CN110128333B - Cu metal complex and synthetic method and application thereof - Google Patents
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Abstract
The invention discloses a Cu metal complex and a synthesis method and application thereof. The chemical formula of the Cu metal complex is C32H20Cl2CuN4O2.5(630.13), having the formula:
. The complex of the invention takes 2-quinoline formaldehyde and 2-amino-5-chlorophenol as ligands, takes Cu ions as central ions and synthesizes hexa-coordinated Cu metal complex with 2 ligands, and the yield can reach more than 95%. The Cu metal complex has an inhibiting effect on the activity of breast cancer cell strains and cervical cancer cell strains, has a strong anticancer effect, and has better breast cancer and cervical cancer resisting effects than the traditional medicines and lower toxicity.
Description
Technical Field
The invention relates to the technical field of metal complexes, in particular to a Cu metal complex and a synthetic method and application thereof.
Background
The breast cancer and the cervical cancer are one of the diseases seriously harming the life health of women, and the treatment is carried out by adopting chemotherapy, radiotherapy and the like at present. Most of the currently used drugs are small molecule drugs, but many problems are encountered in clinical use, such as drug solubility and drug resistance easily generated in the use process. Cisplatin has been used as a first-line chemotherapeutic drug for the treatment of many cancers, but it is severely limited by dose-limiting side effects such as neurological, hepatic and renal toxicity. Therefore, in recent years, research has been conducted on the development of novel metal anticancer drugs in order to reduce side effects.
Due to Cu2+The copper complex is an important metal ion which plays an important role in the growth of a human body, such as the promotion of blood vessel growth and metabolism, antioxidation and the like, and the copper ion also participates in a plurality of highly conserved biochemical processes and has important physiological activity and oxidation property, so that the copper complex is likely to become a new generation of anti-tumor drugs. At present, many synthesized copper complexes are available, for example, patent application No. 201810500539.1 discloses a quinoline thiosemicarbazone-pyridine copper complex, a preparation method and an application thereof, wherein thiosemicarbazone, quinoline and pyridine pharmacophores are combined, and copper ions are introduced into ligands to form a complex, and the complex has biological activity and high anti-tumor cell proliferation performance; as another example, the prior art discloses that 2-quinolinecarboxaldehyde and 2-amino-5-chlorophenol are taken as ligands, and nitrate ions and methanol are synthesized into a penta-coordinated copper complex, which is mainly used for researching the influence on a T24 cell line of bladder cancer. Many researches on copper complexes are carried out, but the existing Cu metal ion complexes have few researches on the aspects of resisting breast cancer, resisting cervical cancer and the like, and the obtained effects are not ideal enough.
Disclosure of Invention
The first purpose of the invention is to provide a hexacoordinate Cu metal complex taking 2-quinoline formaldehyde and 2-amino-5-chlorophenol as ligands.
It is a second object of the present invention to provide a method for synthesizing the above-mentioned Cu metal complex.
The third purpose of the invention is to provide the application of the Cu metal complex in the aspects of resisting breast cancer and cervical cancer.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a Cu metal complex with a chemical formula of C32H20Cl2CuN4O2.5(630.13), the structural formula is as follows:
the synthesis method of the Cu metal complex comprises the following steps:
(1) dissolving 10mM 2-quinoline formaldehyde in 20-30mL ethanol, and stirring at 50-60 deg.C for 30-40min to obtain solution I;
(2) dissolving 8-10mmol of 2-amino-5-chlorophenol in 15-20ml of methanol/ethanol to obtain a solution II, dropwise adding the solution II into the solution I, stirring, heating to 50-60 ℃, refluxing for 12-15h, cooling to room temperature, pouring into a beaker, naturally volatilizing until a mauve crystal is separated out, filtering, washing the crystal with ethanol, and drying to obtain a ligand L, wherein the chemical formula of the ligand L is C16H11ClN2O has a structural formula
(3) 1mmol of CuCl2·2H2Dissolving O in 10-15mL of ethanol to obtain a solution III, dissolving 1.8-2.5mmol of ligand L in 20-30mL of ethanol to obtain a solution IV, dropwise adding the solution III into the solution IV, and stirring at normal temperature for 8 hours to obtain a solution V;
(4) and filtering the solution V, pouring the solution V into a beaker, sealing the cup mouth by using a sealing film, pricking a small hole on the sealing film, placing the beaker in a fume hood for volatilization, and separating out brownish red blocky crystals after 3-7 days to obtain the Cu metal complex.
