CN112079850B - Novel copper binuclear structure metal complex, preparation method and application thereof - Google Patents
Novel copper binuclear structure metal complex, preparation method and application thereof Download PDFInfo
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
The invention provides a novel copper binuclear structure metal complex, a preparation method and application thereof, and belongs to the technical field of drug synthesis. The coordination structure of the metal complex is shown in figure 1. The preparation method of the novel copper binuclear structure metal complex comprises the following steps: weighing o-methylbenzoic acid and dissolving in DMF, and adding a small amount of water after complete dissolution to prepare o-methylbenzoic acid solution; adding copper nitrate trihydrate into water to prepare copper nitrate aqueous solution, slowly dripping the copper nitrate aqueous solution into o-methylbenzoic acid solution under stirring, continuing stirring for a period of time after the dripping is finished, placing a sealing film in a shade place, precipitating fine pale blue crystals after 7-10d, filtering and drying to obtain the novel copper binuclear structure metal complex. The metal complex provided by the invention has better anticancer activity and simple preparation method.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a novel copper binuclear structure metal complex, a preparation method and application thereof.
Background
Cancer is usually treated by radiation, surgery, chemotherapy and targeted therapy or a combination of these methods, and surgery and radiation therapy can only ensure that no residual cancer cells are present in the operative field. Chemotherapy is a treatment method for killing cancer cells by using chemical substances, and medicines used in the chemotherapy generally identify cancer cells through high-speed cell division, so that high-speed growth cells (bone marrow cells, hair follicle cells and the like) can be affected by the chemotherapeutics, and chemotherapy complications occur. Targeted therapy is a therapeutic approach with target recognition capability, where cancer cell surfaces often contain specific proteins that are not found in normal cells, and targeted drugs can use these proteins to recognize cancer cells and then kill them, while those normal cells without specific proteins cannot, and therefore have much fewer side effects than chemotherapy.
The combination of the transition metal complex and DNA is key to research on novel high-potency and low-toxicity antitumor drugs. Copper is an important element with two valence states, a large number of biological enzymes need copper elements to excite activity, copper elements also participate in the synthesis of various enzymes of a human body, copper ions exist in biological tissues in the form of trace elements of the human body, and research proves that cis-platinum plays a role in resisting tumors but does not participate in copper ion transport proteins, and the reason is that the copper ions have valence variability, and when Cu (II) and Cu (I) are converted, ROS are generated, cancer cells are destroyed, and apoptosis occurs. However, platinum anticancer drugs have large toxic and side effects, and patients with cancer treated usually have serious toxic and side effects such as thrombocytopenia, nausea and vomiting, kidney and nerve injury and the like.
The carboxylic acid metal copper complex has good chemical and biological activity. The relationship between the structure of the metallic copper complex and the action modes and biological activities of DNA and Human Serum Albumin (HSA) is discussed, so that people can be helped to know the action mechanism and pharmacokinetics of drug molecules on the molecular level, and the metallic copper complex has important significance for the synthesis and design of new drugs.
Disclosure of Invention
The invention aims at: aiming at the problems, the invention provides a novel copper binuclear structure metal complex, a preparation method and application thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a novel copper binuclear structure metal complex has the following coordination structure:
wherein, the unit structure diagram of the complex is as follows:
the invention also provides a preparation method of the novel copper binuclear structure metal complex, which comprises the following steps: weighing o-methylbenzoic acid and dissolving in DMF, and adding a small amount of water after complete dissolution to prepare o-methylbenzoic acid solution; adding copper nitrate trihydrate into water to prepare copper nitrate aqueous solution, slowly dripping the copper nitrate aqueous solution into o-methylbenzoic acid solution under stirring, continuing stirring for a period of time after the dripping is finished, placing a sealing film in a shade place, precipitating fine pale blue crystals after 7-10d, filtering and drying to obtain the novel copper binuclear structure metal complex.
In the present invention, preferably, the molar ratio of the o-methylbenzoic acid to the copper nitrate trihydrate is 1:0.8-1.2, and the DMF is excessive.
In the present invention, it is preferable that the dripping time of the copper nitrate aqueous solution is 20 to 40 minutes.
