CN114591511A - Copper-based coordination polymer for simulating natural superoxide dismutase and preparation method and application thereof - Google Patents

Abstract

The invention discloses a copper-based coordination polymer simulating natural superoxide dismutase and a preparation method and application thereof. The invention prepares a nitric oxide bidentate ligand isonicotinic acid and copper sulfate to obtain a compound with antioxidant activity. A copper-based coordination polymer that mimics natural superoxide dismutase: [Cu ₄ (ino) ₄ (OH) ₂ SO ₄ (H ₂ O) ₄ ] _n , where ino is the bidentate ligand after nitrogen oxidation. acid; this product has a wide range of applications in the field of antioxidants. The preparation method of the invention is simple, the cost is low, the yield is high, and the product polymer has better superoxide dismutase activity, which lays a foundation for the subsequent synthesis of an enzyme-like mimic with better performance, and provides a basis for the compound in biomedicine. Research in the field of clinical application lays the foundation.

Description

A kind of copper-based coordination polymer simulating natural superoxide dismutase and its preparation method and application

technical field

The invention relates to the research of composite functional materials in the field of biomedicine, in particular to a copper-based coordination polymer simulating natural superoxide dismutase and a preparation method and application thereof.

Background technique

Coordination polymers (CPs) are one-, two-, and three-dimensional infinite chain or network structures composed of metal ions or metal clusters linked with bridging organic ligands. The unique properties of metal ions and the potential to design desired topologies have also made these CPs attract the attention of researchers. Recently, CPs have gained increasing research interest in the field of composite functional materials, which can be regarded as "enzyme mimetic" composite materials, providing us with great opportunities. CPs can not only simulate biological nanomaterials, but also develop some artificially useful materials in the near future.

The intracellular redox state is a determinant of cell fate and should be tightly regulated. Oxidative stress is an important process that is implicated in the etiology of many diseases, including cardiovascular disease, inflammation, and cancer. Oxidative stress refers to the pathological process of tissue damage due to excessive production of reactive oxygen species (ROS) or reduced scavenging ability during metabolism, and is an imbalance between antioxidants and prooxidants. Antioxidants have neuroprotective effects by scavenging free radicals and inhibiting lipid peroxidation, and antioxidant treatment can alleviate oxidative damage to a certain extent.

Among them, superoxide anion radical (O ₂ ^·- ) is the most important ROS species in biological systems, and also the main source of other ROS species such as hydrogen peroxide (H ₂ O ₂ ) and hydroxyl radical (·OH). Therefore, how to remove excess reactive oxygen species in organisms has become a hot spot in contemporary chemical research. ROS scavengers can generally be divided into natural ROS scavengers and non-natural ROS scavengers. Among them, one of the most widely distributed natural ROS scavengers is superoxide dismutase (SOD), which is medically known as "human scavenger". Superoxide dismutase has outstanding characteristics such as anti-aging and anti-inflammatory. It can catalyze O ₂ ^·- , thereby reducing the content of ROS species in the body, limiting the accumulation of O ₂ ^·- , and is an important member of the natural antioxidant defense system.

Natural superoxide dismutase (Cu, Zn-SOD) is considered to play an indispensable role in the first line of antioxidant defense and is an essential enzyme in natural antioxidant biological systems. There are two active centers in the structure of natural Cu,Zn-SOD: Cu ²⁺ and Zn ²⁺ . Studies have shown that the presence of copper ions is necessary for the activity of Cu,Zn-SOD, it directly interacts with superoxide anion radicals, and zinc ions play a role in stabilizing the environment around the active center in this structure. Enzymatic and non-enzymatic antioxidants play a crucial role in protecting the body from peroxidative damage. However, natural enzymes in nature are very sensitive to the environment, have poor stability, large molecular weight and low permeability, and are not suitable for pharmacological applications as active substances. Therefore, it is necessary to study the structure and function of low molecular weight complexes as active centers of metalloenzymes ization model.

Coordination polymers (CPs) have attracted much attention due to their attractive structures and potential applications in crystallographic engineering and materials science. Among them, organic ligands play a crucial role in the self-assembly process of CPS, and organic ligands with abundant coordination sites are usually preferred. Therefore, the synthesis of stable, non-toxic, and highly active functional coordination polymer materials as superoxide dismutase mimetics (SOD-mimics) has high research value and great potential in clinical medicine applications.

SUMMARY OF THE INVENTION

The present invention aims to provide a copper-based coordination polymer simulating natural superoxide dismutase and a preparation method thereof, in order to overcome the limitation of natural superoxide dismutase in clinical application.

