CN112125926B - Novel chlorine-containing carboxylic acid metal complex, preparation method and application thereof - Google Patents
Novel chlorine-containing carboxylic acid metal complex, preparation method and application thereof Download PDFInfo
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- 229910052801 chlorine Inorganic materials 0.000 title claims abstract description 40
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
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- 150000004696 coordination complex Chemical class 0.000 claims abstract description 32
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims abstract description 27
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- KZHGPDSVHSDCMX-UHFFFAOYSA-N 6-methoxy-1,3-benzothiazol-2-amine Chemical compound COC1=CC=C2N=C(N)SC2=C1 KZHGPDSVHSDCMX-UHFFFAOYSA-N 0.000 claims abstract description 11
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- 229960005542 ethidium bromide Drugs 0.000 description 8
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- 238000012360 testing method Methods 0.000 description 7
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 6
- 244000309466 calf Species 0.000 description 6
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- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 description 1
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- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention provides a novel chlorine-containing carboxylic acid 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 chlorine-containing carboxylic acid metal complex comprises the following steps: dissolving 2-chloro-5-nitrobenzoic acid and 2-amino-6-methoxybenzothiazole in a solvent, stirring and dissolving to prepare a mixed solution; dissolving copper nitrate in a solvent, stirring and dissolving to obtain a copper nitrate solution, dripping the copper nitrate solution into the mixed solution, regulating the pH value to be between 5 and 7 after dripping, stirring and reacting for a period of time at room temperature, sealing the film, placing the film in a shade place, and standing for 12-28d to precipitate brown blocky crystals. 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 chlorine-containing carboxylic acid metal complex, a preparation method and application thereof.
Background
Deoxyribonucleic acid (DNA) is an important vital genetic information carrier involved in the expression of genetic information in cells. DNA is a target molecule of a plurality of medicines, and the interaction between the medicines and the DNA is researched, so that the medicinal mechanism of the medicine molecules can be known, and theoretical basis is provided for the design and development of new medicines. The metal complex has potential application in the biomedical field, thus, an in vitro model of combining the metal complex and DNA is established, the problems of combining mode, combining site and interaction of the metal complex and the DNA are researched, and the design and in vitro screening of antitumor drugs are very significant.
HSA is a carrier protein with abundant content in the human circulatory system, has a plurality of binding sites, and can be combined with a plurality of endogenous and exogenous substances, thereby playing important roles in storage, transportation and the like. Research on the interaction of HSA with metal complexes is of great importance in elucidating the transport and pharmacological mechanisms of metal complexes in vivo.
In recent years, the medicinal value of the metal complex is gradually discovered by people and applied to clinic, but the platinum metal medicament is hindered from being used clinically due to the problems of large toxic and side effects, strong drug resistance and the like, so that the search for a novel metal complex as an anticancer medicament becomes a hot research field.
Disclosure of Invention
The invention aims at: aiming at the problems, the invention provides a novel chlorine-containing carboxylic acid 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 metal complex containing chlorocarboxylic acid is provided, which 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 chlorine-containing carboxylic acid metal complex, which comprises the following steps: dissolving 2-chloro-5-nitrobenzoic acid and 2-amino-6-methoxybenzothiazole in a solvent, stirring and dissolving to prepare a mixed solution; dissolving copper nitrate in a solvent, stirring and dissolving to obtain a copper nitrate solution, dripping the copper nitrate solution into the mixed solution, regulating the pH value to be between 5 and 7 after dripping, stirring and reacting for a period of time at room temperature, sealing the film, placing the film in a shade place, and standing for 12-28d to precipitate brown blocky crystals.
In the present invention, the molar ratio of the 2-chloro-5-nitrobenzoic acid, the 2-amino-6-methoxybenzothiazole and the copper nitrate is preferably 9:3:1.5-2.
In the present invention, preferably, the solvent is methanol.
In the present invention, it is preferable to adjust the pH to 1.0 mol.L -1 NaOH solution of (d).
In the present invention, preferably, the copper nitrate solution is added dropwise for 20 to 40 minutes, and the stirring reaction is continued at room temperature for 20 to 50 minutes.