In the present invention, it is preferable that the stirring is continued for a period of time of 20 to 40 minutes.
In the present invention, it is preferable that the drying means drying at 45-55℃for 2-4 hours.
The invention also provides application of the novel copper binuclear structure metal complex in preparing cancer treatment medicines. More specifically, the application in preparing medicaments for treating cervical cancer, lung cancer and liver cancer.
In summary, due to the adoption of the technical scheme, the beneficial effects of the invention are as follows:
1. the invention provides a novel copper binuclear structure metal complex with anticancer activity, and pharmacological analysis is carried out to prove that the novel copper binuclear structure metal complex has better anticancer activity, and is used for treating IC of cells after 48h of actions with cervical cancer cells Hela, lung cancer cells A549 and liver cancer cells HepG2 50 Values were 156.2. Mu.M, 187.8. Mu.M, 62.93. Mu.M, respectively; the preparation method is simple, has low requirements on equipment, and is suitable for popularization and application in the field of anticancer.
2. The invention confirms that the combination mode of the synthesized novel copper binuclear structure metal complex and CT-DNA is insertion type through ultraviolet absorption spectrum, fluorescence spectrum and viscosity; the combination mode of the synthesized novel copper binuclear structure metal complex and HSA is proved by ultraviolet absorption spectrum and fluorescence spectrum to be inserted, and the novel copper binuclear structure metal complex and the HSA have stronger combination and a combination constant K a =1.97×10 4 L·mol -1 The number of combined bits is 1.
Drawings
FIG. 1 is a coordination structure diagram of a novel copper binuclear structure metal complex synthesized by the present invention.
FIG. 2 is a block diagram of a novel copper dinuclear structure metal complex synthesized in accordance with the present invention.
FIG. 3 is a graph showing the ultraviolet absorption spectrum of interaction between novel copper binuclear structured metal complex synthesized by the present invention and calf thymus DNA (CT-DNA).
FIG. 4 is a fluorescence spectrum of interaction between novel copper binuclear structured metal complex synthesized by the present invention and calf thymus DNA (CT-DNA).
FIG. 5 is a graph showing the viscosity change of CT-DNA after the novel copper binuclear structural metal complex synthesized by the present invention reacts with calf thymus DNA (CT-DNA).
FIG. 6 is a graph showing the ultraviolet absorption spectrum of the interaction between the novel copper binuclear structural metal complex synthesized by the present invention and Human Serum Albumin (HSA).
FIG. 7 is a fluorescence spectrum of interaction of novel copper binuclear structured metal complex synthesized according to the present invention with Human Serum Albumin (HSA).
FIG. 8 shows cytotoxicity test results of the novel copper binuclear structural metal complex synthesized by the invention on cervical cancer cells Hela, lung cancer cells A549 and liver cancer cells HepG 2.
Detailed Description
The present invention will be further described with reference to the following examples in order to more clearly illustrate the present invention.
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, steps, operations, devices, components, and/or groups thereof.
In order to obtain more complexes with higher anticancer activity, the invention provides the following novel copper binuclear structure metal complexes through research and verification. In an exemplary embodiment of the present invention, a novel copper binuclear structure metal complex is provided, wherein the coordination structure of the complex is shown in FIG. 1, and the unit structure of the complex is shown in FIG. 2.
In the embodiment, o-methylbenzoic acid and DMF ligand react with copper nitrate trihydrate to generate a binuclear penta-coordination complex taking copper ions as the center, and the structure improves the anticancer activity of the complex.
The novel copper binuclear structural metal complex with anticancer activity belongs to a triclinic system, P-1 space group, and the unit cell parameters are a= 10.370 (5) nm, b= 10.536 (4) nm and c= 11.059 (5) nm; α= 62.737 (6) °, β= 73.355 (7) °, γ= 63.231 (7) °; z=1, dc=1.416 mg/m3, F (000) =422.
