CN114685536B - Binuclear cadmium complex with anticancer activity and preparation method and application thereof - Google Patents
Binuclear cadmium complex with anticancer activity and preparation method and application thereof Download PDFInfo
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- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229910052793 cadmium Inorganic materials 0.000 title claims abstract description 86
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000013110 organic ligand Substances 0.000 claims abstract description 38
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- 238000010992 reflux Methods 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- MCFKRQUELFKUCE-UHFFFAOYSA-N 4-fluoro-N-[(2-hydroxy-3-methoxyphenyl)methylideneamino]benzamide Chemical compound FC1=CC=C(C(=O)NN=CC2=C(C(=CC=C2)OC)O)C=C1 MCFKRQUELFKUCE-UHFFFAOYSA-N 0.000 claims description 13
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 11
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- MSEBQGULDWDIRW-UHFFFAOYSA-N methyl 4-fluorobenzoate Chemical compound COC(=O)C1=CC=C(F)C=C1 MSEBQGULDWDIRW-UHFFFAOYSA-N 0.000 claims description 6
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- XIEPJMXMMWZAAV-UHFFFAOYSA-N cadmium nitrate Chemical compound [Cd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XIEPJMXMMWZAAV-UHFFFAOYSA-N 0.000 abstract description 19
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- LZSOIDYOUFWHOQ-UHFFFAOYSA-N N-[(2-hydroxy-3-methoxyphenyl)methylideneamino]-4-(1,2,2-triphenylethenyl)benzamide Chemical compound COC1=CC=CC(C=NNC(C(C=C2)=CC=C2C(C2=CC=CC=C2)=C(C2=CC=CC=C2)C2=CC=CC=C2)=O)=C1O LZSOIDYOUFWHOQ-UHFFFAOYSA-N 0.000 description 10
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07C241/04—Preparation of hydrazides
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Abstract
The invention discloses a binuclear cadmium complex with anticancer activity and a preparation method and application thereof, wherein the binuclear cadmium compound is an infinite net-shaped structure material formed by connecting cadmium salt and an organic ligand in a coordinate bond mode, and the binuclear cadmium complex is bis- [ 4-fluoro-N '- (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine ]. cadmium dinitrate or bis- [ N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine ]. cadmium dinitrate. The binuclear cadmium complex of the invention takes the binuclear planar cadmium unit as a metal ligand and is assembled into a metal organic framework with a stable planar structure, has strong capacity of inducing apoptosis of tumor cells for human breast cancer cells and human lung cancer cells, and also has obvious antitumor cell activity. Therefore, the binuclear cadmium complex is a material which is very promising for developing novel antitumor drugs and has a strong application value for developing antitumor drugs.
Description
Technical Field
The invention belongs to the technical field of metal organic framework materials, and particularly relates to a binuclear cadmium complex with anticancer activity, and a preparation method and application thereof.
Background
The metal complex has adjustable structure, and the positive charge is very beneficial to the interaction with the phosphate skeleton of DNA, and the interaction with the DNA is widely researched. These studies have expanded the biochemical field of knowledge of the interaction of metal complexes with DNA to some extent, but these studies are currently mainly aimed at mononuclear metal complexes, and have performed less than planar binuclear metal complexes. Therefore, the design and synthesis of the planar binuclear metal complex taking DNA as a target point can provide another wide space for developing novel anti-tumor and anti-cancer drugs.
The acylhydrazone compounds are Schiff base organic framework materials, have multiple biospecificity, including antituberculosis, antibiosis, antifungal, anti-inflammation, antinociception, antiplatelet activity and other characteristics, and the coordination compounds containing different types of ligand systems show stronger anticancer characteristics to different human cancer cell strains, thereby showing that the ligand function has important significance. The proper ligand can enhance the specificity selectivity of the ligand to tumor parts and reduce the toxic and side effects on healthy cells. Acylhydrazone groups have proven to be a very versatile and promising motif in drug design and pharmaceutical chemistry. In addition, due to the diversity of N and O coordination sites, acylhydrazone groups exhibit interesting bioactivity specificity. The acylhydrazone Schiff base cadmium complex has wide application prospects, including catalysis, luminescent probes and molecular sensors, and the research on the biological activity of the acylhydrazone Schiff base cadmium (III) complex is rare at present.
