CN111116616A - Preparation method and application of Schiff base complex of zinc - Google Patents
Preparation method and application of Schiff base complex of zinc Download PDFInfo
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- 239000002262 Schiff base Substances 0.000 title claims abstract description 70
- 150000004753 Schiff bases Chemical class 0.000 title claims abstract description 60
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- 238000001914 filtration Methods 0.000 claims description 7
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- 238000005882 aldol condensation reaction Methods 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
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- KYKPXQXTNFUVHP-UHFFFAOYSA-N C(C=1C(O)=CC=CC1)=O.C1=CC=CC2=CC=CC=C12 Chemical compound C(C=1C(O)=CC=CC1)=O.C1=CC=CC2=CC=CC=C12 KYKPXQXTNFUVHP-UHFFFAOYSA-N 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 201000010881 cervical cancer Diseases 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims description 4
- 229940116357 potassium thiocyanate Drugs 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
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- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 208000035269 cancer or benign tumor Diseases 0.000 claims 1
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- 210000004027 cell Anatomy 0.000 description 18
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- 230000000694 effects Effects 0.000 description 9
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 6
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
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- OMBRFUXPXNIUCZ-UHFFFAOYSA-N dioxidonitrogen(1+) Chemical compound O=[N+]=O OMBRFUXPXNIUCZ-UHFFFAOYSA-N 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 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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Abstract
The invention belongs to the technical field of anti-cancer drugs, and particularly relates to a preparation method and application of a Schiff base complex of zinc. The molecular formula of the complex is as follows: c18H19ZnN3O2And S. The Schiff base complex of zinc has good crystal form stability, and the preparation method and the post-treatment mode are relatively simple. In the anti-tumor activity test, the compound has obvious anti-tumor activity and can provide important practical basis for the research of anti-tumor drugs in the future.
Description
Technical Field
The invention belongs to the technical field of anti-cancer drugs, and particularly relates to a preparation method and application of a Schiff base complex of zinc.
Background
Since the discovery of the first metal-coordinated drug cisplatin for cancer therapy, many other metal-based complexes have been investigated as potential chemotherapeutic drugs to minimize the side effects and resistance caused by cisplatin. In the living system, zinc can participate in various metabolic processes such as synthesis and degradation of saccharides, lipids, proteins and nucleic acids in the form of supramolecules. The research of Schiff alkali metal complexes starts in the fifties of the 20 th century, and the Schiff alkali metal complexes are widely applied to various aspects such as antibacterial and anti-tumor activity research, superoxide radical inhibition activity, chemical analysis, interaction with DNA and the like due to unique structures, and particularly have stronger antibacterial and anti-cancer biological activities, so that people pay more and more attention to the biological and medicinal values of the complexes. The method takes 4- (2-aminoethyl) morpholine and naphthalene salicylaldehyde as raw materials, takes methanol and acetonitrile as solvents to prepare 4- (2-aminoethyl) morpholine naphthalene salicylaldehyde solution, and then continuously reacts with zinc acetate and potassium thiocyanate to synthesize the Schiff base complex taking thiocyanate as a bridging. The synthesized complex is characterized by utilizing elemental analysis, infrared spectrum and XRD single crystal diffraction, and the antitumor activity of the complex is preliminarily investigated by utilizing an MTT method activity test. The Schiff base complex has obvious antitumor activity in an activity test, provides a preparation method for designing and synthesizing the Schiff base complex in the future, and provides a practical basis for the specific application in the antitumor in the future.
Disclosure of Invention
The invention mainly aims to provide a zinc Schiff base complex which has the characteristics of relatively low toxicity, high activity and the like compared with cisplatin.
It is a further object of the present invention to provide a process for the preparation of the above-mentioned Schiff base complex of zinc.
The invention further aims to provide the application of the Schiff base complex of zinc in the aspect of antitumor activity.