Preferably, in step (2), 10mmol of 2-amino-5-chlorophenol is dissolved in 20ml of methanol/ethanol.
Preferably, in step (3), 2mmol of ligand L is dissolved in 20ml of ethanol.
The Cu metal complex is applied to the aspect of resisting breast cancer or cervical cancer.
The Cu metal complex is applied to preparing anti-breast cancer drugs or anti-cervical cancer drugs.
Has the advantages that:
the hexa-coordinated copper complex is synthesized by taking 2-quinolinecarboxaldehyde and 2-amino-5-chlorophenol as ligands and taking copper ions as central ions and 2 ligands, and the adopted synthesis method is simple and easy to operate, and the yield can reach more than 95%.
The DNA of cancer cells is different from that of normal cells, and the DNA is an ideal choice as a target of antitumor drugs, so the DNA intercalator is widely applied to antitumor. At present, many drug molecules which generate good anti-tumor effects by acting on DNA, such as adriamycin, epiadriamycin, mitoxantrone and other anti-tumor drugs, are very common anti-tumor drugs in clinic, but the drugs have large toxic and side effects. Tests prove that the Cu metal complex can directly generate an embedding effect with DNA, and has strong anticancer effect in experiments of inhibiting breast cancer cell lines and cervical cancer cell lines, and the double-ligand copper complex has better breast cancer and cervical cancer resistance and lower toxicity than the traditional medicines.
Drawings
FIG. 1 is a crystal structure diagram of a Cu metal complex of the present invention.
Detailed Description
The invention is further described with reference to the following figures and specific examples.
Example 1
A Cu metal complex with a chemical formula of C32H20Cl2CuN4O2.5(630.13), the structural formula is as follows:
the synthesis method of the Cu metal complex comprises the following steps:
(1) dissolving 10mM 2-quinoline formaldehyde in 20mL ethanol, and stirring at 60 ℃ for 30min to prepare a solution I;
(2) dissolving 10mmol of 2-amino-5-chlorophenol in 20mL of ethanol to obtain a solution II, dropwise adding the solution II into the solution I, stirring and heating to 60 ℃, refluxing for 12h, cooling to room temperature, pouring into a 50mL beaker for natural volatilization until a mauve crystal is separated out, filtering, washing the crystal with ethanol for 1 time, and drying to obtain a ligand L, wherein the chemical formula of the ligand L is C16H11ClN2O；
(3) 1mmol of CuCl2·2H2Dissolving O in 10mL of ethanol to obtain a solution III, dissolving 2mmol of ligand L in 20mL of ethanol to obtain a solution IV, dropwise adding the solution III into the solution IV, and stirring at normal temperature for 8 hours to obtain a solution V;
(4) filtering the solution V, pouring the solution V into a 50mL beaker, sealing the cup mouth by using a sealing film, pricking 15 small holes on the sealing film, placing the beaker in a fume hood to slowly volatilize, and separating out brownish red blocky crystals within 3-7 days to obtain a Cu metal complex; the weight yield was 96.0%.
The crystal structure was measured by using a single crystal diffractometer, and the single crystal structure of the Cu metal complex prepared in example 1 was measured by using a Bruker SMART APEX CCD surface-sensitive diffractometer using a wavelength of
And (3) MoK α ray diffraction of (1). All structures were solved using the direct method and refined using the SHELXTL program using full matrix least squares on F2. All non-hydrogen atoms were refined using anisotropic thermal parameters. Finally, the compound is determined to be a new compound which has not been reported, and the structure of the compound is solved by olex2 software, as shown in figure 1.
Example 2
A Cu metal complex has the chemical formula and the structural formula as in example 1, and the synthesis method comprises the following steps:
(1) dissolving 10mM 2-quinoline formaldehyde in 30mL ethanol, and stirring at 55 ℃ for 35min to prepare a solution I;
(2) dissolving 8mmol of 2-amino-5-chlorophenol in 15ml of ethanol to obtain solution II, dropwise adding the solution II into the solution I, and stirringHeating to 55 deg.C, refluxing for 13 hr, cooling to room temperature, pouring into a beaker, naturally volatilizing until mauve crystal is precipitated, filtering, washing crystal with ethanol, and drying to obtain ligand L with chemical formula C16H11ClN2O；
(3) 1mmol of CuCl2·2H2Dissolving O in 15mL of ethanol to obtain a solution III, dissolving 1.8mmol of ligand L in 20mL of ethanol to obtain a solution IV, dropwise adding the solution III into the solution IV, and stirring at normal temperature for 8 hours to obtain a solution V;
(4) filtering the solution V, pouring the solution V into a 50mL beaker, sealing the cup mouth by using a sealing film, pricking 10 small holes on the sealing film, placing the beaker in a fume hood for volatilization, and separating out brownish red blocky crystals within 3-7 days to obtain a Cu metal complex; the weight yield was 95.4%.