Disclosure of Invention
The invention aims to provide a binuclear cadmium complex with anticancer activity and a preparation method and application thereof.
According to one aspect of the present invention, there is provided a binuclear cadmium complex having anticancer activity, the binuclear cadmium complexThe cadmium complex is a net structure material formed by connecting cadmium salt and an organic ligand in a coordination bond mode, and the binuclear cadmium complex is bis- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine]Cadmium dinitrate or bis- [ N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoylhydrazine]Cadmium dinitrate, the structure of the binuclear cadmium complex is shown as the following formula (I),
the compound is shown in a formula (I),
wherein R is one of the following functional groups,
，
。
in some embodiments, the cadmium salt is cadmium nitrate tetrahydrate.
In some embodiments, the organic ligand is 4-fluoro-N '- (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine or N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine.
In some embodiments, 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine is obtained by reacting 4-fluorobenzoyl hydrazine with o-vanillin, and 4-fluorobenzoyl hydrazine is obtained by reacting methyl 4-fluorobenzoate with hydrazine hydrate.
In some embodiments, N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine is obtained from the reaction of 4-tetraphenylvinylcarboxylic acid hydrazide with o-vanillin.
In some embodiments, 4-tetraphenylvinylcarboxylic acid hydrazide is obtained by reacting 4- (1, 2, 2-triphenylvinyl) -benzoic acid methyl ester with hydrazine hydrate.
According to another aspect of the invention, the application of the binuclear cadmium complex with anticancer activity in preparing the tumor drugs for resisting human lung cancer cell line A549 and human breast cancer estrogen-dependent cancer cell line MCF-7 is provided.
According to still another aspect of the present invention, there is provided a method for preparing a binuclear cadmium complex having anticancer activity, comprising the steps of:
s1, hydrazide compound synthesis:
slowly dripping hydrazine hydrate into a mixture of methanol and a reactant, heating and refluxing, cooling to room temperature after the reflux is finished, adding ice water, filtering and drying after a first precipitate appears, recrystallizing methanol, and drying at 50 ℃ to obtain a hydrazide compound;
s2 organic ligand synthesis:
adding a hydrazide compound and o-vanillin into a reaction container, adding ethanol, heating and refluxing, cooling to room temperature after refluxing is finished, filtering, collecting a second precipitate, washing the second precipitate for 1-2 times by using methanol, and drying at 50 ℃ to obtain an organic ligand;
s3 synthesis of the binuclear cadmium complex:
mixing organic ligand, cadmium salt, methanol and N, N-dimethylformamide uniformly, performing ultrasonic treatment, sealing in a reaction container, reacting at 70 ℃ for 3 days, cooling to room temperature after the reaction is finished to obtain yellow powdery crystals, and washing and precipitating to obtain the binuclear cadmium complex.
In some embodiments, the reactant in step S1 is methyl 4-fluorobenzoate or methyl 4- (1, 2, 2-triphenylvinyl) -benzoate, and the molar ratio of the reactant to the hydrazine hydrate is 1: 3.
In some embodiments, the hydrazide compound in steps S1 and S2 is 4-fluorobenzoyl hydrazine or 4-tetraphenyl vinyl carboxylic acid hydrazide, and the molar ratio of the hydrazide compound to o-vanillin is 1: 1.
The invention has the beneficial effects that: the binuclear cadmium complex with anticancer activity is a metal organic framework material, has simple preparation method and low cost, is self-assembled into small molecules with good plane lines by utilizing the synthesized Schiff base ligand, has better pi conjugated planes and good luminescence performance, takes the binuclear plane cadmium unit as the metal ligand, is assembled into a metal organic framework with a stable plane structure, has stronger capacity of inducing apoptosis of tumor cells on human breast cancer cells and human lung cancer cells, and also has obvious antitumor cell activity. Therefore, the binuclear cadmium complex, namely the bis- [ 4-fluoro-N '- (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine ]. the cadmium dinitrate, the bis- [ N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine ]. the cadmium dinitrate is a material with a very promising prospect for developing novel antitumor drugs and has a relatively high application value for developing the antitumor drugs.
Drawings
FIG. 1 is a mass spectrum of organic ligand 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine (F-L) according to one embodiment of the present invention.
FIG. 2 shows a mass spectrum of a binuclear cadmium complex bis- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoylhydrazine ]. cadmium dinitrate (Cd-F-L) according to an embodiment of the present invention.