In order to achieve the purpose of the present invention, the technical scheme adopted in the present invention is:

A copper-based coordination polymer simulating natural superoxide dismutase, the chemical formula of the copper-based coordination polymer is [Cu ₄ (ino) ₄ (OH) ₂ SO ₄ (H ₂ O) ₄ ] _n , where ino is the bidentate ligand isonicotinic acid after nitrogen oxidation; the copper-based coordination polymer belongs to the monoclinic system, the space group is C 2/c space group, and the molecular formula is C ₂₄ H ₂₆ Cu ₄ N ₄ O ₂₂ S, molecular weight 1008.72, unit cell parameters: a = 19.809(8) Å, b = 6.844(3) Å, c = 19.533(12) Å, α = 90 °, β = 140.9 °, γ = 90 °, V = 1670.12 Å ³ .

A preparation method of a copper-based coordination polymer simulating natural superoxide dismutase, comprising the following steps:

1) Dissolve 0.2 mmol of isonicotinic acid in 3 mL of deionized water, add 1 moL/L of sodium hydroxide, adjust the pH of the solution to 6-10, and drop the solution into the bottom of the container;

2) Dissolve 0.1 mmol of copper sulfate pentahydrate in 3 mL of N,N-dimethylformamide (DMF), and add it dropwise slowly and uniformly along the container wall to form a boundary diffusion layer with the solution obtained in step 1);

3) Seal with parafilm, and after standing for two days, blue bulk crystals are precipitated, that is, a copper-based coordination polymer that simulates natural superoxide dismutase.

The application of the copper-based coordination polymer simulating natural superoxide dismutase is used as an antioxidant material.

Compared with the prior art, the beneficial effects of the present invention are embodied in:

1) the preparation method of the present invention is simple, the cost is low, and the yield is high, and the XRD powder diffraction analysis data shows that the obtained product has a high purity;

2) Copper is an essential element for most aerobic organisms and is a structural and catalytic cofactor, therefore, it plays a major role in many redox metalloenzymes and can be used as a promising mimetic of enzyme active sites. The excellent biological activity of copper complexes has inspired the scientific community to develop novel, highly selective and copper-based drugs.

The invention synthesizes a series of copper-based coordination polymers based on the structural characteristics of natural enzymes in the body. Such polymers have good superoxide dismutase activity. It lays a foundation for the subsequent synthesis of enzyme-like mimics with better performance, and lays a foundation for the research of the complexes in the field of clinical application of biomedicine.

Description of drawings

Fig. 1 is the structure of nitroxide isonicotinic acid;

Fig. 2 is the coordination environment diagram of the copper-based coordination polymer simulating natural superoxide dismutase;

Figure 3 is a molecular packing diagram of a copper-based coordination polymer simulating natural superoxide dismutase;

4 is an X-ray single crystal diffraction pattern of a copper-based coordination polymer simulating natural superoxide dismutase;

5 is a thermogravimetric analysis diagram of a copper-based coordination polymer simulating natural superoxide dismutase;

Fig. 6 is the infrared spectrogram of the copper-based coordination polymer simulating natural superoxide dismutase;

Fig. 7 is a graph showing the change of the absorbance with the illumination time of the copper-based coordination polymer solution simulating natural superoxide dismutase at different concentrations by the NBT photoreduction method;

Figure 8 is a fitting curve of the copper-based coordination polymer simulating natural superoxide dismutase inhibiting the generation of superoxide anion free radicals as a function of the concentration of the complex solution.

Detailed ways

The present invention will be described in detail below through the accompanying drawings and specific embodiments.

The copper-based coordination polymer simulating natural superoxide dismutase described in the present invention is specifically four five-coordinated copper atoms connected through four nitrogen-oxidized isonicotinic acid carboxyl groups, two μ ₃ -OH and one bridge The bidentate sulfate radicals are connected together, and a cage-like structure composed of Cu ₂ O ₄ S can be seen in the center of the structural unit. All copper atoms have a square pyramid coordination around them. Nitric oxide isonicotinic acid acts as a bridging ligand, bridging two copper atoms separately via bidentate coordination of the carboxyl oxygen atom. The O atom in the NO group does not participate in the coordination of the Cu(II) atom, but forms a hydrogen bond with the water molecule participating in the coordination. The S atom in the sulfuric acid group is located in a special position in the space structure, and acts as a bidentate bridge between the copper atoms Cul and CulB.

Example 1

The preparation method of a class of novel antioxidants comprises the following steps:

1) Weigh isonicotinic acid (0.2 mmol, 278 mg), dissolve it in 3 mL of deionized water, add the prepared 1 moL/L sodium hydroxide to adjust the pH of the solution to 6, and add the solution to the bottom of the test tube with a dropper;

2) Weigh copper sulfate pentahydrate (0.1 mmol, 250 mg) and dissolve it in 3 mL of N,N-dimethylformamide (DMF), and add it into the test tube slowly and uniformly along the test tube wall with a syringe to make it. It forms a boundary diffusion layer with the solution dissolved in the lower ligand;

3) Seal the mouth of the test tube with parafilm and let it stand. Two days later, a small amount of blue bulk crystals precipitated. Among them, the blue bulk crystal is the target product.

