CN112125925A - Preparation method of anti-tumor compound thiazolidone binuclear copper compound - Google Patents

Preparation method of anti-tumor compound thiazolidone binuclear copper compound Download PDF

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CN112125925A
CN112125925A CN202010980124.6A CN202010980124A CN112125925A CN 112125925 A CN112125925 A CN 112125925A CN 202010980124 A CN202010980124 A CN 202010980124A CN 112125925 A CN112125925 A CN 112125925A
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thiazolidone
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邵佳
魏金霞
任海霞
张弋
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Tianjin First Central Hospital
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Abstract

A preparation method of an antitumor compound thiazolidone binuclear copper compound comprises the steps of firstly, synthesizing a ligand precursor compound, putting sodium methoxide into a single-neck flask of absolute methanol, and mixing 2-cyanopyridine and thiosemicarbazide according to a molar ratio of 4: 1:1 feeding. Heating and refluxing the mixed solution for 4-8h, and recrystallizing with ethanol to obtain thiosemicarbazone product; the use of ethyl bromoacetate allows the thiazolone ligand to be synthesized at room temperature, after which the ligand binds to copper ions to produce the thiazolidinone binuclear copper compound. The improved preparation method of the thiazolone ligand avoids the use of extremely dangerous metal sodium, reduces the energy consumption by using ethyl bromoacetate, and saves energy. The synthesized copper complex has good DNA cutting effect and good anticancer activity on various cells, and has the possibility of being used as a future antitumor drug.