FIG. 3 is a crystal structure diagram of a binuclear cadmium complex bis- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoylhydrazine ]. cadmium dinitrate (Cd-F-L) according to an embodiment of the present invention.
FIG. 4 is a mass spectrum of an organic ligand N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine (TPE-L) according to another embodiment of the present invention.
FIG. 5 is a mass spectrum of a binuclear cadmium complex, bis- [ N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoylhydrazine ]. cadmium dinitrate (Cd-TPE-L), according to another embodiment of the present invention.
FIG. 6 is a crystal structure diagram of a binuclear cadmium complex, bis- [ N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoylhydrazine ]. cadmium dinitrate (Cd-TPE-L), according to another embodiment of the present invention.
FIG. 7 is a Fourier transform infrared spectrum of the organic ligand 4-fluoro-N '- (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine (F-L) and the binuclear cadmium complex bis- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine ]. cadmium dinitrate (Cd-F-L) in accordance with one embodiment of the present invention.
FIG. 8 is a Fourier transform infrared spectrum of an organic ligand N '- (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine (TPE-L) and a binuclear cadmium complex bis- [ N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine ]. cadmium dinitrate (Cd-TPE-L) according to another embodiment of the present invention.
FIG. 9a shows an embodiment of the present invention in which 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine (F-L) as an organic ligand 2 Emission spectrum of mixed solution of O and H 2 FIG. 9b is a graph showing the relationship of O content, and the binuclear cadmium complex bis- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine according to an embodiment of the present invention]Cadmium dinitrate (Cd-F-L) in DMF/H 2 Emission spectrum of mixed solution of O and H 2 Graph of the relationship of O content.
FIG. 10a is a bar graph of AnnexinV-FITC/PI double-stained apoptosis after 24h treatment of MCF-7 cells with different concentrations of the binuclear cadmium complex bis- [ 4-fluoro-N '- (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine ]. cadmium dinitrate (Cd-F-L) according to an embodiment of the present invention, and FIG. 10b is a bar graph of apoptosis rate after 24h treatment of MCF-7 cells with different concentrations of the binuclear cadmium complex bis- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine ]. cadmium dinitrate (Cd-F-L) according to an embodiment of the present invention.
FIG. 11a is a bar graph of the apoptosis of annexin V-FITC/PI double-stained cells after treating A549 cells for 24h with different concentrations of the binuclear cadmium complex bis- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine ]. with cadmium dinitrate (Cd-F-L) according to an embodiment of the present invention, and FIG. 11b is a bar graph of the apoptosis rate after treating A549 cells for 24h with cadmium dinitrate (Cd-F-L) according to an embodiment of the present invention.
FIG. 12 shows the NMR spectrum of N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine (TPE-L), which is another embodiment of the present invention.
Detailed Description
The present invention is described in further detail in the following detailed description with reference to specific embodiments, which are intended to be illustrative only and not to be limiting of the scope of the invention, as various equivalent modifications of the invention will become apparent to those skilled in the art after reading the present invention and are intended to be included within the scope of the appended claims. All the raw materials and reagents of the present invention are commercially available raw materials and reagents, unless otherwise specified.
Example 1
In this example, hydrazine hydrate was 50% hydrazine hydrate supplied from national chemical group chemical reagent Co., Ltd, methyl 4-fluorobenzoate was 99% methyl 4-fluorobenzoate supplied from national chemical reagent Co., Ltd, methanol was analytically pure methanol supplied from national chemical reagent Co., Ltd, o-vanillin was 99% o-vanillin supplied from national chemical reagent Co., Ltd, ethanol was analytically pure ethanol supplied from national chemical reagent Co., Ltd, cadmium nitrate tetrahydrate was analytically pure cadmium nitrate tetrahydrate supplied from national chemical reagent Co., Ltd, and N, N-dimethylformamide was 99.8% N, N-dimethylformamide supplied from national chemical reagent Co., Ltd, and the reagents of example 1 were used in examples 2 to 7 below.