The complex obtained by the test verification of the invention has better anticancer activity, so the invention also provides the application of the novel chlorine-containing carboxylic acid 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 chlorine-containing carboxylic acid metal complex with anticancer activity and a preparation method thereof, and pharmacological analysis proves that the complex has better anticancer activity, and has an effect on IC of cells after 48h with cervical cancer cells Hela, lung cancer cells A549 and liver cancer cells HepG2 50 Values were 25.17. Mu.M, 20.88. Mu.M, 20.53. Mu.M, respectively; the preparation method is simple and the equipment is opposite toHas low requirement and is suitable for popularization and application in the field of anticancer.
2. The invention confirms that the combination mode of the synthesized novel chlorine-containing carboxylic acid metal complex and CT-DNA is insertion type through ultraviolet absorption spectrum, fluorescence spectrum and viscosity; the ultraviolet absorption spectrum and the fluorescence spectrum prove that the synthesized novel chlorine-containing carboxylic acid metal complex has the combination mode of insertion type with HSA, stronger combination with HSA and a combination constant K a ＝3.344×10 5 L·mol -1 The number of combined bits is 1.
3. After the novel chlorine-containing carboxylic acid metal complex synthesized by the invention acts on HepG2 cells for 24h and 48h, the ratio of the number of cells in the G0/G1 phase increases along with the increase of the drug concentration, which proves that the complex blocks the cycle of the HepG2 cells in the G0/G1 phase.
4. The novel chlorine-containing carboxylic acid metal complex synthesized by the invention has an influence on apoptosis of HepG2 cells, and can induce apoptosis of the HepG2 cells.
[ description of the drawings ]
FIG. 1 is a schematic diagram showing the coordination structure of the novel metal complex containing a chlorine-containing carboxylic acid of the present invention.
FIG. 2 is a block diagram of the novel metal complex containing chlorocarboxylic acid of the present invention.
FIG. 3 is a diagram of a novel metal complex TG containing chlorocarboxylic acid synthesized by the present invention.
FIG. 4 is a graph showing the ultraviolet absorbance spectrum of interaction between novel chlorine-containing carboxylic acid metal complex synthesized by the present invention and calf thymus DNA (CT-DNA).
FIG. 5 is a fluorescence spectrum of interaction of novel chlorine-containing carboxylic acid metal complexes synthesized according to the present invention with calf thymus DNA (CT-DNA).
FIG. 6 is a graph showing the viscosity change of CT-DNA after the novel chlorine-containing carboxylic acid metal complex synthesized by the present invention has acted on calf thymus DNA (CT-DNA).
FIG. 7 is a graph showing the ultraviolet absorption spectrum of the interaction of the novel chlorine-containing carboxylic acid metal complex synthesized by the present invention with Human Serum Albumin (HSA).
FIG. 8 is a fluorescence spectrum of interaction of novel chlorine-containing carboxylic acid metal complexes synthesized according to the present invention with Human Serum Albumin (HSA).
FIG. 9 is a graph showing the results of cytotoxicity test of the novel chlorocarboxylic acid-containing metal complex synthesized by the present invention on cervical cancer cells Hela, lung cancer cells A549 and liver cancer cells HepG 2.
FIG. 10 is a graph showing the results of the test of the effect of the novel chlorocarboxylic acid-containing metal complex synthesized by the present invention on the HepG2 cell cycle of hepatoma cells.
FIG. 11 is a graph showing the results of the test of the effect of the novel chlorocarboxylic acid-containing metal complex synthesized by the present invention on apoptosis of hepatoma cell HepG 2.
[ detailed description ] of the 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 metal complexes containing chlorine carboxylic acid through research and verification. In one exemplary embodiment of the present invention, a novel metal complex containing a chlorocarboxylic acid is provided, the coordination structure of which is shown in FIG. 1. Wherein, the unit structure diagram of the complex is shown in figure 2.
In the embodiment, 2-chloro-5-nitrobenzoic acid and 2-amino-6-methoxybenzothiazole are used as ligands and react with copper nitrate to generate a hexacoordination complex taking copper ions as the center, and the structure greatly improves the anticancer activity of the complex.