Example 2

The preparation method of a class of novel antioxidants comprises the following steps:

1) Weigh isonicotinic acid (0.2 mmol, 278 mg), dissolve it in 3 mL of deionized water, add the prepared 1 moL/L sodium hydroxide to adjust the pH of the solution to 7, and add the solution to the bottom of the test tube with a dropper;

2) Weigh copper sulfate pentahydrate (0.1 mmol, 250 mg) and dissolve it in 3 mL of N,N-dimethylformamide (DMF), and add it into the test tube slowly and uniformly along the test tube wall with a syringe to make it. It forms a boundary diffusion layer with the solution dissolved in the lower ligand;

3) Seal the mouth of the test tube with parafilm and let it stand. After five days, blue bulk crystals were precipitated. Among them, the blue bulk crystal is the target product.

Example 3

The preparation method of a class of novel antioxidants comprises the following steps:

1) Weigh isonicotinic acid (0.2 mmol, 278 mg), dissolve it in 3 mL of deionized water, add the prepared 1 moL/L sodium hydroxide to adjust the pH of the solution to 9, and add the solution to the bottom of the test tube with a dropper;

2) Weigh copper sulfate pentahydrate (0.1 mmol, 250 mg) and dissolve it in 3 mL of N,N-dimethylformamide (DMF), and add it into the test tube slowly and uniformly along the test tube wall with a syringe to make it. It forms a boundary diffusion layer with the solution dissolved in the lower ligand;

3) Seal the mouth of the test tube with parafilm and let it stand. Two days later, a large number of blue bulk crystals were precipitated, which was the target product.

Example 4

The preparation method of a class of novel antioxidants comprises the following steps:

1) Dissolve isonicotinic acid (0.2 mmol, 278 mg) in 3 mL of deionized water, add the prepared 1 moL/L sodium hydroxide, adjust the pH of the solution to 10, and add the solution to the bottom of the test tube with a dropper;

2) Weigh copper sulfate pentahydrate (0.1 mmol, 250 mg) and dissolve it in 3 mL of N,N-dimethylformamide (DMF), and add it into the test tube slowly and uniformly along the test tube wall with a syringe to make it. It forms a boundary diffusion layer with the solution dissolved in the lower ligand;

3) Seal the mouth of the test tube with parafilm and let it stand. Two days later, blue bulk crystals and black flocculent impurities were precipitated. Among them, the blue bulk crystal is the target product.

In the above-mentioned embodiments, the third embodiment has the highest yield and the purest product, therefore, the third embodiment is the best embodiment. In the synthesis of subsequent mass production, the reaction ratio of isonicotinic acid and copper sulfate (n _ino : n _CuSO4 = 2: 1) and the concentration of the upper and lower reaction solutions (C _ino = 0.2 mmol/3 mL H ₂ ) can be fixed. O; C _CuSO4 =0.1 mmol/3 Ml DMF) to achieve high-yield, high-purity mass production. The chemical formula of the copper-based coordination polymer is: [Cu ₄ (ino) ₄ (OH) ₂ SO ₄ (H ₂ O) ₄ ] _n , wherein n is a positive integer, and ino is the bidentate ligand after nitrogen oxidation Isonicotinic acid. X-ray single crystal diffraction analysis shows that the copper-based coordination polymer is monoclinic, belongs to the C 2/c space group, has a molecular formula of C ₂₄ H ₂₆ Cu ₄ N ₄ O ₂₂ S, and has a molecular weight of 1008.72. The cellular parameters are: a = 19.809(8) Å, b = 6.844(3) Å, c = 19.533(12) Å, α = 90 °, β = 140.9 °, γ = 90 °, V = 1670.12 Å ³ .

Figure 1 shows the structure of the functional organic ligand nitric oxide isonicotinic acid, which can coordinate through the carboxyl group and the NO bond after nitrogen oxidation, and is a bidentate ligand. The coordination environment of the copper-based coordination polymer simulating natural superoxide dismutase is shown in Figure 2. In the Cu ₄ (ino) ₄ (OH) ₂ SO ₄ (H ₂ O) ₄ structure, four five-coordinate The copper atoms are linked together by four carboxyl groups of nitroxidized isonicotinic acid, two μ3-OH, and a bridging bidentate _sulfate group, and a cage composed of _Cu2O4S can be seen in the center of the building block. like structure. Its molecular packing diagram is shown in Figure 3. All copper atoms have a square pyramid coordination around them. Nitric oxide isonicotinic acid acts as a bridging ligand, bridging two copper atoms separately via bidentate coordination of the carboxyl oxygen atom. The S atom in the sulfuric acid group is located in a special position in the space structure, and acts as a bidentate bridge between the copper atoms Cul and CulB.