Example 2 dinuclear cadmium Complex bis- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoylhydrazine ] Dichlorohydrine dinitrate (Cd-F-L) with anticancer Activity and preparation thereof
S1, hydrazide compound synthesis:
slowly dripping 0.06mol of 50% hydrazine hydrate solution into a mixture of 30ml of methanol and 0.02mol of 4-fluorobenzoic acid methyl ester, heating and refluxing, cooling to room temperature after the reflux is finished, adding ice water, and precipitating first
After the product appeared, it was filtered, dried and recrystallized from methanol, and dried at 50 ℃ to obtain 4-fluorobenzoylhydrazine with a yield of 88.31%;
s2 organic ligand synthesis:
adding 10mm into a 100ml round-bottom flaskAdding 40ml of ethanol into the ol 4-fluorobenzoyl hydrazine and 10mmol of o-vanillin, heating and refluxing, cooling to room temperature after refluxing is finished, filtering, collecting a second precipitate, washing the second precipitate for 1-2 times by using methanol, and drying at 50 ℃ to obtain an organic ligand 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine (F-L), wherein the yield is as follows: 80.15%, identified by mass spectrometry: ESI-MS (m/z): 289.09. 289.09, as shown in FIG. 1. The structural formula of the organic ligand is shown as the following formula (II):
formula (II);
s3, synthesis of the binuclear cadmium complex:
taking 0.2mmol of organic ligand 4-fluoro-N '- (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine (F-L), 0.2mmol of cadmium nitrate tetrahydrate, 2ml of methanol and 0.5 ml of N, N-dimethylformamide, uniformly mixing, sealing in a 10ml glass bottle after ultrasonic treatment, reacting for 3 days at 70 ℃, cooling to room temperature after the reaction is finished to obtain yellow powdery crystals, washing and precipitating to obtain a binuclear cadmium complex di- [ 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine ]. cadmium dinitrate (Cd-F-L), wherein the yield is 85%, and the mass spectrometry analysis and identification: ESI-MS (m/z): 798.28. Found: 798.28, shown in FIG. 2.
X-ray diffraction analysis is carried out on the binuclear cadmium complex Cd-F-L to obtain a crystal structure diagram of the binuclear cadmium complex Cd-F-L, as shown in figure 3, a crystal data table of the binuclear cadmium complex Cd-F-L is shown in a table 1, and a key length and key angle data table is shown in a table 2.
TABLE 1 Crystal data Table of binuclear cadmium complex Cd-F-L
Note: a R 1 = å||Fo| -|Fc||/å|Fo|， b wR 2 ={åw[(Fo) 2 -(Fc) 2 ] 2 /åw[(Fo) 2 ]2} 1/2 。
TABLE 2 bond Length and bond Angle data Table for binuclear cadmium Complex Cd-F-L
Note: symmetric transformations for generating equivalent atoms # 1: -x + 1, -y +1, -z + 1; # 2: -x + 1, -y, -z + 1.
Example 3 dinuclear cadmium Complex bis- [ N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoylhydrazine ] Dichlorous dinitrate (Cd-TPE-L) with anticancer Activity and preparation thereof
S1, hydrazide compound synthesis:
slowly dropping 10mmol of 50% hydrazine hydrate solution into a mixture of 50ml methanol and 10mmol of 4- (1, 2, 2-triphenylvinyl) -methyl benzoate, refluxing for 10h at 70 ℃, cooling to room temperature after the reflux is finished, filtering, drying and recrystallizing with methanol after a first precipitate appears, and drying at 50 ℃ to obtain 4-tetraphenylvinylcarboxylic acid hydrazide;
s2 organic ligand synthesis:
adding 2mmol of 4-tetraphenyl vinyl carboxylic acid hydrazide and 2mmol of o-vanillin into a 100ml round-bottom flask, adding 30ml of ethanol, heating and refluxing, cooling to room temperature after refluxing is finished, filtering, collecting a second precipitate, washing the second precipitate for 1-2 times by using methanol, and drying at 50 ℃ to obtain the organic ligand N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine (TPE-L), wherein the yield is as follows: 73.78%, and is identified by nuclear magnetic resonance hydrogen spectrum: 1H NMR (600 MHz, DMSO). delta. (ppm): 12.01 (s, 1H), 10.98 (s, J = 6.9, 1H), 8.61 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.20-7.10 (m, 12H),7.05-6.98 (m, 7H), 6.86 (t, J = 7.9 Hz, 1H), 3.81 (s, 3H), as shown in fig. 12. And (3) identifying by mass spectrometry: ESI-MS (m/z) Calcd. for [ C 35 H 28 N 2 O 3 -e] + 525.21. 525.21, as shown in FIG. 4. The structural formula of the organic ligand (TPE-L) is shown as the following formula (III):
s3 synthesis of the binuclear cadmium complex:
0.1mmol of organic ligand N '- (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine (TPE-L), 0.1mmol of cadmium nitrate tetrahydrate, 2ml of methanol and 1ml of N, N-dimethylformamide are uniformly mixed, the mixture is sealed in a 10ml glass bottle after ultrasonic treatment, the mixture reacts for 3 days at 70 ℃, after the reaction is finished, the temperature is reduced to room temperature to obtain yellow powdery crystals, and washing and precipitating to obtain a binuclear cadmium complex bis- [ N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine]Cadmium dinitrate (Cd-TPE-L), with a yield of 73%, identified by mass spectrometry: ESI-MS (m/z) Calcd. for [ Cd ] 2 C 70 H 54 N 4 O 6 -e] + 1271.40. 1272.05, as shown in FIG. 5.