The novel chlorine-containing carboxylic acid metal complex with anticancer activity belongs to a triclinic system, P-1 space group, and the unit cell parameters are a= 7.7070 (4) nm, b= 9.2158 (4) nm and c= 12.2725 (6) nm; α= 103.303 (4) °, β= 104.468 (4) °, γ= 96.042 (4) °;Z＝1，Dc＝1.694mg/m 3 f (000) =419, final structural residual factor R 1 ＝0.0266，wR 2 ＝0.0727。
In some embodiments of the present invention, there is also provided a method for preparing the above novel metal complex containing chlorocarboxylic acid, comprising the steps of: dissolving 2-chloro-5-nitrobenzoic acid and 2-amino-6-methoxybenzothiazole in a solvent, stirring and dissolving to prepare a mixed solution; dissolving copper nitrate in a solvent, stirring and dissolving to obtain a copper nitrate solution, dripping the copper nitrate solution into the mixed solution, regulating the pH value to be between 5 and 7 after dripping, stirring and reacting for a period of time at room temperature, sealing the film, placing the film in a shade place, and standing for 12-28d to precipitate brown blocky crystals.
In order to allow the ligand starting materials to react sufficiently and obtain the target complex, the molar ratio of the 2-chloro-5-nitrobenzoic acid, the 2-amino-6-methoxybenzothiazole and the copper nitrate is 9:3:1.5-2.
In order to ensure that ligand raw materials can be uniformly dispersed and fully reacted, and simultaneously improve the separation and purification efficiency of products, the preferred solvent is methanol.
In order to precipitate the ligand compound, the pH was adjusted to 1.0 mol.L -1 NaOH solution of (d).
For better reaction, it is preferable that the stirring reaction is continued at room temperature for 20 to 50 minutes.
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
Synthesis of the complex: 2-chloro-5-nitrobenzoic acid (0.9 mmol) and 2-amino-6-methoxybenzothiazole (0.3 mmol) were dissolved in 5ml methanol and stirred to prepare a mixed solution; dissolving copper nitrate (0.15 mmol) in 10ml methanol solvent, stirring to obtain copper nitrate solution, dripping the copper nitrate solution into the mixed solution within 20min to obtain yellowish green solution, and dripping completely with 1.0mol.L -1 The pH value of the NaOH solution is regulated to 5, the stirring reaction is carried out for 20min at room temperature, the sealing film is placed in a shade place,and (5) standing for 12d to separate out brown blocky crystals.
Example 2
Synthesis of the complex: 2-chloro-5-nitrobenzoic acid (0.9 mmol) and 2-amino-6-methoxybenzothiazole (0.3 mmol) were dissolved in 5ml methanol and stirred to prepare a mixed solution; dissolving copper nitrate (0.18 mmol) in 10ml methanol solvent, stirring to obtain copper nitrate solution, dripping the copper nitrate solution into the mixed solution within 30min to obtain yellowish green solution, and dripping completely with 1.0mol.L -1 The pH value of the NaOH solution is regulated to 6, the stirring reaction is carried out for 30min at room temperature, the sealing film is placed in a shady place, and the sepia massive crystals are separated out after the sealing film is placed for 20 d.
Example 3
Synthesis of the complex: 2-chloro-5-nitrobenzoic acid (0.9 mmol) and 2-amino-6-methoxybenzothiazole (0.3 mmol) were dissolved in 5ml methanol and stirred to prepare a mixed solution; dissolving copper nitrate (0.2 mmol) in 10ml methanol solvent, stirring to obtain copper nitrate solution, dripping the copper nitrate solution into the mixed solution within 40min to obtain yellowish green solution, and dripping completely with 1.0mol.L -1 The pH value of the NaOH solution is regulated to 7, the stirring reaction is carried out for 50min at room temperature, the sealing film is placed in a shady place, and the sepia massive crystals are separated out after standing for 28 d.
2. Confirmation of Complex
The tan bulk crystals prepared in examples 1-3 were subjected to infrared testing, elemental analysis testing, and crystallographic testing, with the following results:
infrared data: r (KBr) v/cm -1 :3409,2918,2849,1612,1547,1473,1463,1343,1280,1212,1061,729,719。
Elemental analysis data: elemental analysis per [ C ] 30 H 22 Cl 2 CuN 6 O 10 S 2 ]Calculated (%) C,43.67; h,2.69; n,10.19. Experimental values (%) C,43.42; h,2.75; n,10.60.