The invention also provides a preparation method of the novel copper binuclear structure metal complex, which comprises the following steps: weighing o-methylbenzoic acid and dissolving in DMF, and adding a small amount of water after complete dissolution to prepare o-methylbenzoic acid solution; adding copper nitrate trihydrate into water to prepare copper nitrate aqueous solution, slowly dripping the copper nitrate aqueous solution into o-methylbenzoic acid solution under stirring, continuing stirring for a period of time after the dripping is finished, placing a sealing film in a shade place, precipitating fine pale blue crystals after 7-10d, filtering and drying to obtain the novel copper binuclear structure metal complex.
In order to allow the ligand starting material to react well and obtain the target complex, in some embodiments of the invention, the molar ratio of o-methylbenzoic acid to copper nitrate trihydrate is 1:0.8-1.2, the DMF is in excess.
For better reaction, in some embodiments of the invention, the aqueous copper nitrate solution is added dropwise for a period of 20-40 minutes.
For better reaction, in some embodiments of the invention, the continued stirring is for a period of time ranging from 20 to 40 minutes.
In some embodiments of the invention, the drying refers to drying at 45-55deg.C for 2-4 hours.
In order to enable those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
1. Preparation example
Example 1
1mmol of o-methylbenzoic acid is weighed and dissolved in 4ml of DMF, and 2ml of water is added after complete dissolution to prepare o-methylbenzoic acid solution; adding 0.8mmol copper nitrate trihydrate into 4ml water to prepare copper nitrate aqueous solution, slowly dripping the copper nitrate aqueous solution into o-methylbenzoic acid solution within 20min under stirring, continuing stirring for a period of time after dripping, placing a sealing film at a shade place, precipitating fine pale blue crystals after 7d, filtering and drying to obtain the novel copper binuclear structure metal complex.
Example 2
1mmol of o-methylbenzoic acid is weighed and dissolved in 4ml of DMF, and 2ml of water is added after complete dissolution to prepare o-methylbenzoic acid solution; adding 1mmol of copper nitrate trihydrate into 4ml of water to prepare a copper nitrate aqueous solution, slowly dripping the copper nitrate aqueous solution into an o-methylbenzoic acid solution within 30min under stirring, continuing stirring for a period of time after dripping, placing a sealing film at a shade place, separating out fine pale blue crystals after 9d, filtering and drying to obtain the novel copper binuclear structure metal complex.
Example 3
1mmol of o-methylbenzoic acid is weighed and dissolved in 4ml of DMF, and 2ml of water is added after complete dissolution to prepare o-methylbenzoic acid solution; adding 1.2mmol of copper nitrate trihydrate into 4ml of water to prepare a copper nitrate aqueous solution, slowly dropwise adding the copper nitrate aqueous solution into an o-methylbenzoic acid solution within 40min under stirring, continuing stirring for a period of time after the dropwise adding, placing a sealing film at a shade place, separating out fine pale blue crystals after 10d, filtering and drying to obtain the novel copper binuclear structure metal complex.
2. Confirmation of Complex
The blue block crystal structures prepared in examples 1 to 3 were confirmed by single crystal-XRD diffraction, and the data of the crystallography, the main bond length and angle, the main torsion angle, and the like of the complex are shown in tables 1, 2, and 3, respectively.
Table 1 Crystal data of the complexes
TABLE 2 principal bond lengths and bond angles of the complexes
Symmetric transformations for generating equivalent atoms:
#1-x,-y+1,-z+ 1
TABLE 3 principal torsion angles of novel copper metal complexes synthesized according to the invention
Symmetric transformations for generating equivalent atoms:
#1x-1,y,z #2x+1,y,z #3-x,-y,-z
3. the novel copper binuclear structure metal complex synthesized by the invention has ultraviolet absorption spectrum under the action of CT-DNA
The baseline was scanned with Tris-HCl/NaCl buffer at ph=7.2, and the blank background was subtracted. Measurement of 50. Mu. Mol.L in the 200-400 nm range -1 Ultraviolet absorbance spectrum of the complex. 80uL of 2mmo/L CT-DNA solution was added dropwise to the reference cell and the sample cell, respectively, using a pipette. After 15 times of addition, the mixture was allowed to react for 5min, and the solution was scanned.