X-ray diffraction analysis is carried out on the binuclear cadmium complex Cd-TPE-L to obtain a crystal structure diagram of the binuclear cadmium complex Cd-TPE-L, as shown in figure 6, a crystal data table of the binuclear cadmium complex Cd-TPE-L is shown in a table 3, and a key length and key angle data table is shown in a table 4.
TABLE 3 Crystal data table of binuclear cadmium complex Cd-TPE-L
Note: a R 1 = å||Fo| -|Fc||/å|Fo|， b wR 2 ={åw[(Fo) 2 -(Fc) 2 ] 2 /åw[(Fo) 2 ]2} 1/2 。
TABLE 4 bond Length and bond Angle data Table for the binuclear cadmium Complex Cd-TPE-L
Note: symmetric transformations for generating equivalent atoms # 1: -x + 1, -y +1, -z + 1; # 2: -x + 1, -y, -z + 1.
Example 4 Fourier transform Infrared Spectroscopy detection of organic ligand 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) Benzohydrazide (F-L) and binuclear cadmium Complex Cd-F-L
In the embodiment, a Fourier transform infrared spectrometer is used for carrying out Fourier transform infrared spectrum detection on an organic ligand 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine (F-L) and a binuclear cadmium complex Cd-F-L, and specific results are shown in an attached figure 7. Directly obtained by the attached FIG. 7, 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine (F-L): 3556 (Ar-OH), 3329(-NH-), 1676 (-C = O-), 1170 (-O-CH) 3 ) The appearance of the characteristic peak is equal to that of the organic ligand F-L, and the binuclear cadmium complex Cd-F-L is 3556cm -1 ，3329 cm -1 Has disappeared the characteristic peak of 1676 cm -1 ，1170 cm -1 The characteristic peaks of the ligand F-L are shifted, and the characteristic peaks all prove that (N, O) in the ligand F-L is coordinated with metal cadmium to form a binuclear cadmium complex.
Example 5 Fourier transform Infrared Spectrum detection of organic ligand N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoylhydrazine (TPE-L) and binuclear cadmium Complex Cd-TPE-L
In the embodiment, a Fourier transform infrared spectrometer is used for carrying out Fourier transform infrared spectrum detection on an organic ligand N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine (TPE-L) and a binuclear cadmium complex Cd-TPE-L, and specific results are shown in an attached figure 8. The organic ligand, N' - (2-hydroxy-3-methoxybenzylidene) -4- (1, 2, 2-triphenylvinyl) benzoyl hydrazine (TPE-L), is directly shown by the attached FIG. 8: 3443 (-NH-), 3179(Ar-OH), 1671 (-C = O-), 1164 (-O-CH) 3 ) The appearance of characteristic peaks is equal, compared with the organic ligand TPE-L, the binuclear cadmium complex Cd-TPE-L is 3443cm -1， 3179 cm -1 ，1676 cm -1 ，1170 cm -1 The characteristic peak of the ligand TPE-L shifts, which indicates that (N, O) in the ligand TPE-L coordinates with metal cadmium to form a binuclear cadmium complex.