Crystallographic data: complex [ C 30 H 22 Cl 2 CuN 6 O 10 S 2 ]The data of the crystallography, the principal bond length and bond angle, the principal twist angle, etc. 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
#1-x+ 2,-y+1,-z+2；#1-x+ 2,-y+1,-z+2；
TABLE 3 principal torsion angles of complexes
#1-x+ 2,-y+1,-z+ 2
3. Thermodynamic stability property test of complexes:
the thermal stability of the complex was determined using a HQT-4 full-automatic microcomputer differential calorimeter. 9.8mg of the crystal is weighed and placed into a clean crucible, nitrogen is used as a protective gas, the flow rate is 15mL/min, the heating rate is 10 ℃/min, and the complex is subjected to thermal stability test at 25.00-800 ℃.
FIG. 3 is a diagram of a novel metal complex TG containing chlorocarboxylic acid synthesized by the present invention. It can be seen that the complex maintains a stable crystal morphology at normal temperature, and has three weight loss stages as the temperature increases. The weight loss was 8.40% before 216.43 ℃, probably the complex lost 1 chloride ion (8.48% of theory); at 216.43-390.16 ℃, the total weight loss is 44.28%, and 1 2-chloro-5-nitrobenzene is lost from the possible complexRadical and 1 methoxy radical (theory 45.46%); at 390.16-767.67 ℃, the complex is also continuously decomposed, and at 767.67 ℃, the sample residue is 22.41%, and Cu can be CuO 2 Or CuO 3 In the form of (CuO) 2 Theoretical value of 23.16%, cuO 3 Theoretical 27.03%).
4. Ultraviolet absorption spectra of the complexes of the invention interacting with DNA
Preparing a solution:
Tris-HCl/NaCl buffer: 50mmol (2.9008 g) of NaCl solid and 5mmol (0.6057 g) of Tris were weighed out separately, dissolved in 1L of double distilled water and then pH adjusted to 7.2 with dilute hydrochloric acid for further use.
CT-DNA solution: an appropriate amount of CT-DNA was weighed and dissolved in Tris-HCl/NaCl buffer (pH=7.2). The absorbance at 260nm and 280nm was measured if A 260 /A 280 =1.8-1.9, indicating that the protein is essentially free and no further treatment is required. Determination of absorbance A at 260nm of CT-DNA 260 (ε＝6600L·mol -1 ·cm -1 ) The concentration is then calculated according to formula (1):
[DNA]＝K×A 260 /6600(mol·L -1 ) (1)
k is the dilution factor. The prepared CT-DNA solution is placed in a refrigerator at 4 ℃ for 3 days for use.
Ultraviolet absorption spectrum of the novel chlorine-containing carboxylic acid metal complex and CT-DNA effect synthesized by the invention: the baseline was scanned with Tris-HCl/NaCl buffer at ph=7.2, and the blank background was subtracted. 2.5mL of Tris-HCl/NaCl buffer solution and 5×10 were added to a blank cuvette (reference cell) and a sample cuvette (sample cell), respectively -5 mol·L -1 And measuring the ultraviolet absorption spectrum of the complex solution in the range of 200-450 nm. 20. Mu.L of 2 mmol.L was added dropwise with a pipette -1 CT-DNA solutions were placed 15 times in the reference and sample wells. After each addition, the reaction was allowed to proceed for 5min, and the complex solution was scanned.