Cul is coordinated to the carboxyl oxygens O2 and O5 of nitroxide isonicotinic acid and to the μ3-OH oxygen on the basal plane with bond lengths ranging from 1.92-1.99 Å, axial Cul-O8 bond lengths of 1.98 Å, and Cul on the basal plane The bond length of -O1 is 2.15 Å. The coordination configuration of Cu2 contains O1 in μ3-OH, carboxyl oxygens O6 and O3, and two water molecules O10 and O11 participating in the coordination, with a bond length ranging from 1.94-1.99 Å, which is consistent with the Cul-O on the basal plane. Corresponding key lengths. Two μ3-OH groups connect the two uncoordinated halves of the building block together in a special bridging manner. The bond length of Cu-μ3-OH ranges from 1.94-1.99 Å, the Cul-O1-CulB bond angle is 92.2°, and the Cu2-O1-Cul bond angle is 117.1°.

Figure 4 is a spectrum simulated according to the obtained X-ray powder diffraction pattern of the copper-based coordination polymer simulating natural superoxide dismutase and the X-ray single crystal diffraction structure of the complex, it can be seen that both The peak positions are consistent, indicating that the sample is of high purity. Figure 5 shows that the copper-based coordination polymer mimicking natural superoxide dismutase has better thermal stability.

SOD activity test of copper-based coordination polymer simulating natural superoxide dismutase, using riboflavin/methionine/nitrotetrazolium chloride (NBT) as substrate, by NBT photoreduction method Determination. O ₂ ^· ˉ reduces yellowish NBT to purple formazan. SODm catalyzes the disproportionation reaction of O ₂ ^· ˉ to generate O ₂ and H ₂ O ₂ , thereby inhibiting the formation of purple formazan. Therefore, after the photoreduction reaction, the darker the blue of the reaction solution, the lower the enzyme activity, and the higher the enzyme activity. In the NBT photoreduction reaction, the reaction between NBT and O ₂ ^· ˉ and the reaction between copper-based coordination polymer and O ₂ ^· ˉ are involved, which are two simultaneous dynamic competition reactions. Therefore, the ability of the mimetic to scavenge O ₂ ^· ˉ is equivalent to the SOD activity of the mimetic.

The experimental results are shown in Figure 7 and Figure 8. Figure 7 is the solution of copper-based coordination polymer simulating natural superoxide dismutase by NBT photoreduction method with different concentrations of copper-based coordination polymer solution under the irradiation of xenon light source. The change of absorbance with light time, Figure 8 is the fitting curve of the copper-based coordination polymer simulating natural superoxide dismutase inhibiting the generation of superoxide anion free radicals with the change of the concentration of the copper-based coordination polymer solution. The copper-based coordination polymer simulating natural superoxide dismutase prepared by the invention has good SOD activity.

Claims (3)

1. a copper-based coordination polymer simulating natural superoxide dismutase, it is characterized in that, the chemical formula of described copper-based coordination polymer is [Cu ₄ (ino) ₄ (OH) ₂ SO ₄ (H ₂ O) ₄ ] _n , wherein ino is the bidentate ligand isonicotinic acid after nitrogen oxidation; the copper-based coordination polymer belongs to the monoclinic system, the space group is C 2/c space group, and the molecular formula is C ₂₄ H ₂₆ Cu ₄ N ₄ O ₂₂ S, molecular weight 1008.72, unit cell parameters: a = 19.809(8) Å, b = 6.844(3) Å, c = 19.533(12) Å, α = 90 °, β = 140.9 ° , γ = 90°, V = 1670.12 Å ³ . 2. a preparation method of the copper-based coordination polymer of simulating natural superoxide dismutase as claimed in claim 1, is characterized in that, comprises the following steps: 1) Dissolve 0.2 mmol of isonicotinic acid in 3 mL of deionized water, add 1 moL/L of sodium hydroxide, adjust the pH of the solution to 6-10, and drop the solution into the bottom of the container; 2) Dissolve 0.1 mmol of copper sulfate pentahydrate in 3 mL of N,N-dimethylformamide, and add it dropwise slowly and uniformly along the container wall to form a boundary diffusion layer with the solution obtained in step 1); 3) Seal with parafilm, and after standing for two days, blue bulk crystals are precipitated, that is, a copper-based coordination polymer that simulates natural superoxide dismutase. 3. The application of the copper-based coordination polymer simulating natural superoxide dismutase as claimed in claim 1, characterized in that, it is used as an antioxidant material.

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