A zinc Schiff base complex of the formula: c18H19ZnN3O2S。
A preparation method of a Schiff base complex of zinc,
(1) dissolving a metal salt of zinc in a mixed solvent under a constant stirring state to obtain a solution 1; wherein the mass-to-volume (mmol/mL) ratio of the zinc metal salt, potassium thiocyanate and mixed solvent is 0.1: 1: 3-5;
(2) dissolving a Schiff base ligand solution in a mixed solvent to obtain a solution 2, wherein the mixing ratio is 1: 5-7 by volume; stirring the solution 1 obtained in the step (1) and the solution 2, and filtering to obtain a solution 3;
(3) and (3) constantly stirring the solution 3 obtained in the step (2) at room temperature for 0.5-1.0 h, filtering, placing the filtered solution in a high-pressure reaction kettle, and crystallizing to obtain a Schiff base complex of light yellow crystal zinc.
And (3) the crystallization treatment in the step (3) is that the temperature in the high-pressure reaction kettle is raised to 100 ℃ and kept for 2h, the temperature is continuously raised to 120 ℃ and kept for 4h, the temperature is gradually raised to 180 ℃ and kept for 8-12 h, then the temperature is slowly lowered to 120 ℃ and kept for 4-6h, the temperature is lowered to 100 ℃ and kept for 2h, and finally the temperature is lowered to room temperature. The Schiff base complex of crystalline zinc is obtained as pale yellow lumps.
In the step (1) and the step (2), the mixed solvent is the same or different and is selected from more than two of methanol, acetonitrile, ethanol and isopropanol.
The mixed solvents in the step (1) or the step (2) are the same or different and are selected from (1-3) according to the volume ratio: 1 of methanol and isopropanol; the volume ratio of (1-3): 1 acetonitrile and ethanol; or the volume ratio of 1: (1-3) methanol and acetonitrile.
In the step (1), the metal salt of zinc is zinc acetate, and the mass-to-volume ratio of the metal salt of zinc to the mixed solvent is 0.1 mmol: 5 mL.
The molar ratio of the zinc metal salt to the Schiff base ligand compound is 1: 1.
the Schiff base ligand compound is an orange Schiff base ligand compound obtained by dissolving 4- (2-aminoethyl) morpholine and naphthalin salicylaldehyde in a mixed solvent and performing aldol condensation reaction at room temperature; wherein the molar volume ratio of the 4- (2-aminoethyl) morpholine to the naphthalin salicylaldehyde to the mixed solvent is 0.1 mmol: 0.1 mmol: (5-10) mL.
An application of a zinc Schiff base complex, and an application of the zinc Schiff base complex in preparing an antitumor drug.
The tumor is breast cancer, non-small cell lung cancer or cervical cancer.
The invention overcomes the defects of the prior art and provides a preparation method of a Schiff base complex of zinc and application of the Schiff base complex in the aspect of antitumor activity. The invention adopts a mixed solvent to dissolve 4- (2-aminoethyl) morpholine and naphthalin salicylaldehyde, so that aldol condensation reaction is carried out on the morpholine and the naphthalin salicylaldehyde, zinc acetate and potassium thiocyanate are dissolved in the mixed solvent, then the mixed solvent and a certain amount of Schiff base ligand enter a high-pressure reaction kettle, the Schiff base complex of zinc is obtained after temperature programming control, the antitumor activity of the Schiff base complex of zinc is determined by an MTT method, experiments show that the complex has obvious inhibition effect on breast cancer cells (MCF7), non-small cell lung cancer cell strains (A549/DDP) and cervical cancer cell strains (C33A), and the inhibition rate effect is obvious, so that the complex has important significance on the future research of antitumor drugs of transition metal Schiff base complexes.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects: the original preparation method of the Schiff base complex mainly adopts a solution slow evaporation method to obtain the complex, and has the defects of relatively complex preparation process, long time consumption, low yield, unstable crystal form and the like. According to the method, the sample is processed in a relatively simple pretreatment mode and then transferred to the high-pressure kettle, and the Schiff base complex is prepared in a program temperature control adjusting mode, so that the prepared complex has a more characteristic structure. The method takes thiocyanate as a bridging ligand, combines two relatively simple Schiff base ligands with coordination metal, changes the original Schiff base ligand coordination form, and increases coordination points. And in the anti-tumor activity test, the compound has the advantages of obvious activity and the like, and provides important basis for the subsequent anti-tumor drug research.