FIG. 4 is a graph showing the ultraviolet absorbance spectrum of interaction between novel chlorine-containing carboxylic acid metal complex synthesized by the present invention and calf thymus DNA (CT-DNA). As can be seen, as the concentration of CT-DNA increases, the complex has a weak subtractive color effect at 269nm, and it is known that the complex has an intercalating effect on CT-DNA. The binding constant of the complex to CT-DNA interaction and its ultraviolet molar absorption coefficient are in accordance with formula (2):
[DNA]/(ε a -ε f )＝[DNA]/[(ε b -ε f )+1/K b (ε b -ε f )] (2)
epsilon in a Molar extinction coefficient (L/(mol.cm)), ε of coordination compound at different CT-DNA concentrations f The molar extinction coefficient (L/(mol.cm)) of the complex in the absence of CT-DNA b The molar extinction coefficient (L/(mol. Cm)) of the complex when the complex is completely bonded to CT-DNA. Calculating the binding constant K of the complex and DNA b ＝4.54×10 2 L·mol -1 。
5. Fluorescence spectrum of the action of the complex synthesized by the invention and CT-DNA
Will be 8 mu mol.L -1 Ethidium Bromide (EB) and 10 mu mol.L -1 The CT-DNA solution was mixed with the same volume (2.5 mL) and reacted for 12 hours. 2.5mL of the EB-CT-DNA mixed solution was added to the sample cell at an excitation wavelength of 525nm and a scanning speed of 240 nm.s -1 The emission spectrum in the wavelength range of 540 to 700nm was measured. 20 μL of 1 mmol.L concentration was added dropwise to the EB-CT-DNA system -1 Is added dropwise 10 times. After each reaction for 5min, the emission spectrum was measured.
FIG. 5 is a fluorescence spectrum of interaction of novel chlorine-containing carboxylic acid metal complexes synthesized according to the present invention with calf thymus DNA (CT-DNA). It can be seen that the maximum emission wavelength of EB-CT-DNA was at 585nm, and that the fluorescence intensity gradually decreased as the concentration of the complex increased. At different r= [ complete ]/[ DNA ] values, the initial fluorescence intensity was reduced from 97.63% to 69.56%. The complex replaces a considerable amount of EB molecules in the EB-CT-DNA system, so that EB is dissociated from CT-DNA molecules, and the fluorescence intensity of the EB-CT-DNA system is reduced, therefore, the complex is presumed to be similar to EB in the CT-DNA action mode and is a classical insertion action mode.
Quenching of fluorescent molecules by fluorescent quenchers can be categorized into dynamic quenching and static quenching. Dynamic quenching is fluorescence quenching due to the mutual collision between the quencher and the excited molecules of the fluorescent molecule, and if the collision of the complex to the EB-CT-DNA molecule is regarded as dynamic quenching, the following Stern-Volmer equation is followed:
I 0 /I＝1+K q τ 0 [C]＝1+K sv [C] (3)
wherein I and I 0 Fluorescence intensity, K of EB-CT-DNA with and without addition of complex, respectively q K is the rate constant of the molecular quenching process sv For dynamic quenching constant τ 0 For the average lifetime of the fluorescent molecule in the absence of quencher [ C]For quencher concentration, the lifetime of fluorescent molecules is about 10 -8 s, obtaining the quenching rate constant K q ＝1.994×10 11 L·mol -1 ·s -1 . It is evident that the quenching constant of the complex to EB-CT-DNA is much greater than the collision quenching constant controlled by the maximum diffusion between the small drug molecule and the biomacromolecule by 2.0X10 10 L·mol -1 ·s -1 Therefore, fluorescence quenching of EB-DNA by the complex is not dynamic quenching due to intermolecular collisions, but rather is static quenching. Binding constant K of Complex to DNA interaction a ＝5.845×10 4 L·mol -1 Binding site n=1.
6. The novel chlorine-containing carboxylic acid metal complex synthesized by the invention has influence on CT-DNA viscosity
The reaction temperature was controlled at 29.0.+ -. 0.1 ℃ by using a constant temperature water tank, and 20mL of 200. Mu. Mol.L was added to the Ubbelohde viscometer -1 CT-DNA solution, gradually increasing the concentration of Complex solution to make the concentration ratio of Complex to CT-DNA [ Complex ]]/[DNA]Time(s) for CT-DNA solution to flow through the effective capillary scale was recorded sequentially, 3 replicates per set of experiments, and averaged, =0, 0.05, 0.1, 0.15, 0.20, 0.25, 0.30. The relative viscosity of the measured solution is expressed as η= (t-t) 0 )/t 0 Calculation, wherein t 0 The time for the buffer solution to flow through the capillary effective graduation is the time for the complex with different concentration to flow through the capillary effective graduation when the complex with different concentration acts on the CT-DNA solution. To (eta/eta) 0 ) 1/3 (η 0 Relative viscosity of CT-DNA solution without Complex) pair [ Complex]/[DNA]By plotting, a change in the effect of the complex on DNA viscosity can be obtained. Ethidium Bromide (EB) served as a positive control.