FIG. 3 is a graph showing the ultraviolet absorption spectrum of interaction between novel copper binuclear structured metal complex synthesized by the present invention and calf thymus DNA (CT-DNA). It can be seen that the complex has a subtractive color effect at 228nm and the absorption peak position undergoes a violet shift as the concentration of CT-DNA increases, thus it is presumed that the complex has an intercalating effect on CT-DNA. Calculating the binding constant K of the complex and DNA b =939.61L·mol -1 。
4. The novel copper binuclear structure metal complex synthesized by the invention has fluorescence spectrum under the action of CT-DNA
Will be 8 mu mol.L -1 Ethidium Bromide (EB) and 10 mu mol.L -1 The CT-DNA solution is uniformly mixed with the same volume and reacted for 12 hours. 3mL of the EB-CT-DNA mixed solution was added to the sample cell at an excitation wavelength of 565nm and a scanning speed of 240 nm.s -1 The emission spectrum in the wavelength range of 540 to 700nm was measured. To the EB-CT-DNA system, 40. Mu.L of 1 mmol.L concentration was added dropwise -1 The complex solution is added dropwise for 14 times, and the emission spectrum is measured after each reaction is carried out for 5 min.
FIG. 4 is a fluorescence spectrum of interaction between novel copper binuclear structured metal complex synthesized by the present invention and calf thymus DNA (CT-DNA). It can be seen that the maximum emission wavelength of EB-CT-DNA was always at 596nm, and that the fluorescence intensity gradually decreased as the concentration of the complex increased. At different r= [ complete ]]/[DNA]At this value, the initial fluorescence intensity was reduced from 96.43% to 68.11%. The complex and CT-DNA function mode is similar to EB and is classical insertion mode. Obtaining a quenching rate constant K q =2.996×10 11 L·mol -1 ·s -1 . Fluorescence quenching of the complex to EB-DNA is static quenching. Binding rate constant K a =5.38×10 3 L·mol -1 Binding site n=1.
5. Influence of the novel copper binuclear structure metal complex synthesized by the invention on CT-DNA viscosity:
the reaction temperature was controlled at 29.0.+ -. 0.1 ℃ with a constant temperature water tank, CT-DNA solution was added to the Ubbelohde viscometer, the concentration of the Complex solution was gradually increased, the concentration ratio of Complex to CT-DNA [ Complex ]/[ DNA ] =0, 0.05, 0.1, 0.15, 0.20, 0.25, 0.30 was made, and the time(s) for the CT-DNA solution to flow through the effective scale of the capillary was recorded in order, and each set of experiments was repeated 3 times, and the average was taken.
FIG. 5 is a graph showing the viscosity change of CT-DNA after the novel copper binuclear structural metal complex synthesized by the present invention reacts with calf thymus DNA (CT-DNA). It can be seen that as the concentration of the complex increases, the viscosity of the DNA increases, indicating that the complex binds to the DNA in an intercalating manner.
6. The novel copper binuclear structure metal complex synthesized by the invention has ultraviolet absorption spectrum under the action of HSA
3mL of 100. Mu. Mol.L was added to the sample cell -1 The reference cell was charged with the same amount of Tris-HCl/NaCl buffer solution and its UV spectrum at 190-400 nm was measured. To each of the two tanks, 10. Mu.L of the complex solution (1 mmol.L) -1 ) 15 times, after each addition, blowing and mixing uniformly, and after 5min of standing at room temperature, scanning and measuring in the same wavelength range.
FIG. 6 is a graph showing the ultraviolet absorption spectrum of the interaction between the novel copper binuclear structural metal complex synthesized by the present invention and Human Serum Albumin (HSA). It can be seen that as the concentration of the complex increases, the absorption peak at 210nm has a subtractive color effect and the absorption peak position has a slight red shift, indicating that the complex interacts with HSA.
7. Fluorescence spectrum of metal complex with novel copper binuclear structure and HSA effect synthesized by the invention
3mL of HSA solution (25. Mu. Mol.L) was added to the sample cell -1 ) The fluorescence spectrum at a wavelength of 300 to 500nm was measured at an excited state of 280 nm. mu.L of the complex solution (1 mmol.L) was added to the sample cell -1 ) After adding for 14 times, blowing and mixing uniformly, standing for 5min at room temperature, and scanning under the same conditions.