Drawings
FIG. 1 is a crystal structure diagram of a Schiff base complex 3 of zinc in the present invention.
FIG. 2 is a crystal packing diagram of Schiff base complex 3 of zinc in the present invention.
FIG. 3 is an infrared spectrum of a Schiff base complex 3 of zinc according to the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Mixing methanol and isopropanol in a volume ratio of 1:1, mixing to obtain a mixed solvent 1;
mixing ethanol and isopropanol in a volume ratio of 3: 1 to obtain a mixed solvent 2.
Methanol and acetonitrile are mixed according to a volume ratio of 1: 2 to obtain a mixed solvent 3.
Example 2
Dissolving 0.1mmol of 4- (2-aminoethyl) morpholine and 0.1mmol of naphthalene salicylaldehyde in 6mL of mixed solvent 1
Carrying out aldol condensation reaction to obtain a Schiff base ligand compound 1.
Example 3
Dissolving 0.1mmol of 4- (2-aminoethyl) morpholine and 0.1mmol of naphthalene salicylaldehyde in 8mL of mixed solvent 2 to perform aldol condensation reaction to obtain Schiff base ligand compound 2.
Example 4
Dissolving 0.1mmol of 4- (2-aminoethyl) morpholine and 0.1mmol of naphthalene salicylaldehyde in 10mL of mixed solvent
3, carrying out aldol condensation reaction to obtain a Schiff base ligand compound 3.
Example 5
Preparation of complex 1 from mixed solvents of different proportions as described in example 1 above to obtain a Schiff base ligand compound:
(1) dissolving 18.35mg of zinc acetate in 4mL of mixed solvent 1 under the stirring state to obtain solution 1;
(2) 38.41mg of Schiff base ligand compound 1 is dissolved in 6mL of mixed solvent 1 to obtain solution 2, the solution 1 obtained in the step (1) is added into the solution 2, the stirring is carried out for about 0.5 to 1 hour, and the solution 3 is obtained after the filtration;
(3) and (3) continuously stirring the solution 3 obtained in the step (2) at room temperature for 0.5h, then placing the solution in a high-pressure reaction kettle, raising the temperature to 120 ℃ by program control, keeping the temperature for 4h, continuing raising the temperature to 180 ℃ and keeping the temperature for 14-16 h, then gradually cooling, keeping the temperature for 4h after cooling to 120 ℃, and finally cooling to room temperature. The obtained zinc Schiff base complex 1 was a pale yellow needle crystal. The crystals were washed 3 times with a small amount of the mixed solvent 3 and then dried in vacuum, and the calculated yield was 36.3%.
Example 6
Preparation of complex 2 according to the Schiff base ligand compound obtained with different proportions of mixed solvents as described in example 1 above:
(1) under the stirring state, dissolving 18.35mg of zinc acetate in 5mL of mixed solvent 2 to obtain solution 1;
(2) 38.41mg of Schiff base ligand compound 1 is dissolved in 7mL of mixed solvent 1 to obtain solution 2, the solution 1 obtained in the step (1) is added into the solution 2, the stirring is carried out for about 0.5 to 1 hour, and the solution 3 is obtained after the filtration;
(3) continuously stirring the solution 3 obtained in the step (2) at room temperature for 1.0h, then placing the solution in a high-pressure reaction kettle, raising the temperature to 80 ℃ by program control, keeping the temperature for 1h, continuing to raise the temperature to 120 ℃ for 6-8 h, gradually raising the temperature to 180 ℃ for 10-12h, then slowly lowering the temperature to 120 ℃ for 4-6h, lowering the temperature to 80 ℃ for 1h, and finally lowering the temperature to room temperature. The Schiff base complex 2 of the snowflake crystal zinc is obtained. The crystals were washed 3 times with a small amount of the mixed solvent 3 and then dried in vacuum, and the calculated yield was 34.6%.