FIG. 6 is a graph showing the viscosity change of the novel chlorine-containing carboxylic acid metal complex synthesized by the present invention acting on calf thymus DNA (CT-DNA). It can be seen that, similar to EB, 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.
7. Interaction of the novel chlorine-containing Carboxylic acid Metal Complex synthesized according to the present invention with Human Serum Albumin (HSA)
1. Ultraviolet absorption spectrum of the complex synthesized by the invention and HSA:
preparing a solution:
Tris-HCl/NaCl buffer (ph=7.4): 0.05mol of tris and 0.15mol of NaCI solid are weighed respectively and dissolved in 1L of double distilled water, and the pH value is adjusted to 7.4 for standby by dilute hydrochloric acid solution.
Preparation of Human Serum Albumin (HSA) solution: an appropriate amount of HSA was weighed and dissolved in Tris-HCl-NaCl (ph=7.4) buffer solution and its concentration was measured after complete dissolution. The concentration of the HSA solution was measured by UV-visible spectrophotometry for its absorbance at 280nm and the concentration was calculated for the well according to the following equation (4):
[HSA]＝K×A 280 /35700mol·L -1 (4)
wherein K is the dilution factor. The prepared HSA stock solution is typically stored at 4 ℃ and used within 4 d.
Ultraviolet absorption spectrum of the novel chlorine-containing carboxylic acid metal complex and HSA function: 2.5mL of 200. Mu. Mol.L -1 The HSA solution of (2) was added to the sample cell, and the same amount of Tris-HCl/NaCl buffer solution was added to the reference cell, and the ultraviolet absorption spectrum thereof in the wavelength range of 190 to 400nm was measured. 2.5. Mu.L of 0.25. Mu. Mol.L was added with a pipette, respectively -1 The complex solution is placed in a reference cell and a sample cell for 9 times, and is scanned and measured after being placed at room temperature for 5min after each time of dripping.
FIG. 7 is a graph showing the ultraviolet absorption spectrum of the interaction of the novel chlorine-containing carboxylic acid metal complex synthesized by the present invention with Human Serum Albumin (HSA). The results showed that as the concentration of the complex increased, the absorption peak at 218nm had a subtractive color effect and the absorption peak position had a slight red shift, indicating that the complex interacted with HSA.
2. Fluorescence spectrum of the complex synthesized by the invention and HSA action:
2.5mL of 5. Mu. Mol.L -1 The HSA solution of (2) is added into a sample cell, and the fluorescence emission spectrum of the complex is measured within the wavelength range of 300-500 nm with the excitation wavelength of 280 nm. Then 1. Mu.L of 1 mmol.L was added with a pipette -1 The complex solution of (2) is placed in a sample cell for 11 times, and is scanned and measured after being placed at room temperature for 5min after each dripping is finished. FIG. 8 is a fluorescence spectrum of interaction of novel chlorine-containing carboxylic acid metal complexes synthesized according to the present invention with Human Serum Albumin (HSA). It can be seen that as the concentration of the complex increases, the fluorescence intensity of HSA decreases. While a slight red shift occurs at the maximum emission wavelength (312 nm). At different r= [ complete ]]/[HSA]At this value, the initial fluorescence intensity was reduced from 91.27% to 28.59%. Indicating that the complex has a quenching effect on the fluorescence of HSA.
The quench intensity can be calculated by Stern-Volmer equation (5):
F 0 /F＝1+K sv [Q]＝1+K q τ 0 [M] (5)
f in the formula 0 And F represents the fluorescence intensity, K, of the fluorescent molecule in the absence and presence of the quencher, respectively sv To quench constant, K q Is the bimolecular quenching reaction rate constant, τ 0 For the average lifetime of the fluorescent molecule in the absence of quencher (τ 0 ＝10 -8 s)，[M]Is the concentration of the complex. Obtaining a quenching rate constant value K q ＝6.516×10 12 L·mol -1 ·s -1 Collision quenching constant value 2.0×10 greater than maximum diffusion control of various quenchers on biomacromolecule 10 L·mol -1 ·s -1 Fluorescence quenching of the complex to HSA is shown to be a process of static quenching.
