand has a smaller impact.

[0182] Although the technical solutions of the present invention have been described and enumerated in detail, it should be understood that modifications to the above embodiments or the adoption of equivalent alternatives are obvious to those skilled in the art. Such modifications or improvements made without departing from the spirit of the present invention are all within the scope of protection claimed by the present invention.

Claims

1. Use of polynuclear metallo-organic cage materials in antiinflammation, characterized in that, The composition of the polynuclear metal-organic cage material comprises a metal cluster, a calix[4]arene ligand, a carboxylic acid ligand; The metal cluster comprises a M4O metal cluster; The carboxylic acid ligand comprises a dicarboxylic acid ligand or a tricarboxylic acid ligand; the dicarboxylic acid ligand is selected from 1,4-terephthalic acid, 4,4'-diphenyldicarboxylic acid, 2,2'-bipyridine-5,5'-dicarboxylic acid; The tricarboxylic acid ligand is selected from 1,3,5-benzenetricarboxylic acid, 1,3,5-tris(4-carboxyphenyl)benzene, 2,4,6-tris(4-carboxyphenyl)-1,3,5-triazine, 4,4'4''-tricarboxylic acid triphenylamine; The metal ion is selected from an alkaline earth metal or a transition metal; the alkaline earth metal comprises one or more of magnesium, calcium, strontium, barium; the transition metal comprises one or more of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc; The calix[4]arene ligand comprises 4-tert-butylsulfonyl calix[4]arene and / or 4-sulfonic acid sulfonyl calix[4]arene.

2. Use according to claim 1, characterized in that, The polynuclear metallo-organic cage material comprises (M4O)6(calix[4]arene)6(carboxylic acid ligand) 12 or (M4O)6(calix[4]arene)6(tricarboxylic acid ligand)8; wherein the 24 metal ions M comprise two or more than two.

3. Use according to claim 1, characterized in that, The polynuclear metal-organic cage material is prepared by a method comprising the following steps, characterized by comprising the following steps: Step one, mixing metal salt, carboxylic acid ligand, calix[4]arene ligand, dissolving in organic solvent to form solution A; the metal ion in the metal salt comprises two or more; Step two, heat reaction of solution A, cooling; Step three, separation and drying of the crystals in the product of step two to obtain the polynuclear metal-organic cage material.

4. Use according to claim 3, characterized in that, In step one, the metal salt is one or more of nitrate, chloride or acetate of an alkaline earth metal or a transition metal, including its hydrated form; In solution A, the molar ratio of the total amount of metal salt to calix[4]arene ligand is 2-10:1; In solution A, the molar ratio of the total amount of metal salt to carboxylic acid contained in the polyacid ligand is 0.2-10:1; In step two, the heat reaction temperature in solution A is 90-140℃, and the reaction time is 2-36 hours.

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