Example 7
Preparation of complex 3 according to the Schiff base ligand compound obtained with different proportions of mixed solvents as described in example 1 above:
(1) under the stirring state, dissolving 18.35mg of zinc acetate in 4mL of mixed solvent 3 to obtain solution 1;
(2) 38.41mg of Schiff base ligand compound 3 is dissolved in 8mL of mixed solvent 3 to obtain solution 2, the solution 1 obtained in the step (1) is added into the solution 2, the stirring is carried out for about 0.5 to 1 hour, and the solution 3 is obtained after the filtration;
(3) continuously stirring the solution 3 obtained in the step (2) at room temperature for 0.8h, then placing the solution in a high-pressure reaction kettle, raising the temperature to 80 ℃ by program control, keeping the temperature for 2h, continuing to raise the temperature to 120 ℃ for 4h, gradually raising the temperature to 180 ℃ for 12-16h, then slowly lowering the temperature to 120 ℃ for 4-6h, lowering the temperature to 80 ℃ for 1h, and finally lowering the temperature to room temperature. This gave a pale yellow, lumpy crystal of zinc as Schiff base complex 3. The crystals were washed 3 times with a small amount of the mixed solvent 3 and then dried in vacuum, and the calculated yield was 39.1%.
Elemental analysis was performed on the obtained Schiff base complex 3 of zinc, and the elemental analysis value (%):
C18H19ZnN3O2s (calculated) C, 53.35; h, 4.69; n, 10.37; (test value) C, 53.31; h, performing a chemical reaction on the mixture of the hydrogen peroxide and the nitrogen peroxide,4.67; and N, 10.40. Infrared analysis (KBr, cm)-1)：1623(C＝N)；2097(υNCS)。
The single crystal structure of Schiff base complex 3 of zinc in FIGS. 1 and 2 was tested using a Bruker SMART 1000CCD area-sensitive diffractometer using a wavelength of
Using SAINT program to perform data reduction on the collected diffraction points, using SADABS program to perform data correction, using SHELXTL 5.1 program package to find the coordinates of all non-hydrogen atoms on the difference fourier map by direct method based on the full-angle least squares method, and then using anisotropic refinement on all non-hydrogen atoms, the crystallographic data of Schiff base complex 3 of zinc is shown in table 1 below, and partial bond lengths and angles are shown in table 2 below.
TABLE 1 Schiff Complex 3 crystallographic data for Zinc
R1＝∑||Fo|-|Fc||/∑|Fo|，wR2＝[∑w(Fo 2-Fc 2)2/∑w(Fo 2)2]1/2.
TABLE 2 part 1 bond length of Complex 3 of Zinc
And 2 key angle (°) data
Application example 1
The Schiff base complex 3 of zinc obtained in example 7 was used to analyze the inhibitory effect on tumor cells, human breast cancer cells (MCF7), non-small cell lung cancer cell line (A549/DDP) and cervical cancer cell line (C33A).
In the present application example, an in vitro toxicity test of the complex was investigated using the MTT method. The experimental cells were incubated at 37 ℃ with 5.0% CO2Growing to logarithmic phase in the incubator, collecting cells by 0.25% trypsinization, adjusting cell suspension concentration to make cell density about 1 × 104Each cell/mL, 100mL per well is inoculated in a 96-well plate, and the cell density is about 3-5 × 103One/well, at 37 ℃ and 5% CO2The culture box is used for culturing for 24 hours. Changing the solution, adding drugs with different concentration gradients, making 3 parallel samples for each concentration, and setting a blank zero-adjusting group (culture medium, MTT and DMSO), a blank group (culture medium, cells, drug dissolution medium with the same concentration, MTT and DMSO) and a positive control group (culture medium, cells, cisplatin, MTT and DMSO). Placing at 37 ℃ and 5% CO2The cultivation was continued for 48 h. The supernatant was aspirated off, 90. mu.l of fresh medium and 10. mu.l of MTT solution (5mg/mL, i.e., 0.5% MTT) were added to each well, and incubation was continued for 4 h. Terminating the culture, discarding the culture solution in the wells, adding 150 μ l DMSO into each well, and placing on a shaker to shake at low speed for 30min to dissolve the crystals completely. Enzyme linked immunosorbent assay (ELISA) detects the inhibition rate and half Inhibition Concentration (IC) of cell proliferation related to the absorbance value OD of each well50) The following formula was used for calculation: growth inhibition rate (OD control-OD experiment)/(OD control-OD blank), all OD values minus blank zero-adjusted group OD values. IC of inhibition effect of Schiff base complex 3 of zinc on human breast cancer cells (MCF7), non-small cell lung cancer cell strain (A549/DDP) and cervical cancer cell strain (C33A)50The values are shown in Table 3 below.