The binding constant and the number of binding sites for the interaction of the complex with human serum albumin HSA can be determined from formula (6):
log[F 0 -F]＝logK a +nlog[M] (6)
k in the formula a The value is a binding constant, n is the number of binding sites, and the binding constant K is calculated by linear fitting a ＝3.344×10 5 L·mol -1 And the number of binding sites n=1, indicating a strong binding effect between the two.
8. The novel chlorocarboxylic acid-containing 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. 9 is a cytotoxicity chart of the novel chlorocarboxylic acid-containing 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 IC of the novel chlorine-containing carboxylic acid complex and the cells after 48 hours of the action of the novel chlorine-containing carboxylic acid complex on lung cancer cells A549, cervical cancer cells Hela and liver cancer cells HepG2 50 The values were 25.17. Mu.M, 20.88. Mu.M, 20.53. Mu.M, respectively. The chlorine-containing carboxylic acid metal complex synthesized by the invention has better anticancer activity on tumor cells, so that the chlorine-containing carboxylic acid 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.
9. The novel chlorocarboxylic acid-containing metal complex synthesized by the invention has influence on the cell cycle of liver cancer cells HepG 2:
the influence of the metal complex on the liver cancer cell HepG2 cell cycle is measured by a flow cytometer, and a graph of the influence of the novel chlorine-containing carboxylic acid metal complex synthesized by the invention on the liver cancer cell HepG2 cell cycle is obtained in FIG. 10.
It can be seen that after the novel copper metal complex acts on HepG2 cells for 24h and 48h, the ratio of the number of cells in the G0/G1 phase gradually increases along with the increase of the drug concentration, which indicates that the complex blocks the cycle of the HepG2 cells in the G0/G1 phase.
10. Influence of the synthesized metal complex containing chlorocarboxylic acid on apoptosis of liver cancer cell HepG2
The influence of the novel metal complex on the apoptosis of liver cancer cells HepG2 is measured by a flow cytometer, and the result is shown in a graph of the influence of the novel metal complex containing chlorocarboxylic acid synthesized by the invention on the apoptosis of liver cancer cells HepG 2. The result shows that the metal complex has an effect on apoptosis of HepG2 cells and can induce apoptosis of the HepG2 cells.
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. Novel metal complexes containing chlorocarboxylic acids, characterized in that the complex has the crystal structure parameters, the main bond lengths and angles and the main torsion angles as 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
#1-x+2,-y+1,-z+2；#1-x+2,-y+1,-z+2；
TABLE 3 principal torsion angles of complexes
#1-x+2,-y+1,-z+2。
2. The method for preparing a novel metal complex containing chlorine as claimed in claim 1, comprising the steps of: dissolving 2-chloro-5-nitrobenzoic acid and 2-amino-6-methoxybenzothiazole in a solvent, stirring and dissolving to prepare a mixed solution; dissolving copper nitrate in a solvent, stirring and dissolving to obtain a copper nitrate solution, dripping the copper nitrate solution into the mixed solution, regulating the pH value to be between 5 and 7 after dripping, stirring and reacting for a period of time at room temperature, sealing the film, placing the film in a shade place, and standing for 12-28d to precipitate brown blocky crystals.
3. The method for preparing a novel metal complex containing chlorine carboxylic acid according to claim 2, wherein: the molar ratio of the 2-chloro-5-nitrobenzoic acid to the 2-amino-6-methoxybenzothiazole to the copper nitrate is 9:3:1.5-2.
4. The method for preparing a novel metal complex containing chlorine carboxylic acid according to claim 2, wherein: the solvent is methanol.
5. The method for preparing a novel metal complex containing chlorine carboxylic acid according to claim 2, wherein: the pH value is regulated by 1.0 mol.L -1 NaOH solution of (d).
6. The method for preparing a novel metal complex containing chlorine carboxylic acid according to claim 2, wherein: the dripping time of the copper nitrate solution is 20-40min, and the continuous stirring reaction time at room temperature is 20-50min.
7. The use of a novel metal complex containing chlorocarboxylic acid according to claim 1 for the preparation of a medicament for the treatment of cancer.
8. The use of a novel metal complex containing chlorocarboxylic acid according to claim 7 for preparing medicaments for treating cervical cancer, lung cancer and liver cancer.
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