FIG. 7 is a fluorescence spectrum of interaction of novel copper binuclear structured metal complex synthesized according to the present invention with Human Serum Albumin (HSA). It can be seen that HSA decreases in absorption intensity with increasing complex concentration at 312nm, but the peak position and peak pattern are substantially unchanged. At different r= [ complete ]]/[HSA]At this value, the initial fluorescence intensity was reduced from 96.39% to 62.72%. Constant value K of quenching rate q =1.26×10 12 L·mol -1 ·s -1 Fluorescence quenching of the complex to HSA is static quenching. Binding constant ka=1.97×10 4 L·mol -1 The number of combined bits n=1.
8. The novel copper binuclear structure metal complex synthesized by the invention has cytotoxicity to tumor cells
And (3) determining cytotoxicity of the complex on cervical cancer cells Hela, lung cancer cells A549 and liver cancer cells HepG2 by using an enzyme-labeled instrument. FIG. 8 is a cytotoxicity chart of the novel copper binuclear structural metal complex synthesized by the invention after acting on lung cancer cells A549, cervical cancer cells Hela and liver cancer cells HepG 2. Calculating to obtain the novel copper binuclear structure metal complex and IC of the cell after 48 hours of action of lung cancer cell A549, cervical cancer cell Hela and liver cancer cell HepG2 50 The values were 156.2. Mu.M, 187.8. Mu.M, 62.93. Mu.M, respectively. The novel copper binuclear structure metal complex synthesized by the invention has better anticancer activity on tumor cells, so that the copper binuclear structure metal complex can be applied to the preparation of cancer treatment medicaments, in particular to the application of cervical cancer, lung cancer and liver cancer treatment medicaments.
The foregoing description is directed to the preferred embodiments of the present invention, but the embodiments are not intended to limit the scope of the invention, and all equivalent changes or modifications made under the technical spirit of the present invention should be construed to fall within the scope of the present invention.
Claims (8)
1. The novel copper binuclear structural metal complex is characterized in that the crystal structure parameters, main bond lengths, bond angles and main torsion angles of the complex are shown in the following tables 1, 2 and 3:
table 1 Crystal data of the complexes
TABLE 2 principal bond lengths and bond angles of the complexes
Symmetric transformations for generating equivalent atoms:
#1-x,-y+1,-z+1
TABLE 3 principal torsion angles of novel copper metal complexes synthesized according to the invention
Symmetric transformations for generating equivalent atoms:
#1x-1,y,z #2x+1,y,z #3-x,-y,-z。
2. the method for preparing a novel copper binuclear structure metal complex as defined in claim 1, comprising the steps of: weighing o-methylbenzoic acid and dissolving in DMF, and adding a small amount of water after complete dissolution to prepare o-methylbenzoic acid solution; adding copper nitrate trihydrate into water to prepare copper nitrate aqueous solution, slowly dripping the copper nitrate aqueous solution into o-methylbenzoic acid solution under stirring, continuing stirring for a period of time after the dripping is finished, placing a sealing film in a shade place, precipitating fine pale blue crystals after 7-10d, filtering and drying to obtain the novel copper binuclear structure metal complex.
3. The method for preparing the novel copper binuclear structure metal complex according to claim 2, which is characterized in that: the molar ratio of the o-methylbenzoic acid to the copper nitrate trihydrate is 1:0.8-1.2, and the DMF is excessive.
4. The method for preparing the novel copper binuclear structure metal complex according to claim 2, which is characterized in that: the dripping time of the copper nitrate aqueous solution is 20-40min.
5. The method for preparing the novel copper binuclear structure metal complex according to claim 2, which is characterized in that: the stirring is continued for a period of time of 20-40min.
6. The method for preparing the novel copper binuclear structure metal complex according to claim 2, which is characterized in that: the drying refers to drying at 45-55 ℃ for 2-4 hours.
7. The use of a novel copper binuclear structured metal complex according to claim 1 for the preparation of a medicament for the treatment of cancer.
8. The use of a novel copper binuclear structured metal complex according to claim 7 for preparing medicines for treating cervical cancer, lung cancer and liver cancer.
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