TABLE 3 comparison of Schiff base Complex 3 of Zinc with cisplatin anti-cancer Activity
From the data in Table 3, it is clear that Schiff base complex 3 of zinc in application example 1 shows excellent inhibitory effect on the above tumor cells. Compared with cisplatin, the complex 3 has obvious cytotoxicity on A549/DDP cells, and the complex 3 shows a certain preference on the A549/DDP cells in three tumor cells. The main reason is probably that Schiff base ligand has unique biological activity of resisting bacteria and inhibiting tumors. On the basis, the Schiff base complex formed by adding a bridging ligand-NCS-and-C ═ N-and the like in coordination is more favorable for inhibiting the growth of tumor cells.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A zinc Schiff base complex, wherein the complex has the formula: c18H19ZnN3O2S。
2. A process for the preparation of the Schiff base complex of zinc according to claim 1,
(1) dissolving a metal salt of zinc in a mixed solvent under a constant stirring state to obtain a solution 1; wherein the mass-to-volume (mmol/mL) ratio of the zinc metal salt, potassium thiocyanate and mixed solvent is 0.1: 1: 3-5;
(2) dissolving a Schiff base ligand solution in a mixed solvent to obtain a solution 2, wherein the mixing ratio is 1: 5-7 by volume; stirring the solution 1 obtained in the step (1) and the solution 2, and filtering to obtain a solution 3;
(3) and (3) constantly stirring the solution 3 obtained in the step (2) at room temperature for 0.5-1.0 h, filtering, placing the filtered solution in a high-pressure reaction kettle, and crystallizing to obtain a Schiff base complex of light yellow crystal zinc.
3. A process for the preparation of a Schiff base complex of zinc according to claim 2,
and (3) the crystallization treatment in the step (3) is that the temperature in the high-pressure reaction kettle is raised to 100 ℃ and kept for 2h, the temperature is continuously raised to 120 ℃ and kept for 4h, the temperature is gradually raised to 180 ℃ and kept for 8-12 h, then the temperature is slowly lowered to 120 ℃ and kept for 4-6h, the temperature is lowered to 100 ℃ and kept for 2h, and finally the temperature is lowered to room temperature. The Schiff base complex of crystalline zinc is obtained as pale yellow lumps.
4. The method for preparing a Schiff base complex of zinc according to claim 2, wherein the mixed solvent in the step (1) and the step (2) is the same or different and is two or more selected from the group consisting of methanol, acetonitrile, ethanol and isopropanol.
5. The method for preparing the Schiff base complex of zinc according to claim 4, wherein the mixed solvents in the step (1) or the step (2) are the same or different and are selected from the group consisting of (1-3): 1 of methanol and isopropanol; the volume ratio of (1-3): 1 acetonitrile and ethanol; or the volume ratio of 1: (1-3) methanol and acetonitrile.
6. The method for preparing a zinc Schiff base complex according to claim 2, wherein in the step (1), the metal salt of zinc is zinc acetate, and the mass-to-volume ratio of the metal salt of zinc to the mixed solvent is 0.1 mmol: 5 mL.
7. The method of preparing a zinc Schiff base complex according to claim 2, wherein the molar ratio of said zinc metal salt to said Schiff base ligand compound is from 1: 1.
8. the method of claim 2, wherein the Schiff base ligand compound is an orange Schiff base ligand compound obtained by aldol condensation of 4- (2-aminoethyl) morpholine and naphthalene salicylaldehyde in a mixed solvent at room temperature; wherein the molar volume ratio of the 4- (2-aminoethyl) morpholine to the naphthalin salicylaldehyde to the mixed solvent is 0.1 mmol: 0.1 mmol: (5-10) mL.
9. Use of a zinc Schiff base complex according to claim 1 in the preparation of an anti-tumor medicament.
10. Use of the Schiff base complex of zinc according to claim 9, wherein the neoplasm is breast cancer, non-small cell lung cancer or cervical cancer.
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