Example 6 emission Spectroscopy detection of organic ligand 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoylhydrazine (F-L) and binuclear cadmium Complex Cd-F-L
Dissolving the binuclear cadmium complex Cd-F-L, Cd-TPE-L, and finding that the binuclear cadmium complex Cd-F-L is dissolved in a methanol, ethanol, DMF or MDSO solvent, the binuclear cadmium complex Cd-F-L, Cd-TPE-L is dissolved in a DMF or MDSO solvent, and the binuclear cadmium complex Cd-F-L, Cd-TPE-L does not emit light in the solvent and stably exists in the solution in the form of the complex.
When water is added into the solution in which the ligand F-L and the binuclear cadmium complex Cd-F-L are dissolved respectively, the solution emits light, the luminous intensity of the solution is enhanced along with the increase of the water content in the solution, and the solution shows an aggregation-induced luminous effect, which is shown in figure 9.
In DMF/H 2 Mixed solution of O, with c = 10 -4 Respectively adding an organic ligand F-L and a binuclear cadmium complex Cd-F-L into the mixed solution at the mol/L concentration, and measuring the emission spectrum and H of the organic ligand F-L under the condition that the lambda ex = 364 nm 2 The relationship of the O content, as shown in FIG. 9a, can be seen that the organic ligand F-L has higher luminous intensity in the solution environment with higher water content, wherein the luminous intensity is highest when the water content is 80%; determination of emission spectrum and H of binuclear cadmium complex Cd-F-L 2 The relation of the O content can be shown in figure 9b, and the luminous intensity of the binuclear cadmium complex Cd-F-L is higher under the solution environment with higher water content, wherein the luminous intensity is highest when the water content is 80%.
Example 7 cytotoxicity screening test of organic ligand F-L, TPE-L and binuclear cadmium Complex Cd-F-L, Cd-TPE-L
7.1 seed plate: MCF-7 cells (human breast cancer cells) and A549 cells (human lung cancer cells) which are cultured and are in logarithmic growth phase are respectively plated, 7000 tumor cells are uniformly planted in each hole of a 96-well plate after counting through a counting plate, 180 mu l of complete culture medium is added into each hole, the tumor cells are not planted in the holes at the outermost periphery of the 96-well plate, and PBS buffer solution with proper volume or autoclaved secondary water is added for liquid sealing. The seeded 96-well plate was then placed at 37 c,5% CO 2 culturing in an incubator, and preparing to add medicine after the tumor cells adhere to the wall for 6-12 h.
7.2 adding medicine: preparing an organic ligand F-L, TPE-L and a binuclear cadmium complex Cd-F-L, Cd-TPE-L into a mother solution with the concentration of 10mM by using DMSO, diluting the mother solution by using a PBS buffer solution or a complete culture medium, obtaining a series of addition liquid medicines with the concentration gradients of 3.06 mu M, 6.125 mu M, 12.5 mu M, 25 mu M and 50 mu M after dilution, and adding the addition liquid medicines into a 96-well plate. When adding medicine, the first row is used as blank control group, DMEM complete culture medium containing 1% DMSO is added into the blank control group to make the final volume 200 μ l, and from the second row, liquid medicine is added according to gradient concentration, each concentration is provided with 5 holes as parallel repetition, after adding medicine, the mixture is placed at 37 deg.C and 5% CO 2 Culturing in incubator to make the medicine act for 24 hr.
7.3 addition of MTT: after 24h of drug action, 10. mu.l of 5 mg/ml MTT working solution (prepared using completely sterile PBS buffer) was added to each well, followed by 5% CO at 37 ℃ 2 And (3) reacting the cells in the incubator for 3-4 hours, wherein the whole process needs to be carried out in a dark place.
7.4 determination: firstly, discarding all culture solution in a 96-well plate, adding DMSO solution with the volume of 150 mu l into each well of the 96-well plate to fully dissolve the culture solution, finally, selecting the position with the wavelength of 492 nm by a multifunctional microplate reader to measure the absorbance in each well, recording the result, and calculating the cell growth inhibition rate according to the formula: growth inhibition (%) = (control OD value-experimental OD value)/control OD value × 100%. All experiments were repeated 3 times and averaged. IC50 was calculated using SPSS18.0 software and the results are detailed in table 5 below.