Example 3
A Cu metal complex has the chemical formula and the structural formula as in example 1, and the synthesis method comprises the following steps:
(1) dissolving 10mM 2-quinoline formaldehyde in 25mL ethanol, and stirring at 50 ℃ for 40min to prepare a solution I;
(2) dissolving 9mmol of 2-amino-5-chlorophenol in 20ml of methanol to obtain a solution II, dropwise adding the solution II into the solution I, stirring and heating to 50 ℃, refluxing for 15h, cooling to room temperature, pouring into a beaker for natural volatilization until a mauve crystal is separated out, filtering, washing the crystal with ethanol, and drying to obtain a ligand L, wherein the chemical formula of the ligand L is C16H11ClN2O；
(3) 1mmol of CuCl2·2H2Dissolving O in 10mL of ethanol to obtain a solution III, dissolving 2.5mmol of ligand L in 30mL of ethanol to obtain a solution IV, dropwise adding the solution III into the solution IV, and stirring at normal temperature for 8 hours to obtain a solution V;
(4) and filtering the solution V, pouring the filtered solution V into a 50mL beaker, sealing the mouth of the beaker by using a sealing film, pricking 15 small holes on the sealing film, placing the beaker in a fume hood for volatilization, and separating out brownish red blocky crystals after 3-7 days to obtain the Cu metal complex with the weight yield of 95.8%.
Effect verification:
first, the interaction of the Cu metal complex and calf thymus DNA (ct-DNA):
(1) preparing a ct-DNA solution: the concentration of DNA was determined from the absorption intensity of DNA at 260nm, and ct-DNA was dissolved in Tris-HCl-NaCl buffer at pH 7.2 to a final concentration of 2 mmol/L;
(2) a Cu complex sample was prepared with Tris-HCl-NaCl buffer at 20. mu. mol/L. A certain volume of Cu complex solution is added into a cuvette, and DNA solution is added according to the same volume. Measuring ultraviolet-visible absorption spectra of concentration ratios of [ DNA ]/[ Cu complex ] ═ 0, 0.2, 0.4, 0.6, 0.8, 1.0 and 1.2 respectively, and incubating for 5-10 min before sample measurement;
(3) the Cu complex has a strong absorption peak at 345nm through detection, a color reduction phenomenon appears, the color reduction rate is 19.7%, the spectrum shows that the change has dependence on DNA concentration in a certain concentration range, the color reduction phenomenon is more obvious along with the increase of the concentration ratio of the DNA to a sample, and the result shows that the compound acts with the DNA in an intercalation mode.
Secondly, the inhibition effect on Hela and MCF-7 cell strains:
in the effect verification, an in vitro toxicity test of the Cu metal complex of the present invention was studied by using the MTT method.
The Cu metal complex prepared in example 1 was taken as a test group;
cisplatin was used as control 1;
taking 2-quinolinecarboxaldehyde and 2-amino-5-chlorophenol as ligands, and taking a penta-coordinated copper complex synthesized with nitrate ions and methanol as a control group 2; the chemical formula of the penta-coordinate copper complex is as follows: c17H14ClCuN3O5
The molecular formula is:
test cells were incubated at 37 ℃ with 5.0% CO2Growth to logarithmic phase in the incubator, 0.25% pancreatin digestion to collect cells, adjustment of cell suspension concentration at 5X 104cells/mL concentration 200mL per well were plated in 96-well plates at 37 deg.C，5.0％CO2Culturing for 12 h. Adding medicines with different concentration gradients (six-coordination Cu metal complexes of a test group), making 5 parallel samples at each concentration, adding cisplatin into a control group 1, adding five-coordination Cu metal complexes into a control group 2, and continuously culturing. After 48h the cells were removed, the supernatant aspirated, and incubated at 37 ℃ with 10. mu.l MTT solution (5mg/mL) followed by 90. mu.l phosphate buffer. After 4h, the liquid in the wells is aspirated, 100 microliters of DMSO is added, and the mixture is shaken for 10-15 min. The enzyme linked immunosorbent assay detector detects the absorbance OD value of each hole with the wavelength of 570 nm. Calculating the half inhibitory concentration IC50The values are shown in table 1 below.
TABLE 1
As shown in the above table 1, the hexa-coordinated Cu complex of the invention is suitable for human breast cancer cell strains MCF-7 and human cervical cancer cell strains Hela IC of different sources50The values of the metal complexes are smaller than those of cisplatin in a control group 1 and a penta-coordinated Cu metal complex in a control group 2, and the cisplatin is an antitumor drug which is already applied to clinical treatment, so that the antitumor activity of the Cu complex is better than that of the cisplatin and the control group 2. Meanwhile, the invention also detects the toxicity to a normal cell strain HL-7702, and the result shows that the toxicity of the hexa-coordinated Cu complex is less than that of cisplatin and a control group 2, and the result shows that the hexa-coordinated Cu complex has obvious inhibition effect on Hela and MCF-7 cell strains.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (5)
1. A Cu metal complex characterized by: the structural formula of the Cu metal complex is as follows:
2. the method for synthesizing a Cu metal complex according to claim 1, comprising the steps of:
(1) dissolving 10mmol of 2-quinoline formaldehyde in 20-30mL of ethanol, and stirring at 50-60 ℃ for 30-40min to prepare a solution I;
(2) dissolving 8-10mmol of 2-amino-5-chlorophenol in 15-20ml of methanol or ethanol to obtain a solution II, dropwise adding the solution II into the solution I, stirring, heating to 50-60 ℃, refluxing for 12-15h, cooling to room temperature, pouring into a beaker, naturally volatilizing until a mauve crystal is separated out, filtering, washing the crystal with ethanol, and drying to obtain a ligand L, wherein the chemical formula of the ligand L is C16H11ClN2O, the structural formula of the ligand L is as follows:
(3) 1mmol of CuCl2·2H2Dissolving O in 10-15mL of ethanol to obtain a solution III, dissolving 1.8-2.5mmol of ligand L in 20-30mL of ethanol to obtain a solution IV, dropwise adding the solution III into the solution IV, and stirring at normal temperature for 8 hours to obtain a solution V;
(4) and filtering the solution V, pouring the solution V into a beaker, sealing the cup mouth by using a sealing film, pricking a small hole on the sealing film, placing the beaker in a fume hood for volatilization, and separating out brownish red blocky crystals after 3-7 days to obtain the Cu metal complex.
3. The method for synthesizing a Cu metal complex according to claim 2, wherein: in the step (2), 10mmol of 2-amino-5-chlorophenol is dissolved in 20ml of methanol or ethanol.
4. The method for synthesizing a Cu metal complex according to claim 2, wherein: in step (3), 2mmol of ligand L is dissolved in 20ml of ethanol.
5. The use of the Cu metal complex of claim 1 in the preparation of a medicament for the treatment of breast cancer or cervical cancer.
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| CN105001246A (en) * | 2015-07-20 | 2015-10-28 | 安庆师范学院 | 8-aminoquinoline Schiff base zinc azide metal complex and preparation method thereof |
| CN105315311A (en) * | 2015-10-10 | 2016-02-10 | 衡阳师范学院 | Nickel complex containing 5-chlorine salicylaldehyde shrinking 4- chlorine o-aminophenol Schiff alkali and pyridine and preparation method and application of nickel complex |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001246A (en) * | 2015-07-20 | 2015-10-28 | 安庆师范学院 | 8-aminoquinoline Schiff base zinc azide metal complex and preparation method thereof |
| CN105315311A (en) * | 2015-10-10 | 2016-02-10 | 衡阳师范学院 | Nickel complex containing 5-chlorine salicylaldehyde shrinking 4- chlorine o-aminophenol Schiff alkali and pyridine and preparation method and application of nickel complex |
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| Bioactive mono/bis (carboxyamide) based Co (II), Ni (II) and Cu (II) complexes: Synthesis, Characterization, DNA binding and Anticancer Potentials;Raman Dhivya et al.;《Appl. Organometal. Chem.》;20181119;第1-16页 * |
| Cu(II)、Ni(II)配合物的合成、抗肿瘤作用及其对细胞周期分步的影响;江名等;《化学通报》;20201231;第83卷(第3期);第253-257页 * |
| Synthesis, structure, protein binding, and cytotoxicity of zinc(II) complexes with tridentate NNO Schiff-base ligands;Mei Li et al.;《Journal of Coordination Chemistry》;20140408;第67卷(第6期);第929-942页 * |
| 人血清白蛋白与Cu(II)配合物的生物活性研究;盖爽爽等;《化学通报》;20181231;第81卷(第3期);第253-257页 * |
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