TABLE 5 24-hour IC of organic ligand F-L, TPE-L and binuclear cadmium complex Cd-F-L, Cd-TPE-L 50 Table of measurement results
According to the table 5, the 24h IC50 values of the binuclear cadmium complex Cd-F-L on the A549 cells and the MCF-7 cells are respectively 10.88 +/-0.51 and 5.28 +/-2.035, which shows that the binuclear cadmium complex Cd-F-L has stronger capacity of inducing apoptosis on the A549 cells and the MCF-7 cells and has better anti-tumor cell activity; the 24h IC50 value of the binuclear cadmium complex Cd-TPE-L to MCF-7 cells is 7.14 +/-0.11, which shows that the binuclear cadmium complex Cd-TPE-L has strong capacity of inducing apoptosis to the MCF-7 cells and also has obvious antitumor cell activity. Therefore, the binuclear cadmium complex Cd-F-L, Cd-TPE-L has an application prospect in preparing antitumor drugs and is a potential antitumor drug.
After MCF-7 cells are respectively treated by dinuclear cadmium complex Cd-F-L solutions with the concentrations of 1.25 mu M, 2.5 mu M and 5 mu M for 24 hours and A549 cells are respectively treated by dinuclear cadmium complex Cd-F-L solutions with the concentrations of 5 mu M, 10 mu M and 20 mu M for 24 hours, the cells are collected for annexin V-FITC/PI double staining, and the apoptosis condition is analyzed by a flow cytometer, wherein the results are shown in the attached figures 10 and 11.
As shown in the attached drawings 10 and 11, the fact that the apoptosis proportion of the binuclear cadmium complex Cd-F-L to MCF-7 and A549 tumor cells is increased along with the increase of the concentration of the binuclear cadmium complex Cd-F-L shows dose dependence shows that the binuclear cadmium complex Cd-F-L achieves the anti-tumor effect by promoting the apoptosis. The binuclear cadmium complex Cd-F-L has obvious antitumor cell activity.
The above description is only for the embodiments of the present invention, and it is obvious to those skilled in the art that various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (6)
1. The binuclear cadmium complex with the anticancer activity is characterized in that the binuclear cadmium complex is formed by connecting cadmium salt and an organic ligand in a coordination bond mode, and has the following crystal structure:
the cadmium salt is cadmium nitrate tetrahydrate, and the organic ligand is 4-fluorine-N' - (2-hydroxy-3-methoxyl benzylidene) benzoyl hydrazine.
2. The dinuclear cadmium complex having anticancer activity as claimed in claim 1, wherein said 4-fluoro-N' - (2-hydroxy-3-methoxybenzylidene) benzoyl hydrazine is obtained by reacting 4-fluorobenzoyl hydrazine with o-vanillin, and said 4-fluorobenzoyl hydrazine is obtained by reacting methyl 4-fluorobenzoate with hydrazine hydrate.
3. Use of the dinuclear cadmium complex with anticancer activity according to any one of claims 1-2 in preparation of anti-tumor drugs against human lung cancer cell line A549 and human breast cancer estrogen-dependent cancer cell line MCF-7.
4. The method for preparing the dinuclear cadmium complex with anticancer activity according to any one of claims 1 to 2, comprising the steps of:
s1, hydrazide compound synthesis:
slowly dripping hydrazine hydrate into a mixture of methanol and a reactant, heating and refluxing, cooling to room temperature after refluxing, adding ice water, filtering, drying, recrystallizing methanol after a first precipitate appears, and drying at 50 ℃ to obtain a hydrazide compound, wherein the reactant is 4-methyl fluorobenzoate;
s2 organic ligand synthesis:
adding the hydrazide compound and o-vanillin into a reaction container, adding ethanol, heating and refluxing, cooling to room temperature after refluxing is finished, filtering, collecting a second precipitate, washing the second precipitate for 1-2 times by using methanol, and drying at 50 ℃ to obtain an organic ligand, wherein the hydrazide compound in the steps S1 and S2 is 4-fluorobenzoyl hydrazine;
s3 synthesis of the binuclear cadmium complex:
and (2) uniformly mixing the organic ligand, cadmium salt, methanol and N, N-dimethylformamide, carrying out ultrasonic treatment, sealing in a reaction container, reacting for 3 days at 70 ℃, cooling to room temperature after the reaction is finished to obtain yellow powdery crystals, and washing and precipitating to obtain the binuclear cadmium complex.
5. The method according to claim 4, wherein the molar ratio of the reactant to the hydrazine hydrate is 1: 3.
6. The preparation method according to claim 4, wherein the molar ratio of the hydrazide compound to o-vanillin is 1: 1.
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