Description

Preparation method of anti-tumor compound thiazolidone binuclear copper compound
Technical Field
The invention relates to an improvement of a synthesis process of thiazolidone ligand, in particular to a preparation method of a thiazolidone copper compound for treating tumors.
Background
According to NCCN clinical practice guidelines: Non-Small Cell Lung Cancer shows that most first-line treatment regimens for Non-Small Cell Lung Cancer (NSCLC) contain platinum drugs (e.g., cisplatin, carboplatin). However, the tumor remission rate of NSCLC patients treated by traditional chemotherapy is only 40-50%, and platinum drugs have poor water solubility and low targeting property, and are easy to cause serious adverse reactions such as nephrotoxicity and ototoxicity, and more importantly, as the treatment time is prolonged, tumor cells generate serious multidrug resistance (MDR), which results in 90% of chemotherapy failure and tumor recurrence.
Copper, as a transition metal element, plays an irreplaceable role in many important physiological processes of the human body. A large number of clinical researches find that the serum copper level has a remarkable correlation with the growth of a plurality of malignant tumors, the uptake of copper in tumor tissues is remarkably higher than that in normal tissues, and copper is closely related to angiogenesis and can provide sufficient nutrition for cancer cells. More importantly, copper ions damage DNA and produce reactive oxygen species within cells in a mechanism distinct from cisplatin to promote apoptosis. Then, a plurality of new copper metal complexes with high efficiency, low toxicity and anticancer performance are continuously synthesized to explore the mechanism of antitumor drug resistance.
The thiazolidone is found to have the activities of regulating blood fat, resisting inflammation and resisting proliferation by previous researches. At present, the anti-tumor activity of thiazolidone is not deeply researched, and the anti-tumor activity mechanism of the thiazolidone is not yet clarified. The thiazolidone is prepared from thiourea derivatives, and has the advantages of low raw material price, simple and convenient preparation and easy mass synthesis. The research finds that the anti-tumor activity of the thiazolidone iron compound is good, but the related copper complex is not reported in the literature. According to the patent, a copper complex is designed and synthesized, and is characterized, and the corresponding antitumor activity is measured, so that an excellent antitumor drug is obtained.
Disclosure of Invention
The invention aims to prepare, characterize and use thiazolidone binuclear copper compound. The invention uses the improved ethyl bromoacetate method, the synthesized thiazolidone ligand has simple preparation method, does not need heating, and the synthesized ligand is purified by a recrystallization method. The synthesis of the complex adopts a room temperature solvent volatilization method, the mixture is stirred in ethanol at room temperature, the filtrate is volatilized to obtain a target product, and the spatial configuration of the target product is obtained by a single crystal diffraction method. The DNA cleavage experiment shows that the compound has good nuclease activity, acts on DNA in an oxidation cleavage mode, and shows high antitumor activity on various cells.
The preparation method of the anti-tumor compound thiazolidone binuclear copper compound comprises the following steps:
1) firstly, synthesizing a ligand precursor compound, namely putting sodium methoxide into a single-neck flask of absolute methanol, and adding 2-cyanopyridine and thiosemicarbazide according to a molar ratio of 4: 1:1 feeding. Heating and refluxing the mixed solution for 4-8h, and recrystallizing with ethanol to obtain thiosemicarbazone product; the present invention is described in the Thiosemicarbazone references "Jia Shao, Zhong-Ying Ma, Ang Li, Ya-Hong Liu, Cheng-Zhi Xie, Zhao-Yan Qiang, Jing-Yuan Xu, Thiosemicabazone Cu (II) and Zn (II) compounds as potential anti-agents: Synthesis, crystal structure, DNA clean, cytoxicity and apoptosis index activity, Journal of organic Biochemistry,2014,136, 13-23". The improvement to the synthesis process is to replace the hazardous metallic sodium with sodium methoxide, eliminating the hazardous handling step of using metallic sodium in the reaction.
2) Synthesis of ligand L: mixing thiosemicarbazone obtained in the previous step with ethyl bromoacetate (1: 1.5) and triethylamine, stirring for 2-6h at room temperature, after the reaction is finished, carrying out reduced pressure rotary evaporation to obtain a solid substance, recrystallizing methanol to obtain a ligand L, and synthesizing the ligand L, the references of Xue-Qing Song, Ya-Hong Liu, Jia Shao, Zhen-Lei Zhuang, Cheng-Zhi Xie, Xin Qiao, Wei-Guo Bao, Jing-Yu xu. The ligand L synthesized by using the improved ethyl bromoacetate is simple in preparation method, free of heating, energy-saving and environment-friendly.
3) Dissolving an equimolar ligand L in ethanol, adding a copper acetate solution dissolved in the ethanol in an equimolar proportion, regulating the pH value by triethylamine, stirring for 12h at room temperature, standing the filtrate for 7 days to precipitate crystals, collecting dark green rod-shaped crystals, washing by diethyl ether, washing by cold methanol, and collecting the crystals for single crystal diffraction. The mole ratio of the copper salt to the main ligand is 1: 1.
The chemical formula of the copper complex provided by the invention is as follows: a thiazolidinone binuclear copper complex characterized by its chemical formula [ CuLAc]2Wherein (Z) -2- ((E) - (1- (pyridine-2-yl) ethylidene) hydrazono) thiazolidin-4-one and Ac is acetate. The complex crystal provided by the invention belongs to a triclinic crystal system, a space point group is P1, and the unit cell parameters are as follows:
Figure BDA0002687241330000031
Figure BDA0002687241330000032
α is 61.86(3) °, β is 75.48(3) °, γ is 87.94(3) °, unit cell volume
Figure BDA0002687241330000033
The structure of the complexes provided by the present invention can be described as follows: the binuclear copper complex is formed by combining an asymmetric thiazolone ligand with copper ions, wherein one acetate is matched with the copper ions, and the carboxylate on the adjacent thiazolone copper unit is weakly matched with the adjacent copper ions to form a binuclear copper structure.
DNA cutting experiments prove that whether the inducer H exists or not2O2In the case where all of the binuclear copper compounds exhibit nuclease cleavage activity in the presence of H2O2In the case where the copper complex cleaves pUC19 DNA more actively than without addition of H2O2In the case of the inducer, the mechanism research shows that the inducer is an oxidation-cleavage mechanism.
Aiming at various tumor cell strains, MTT experiments show that the compound has good anticancer activity on various tumor cells and can be used as a potential anticancer drug.
The invention has the beneficial effects that: the invention provides an improved preparation method of thiazolone ligand, which avoids the use of extremely dangerous metal sodium, and the use of ethyl bromoacetate can ensure that the ligand is synthesized at room temperature, thereby reducing energy consumption and saving energy. The synthesized copper complex has good DNA cutting effect and good anticancer activity on various cells, and has the possibility of being used as an antitumor drug in the future. In addition, the preparation method is simple and reliable, and is easy for mass preparation. Agarose gel electrophoresis experiments prove that the copper compound has good chemical nuclease activity and shows a cutting effect on pUC19 DNA by an oxidative cutting mechanism; MTT experiments prove that the compound has good anticancer activity on various cells, the antitumor activity is stronger than that of cisplatin, and the water solubility is good.
The invention provides preparation, characterization and application of thiazolidone binuclear copper compound. The thiazolidone ligand synthesized by the improved ethyl bromoacetate method is simple in preparation method and free of heating, and the synthesized ligand is purified by a recrystallization method. The synthesis of the complex adopts a conventional room temperature solvent volatilization method, the mixture is stirred in ethanol at room temperature, the filtrate is volatilized to obtain a target product, and the spatial configuration of the target product is obtained by a single crystal diffraction method. The DNA cleavage experiment shows that the compound has good nuclease activity, acts on DNA in an oxidation cleavage mode, and shows high antitumor activity on various cells.
Drawings
FIG. 1 is a structural view of a thiazolidinone binuclear copper of the present invention.
FIG. 2 is a graph showing a concentration-dependent cleavage experiment of pUC19 DNA by the copper complex of the present invention.
FIG. 3 shows the present invention with addition of H2O2Thereafter, the concentration of the copper complex relative to pUC19 DNA was subjected to a cleavage experiment.
FIG. 4 is a diagram showing the mechanism of cleavage of pUC19 DNA by the copper complex of the present invention.
Detailed Description
Example 1
(1) Synthesis of ligand precursor Compounds
Placing sodium methoxide in a single-neck flask of absolute methanol, and adding 2-cyanopyridine and thiosemicarbazide according to a molar ratio of 4: 1:1 feeding. And heating and refluxing the mixed solution for 4-8h, and recrystallizing with ethanol to obtain the thiosemicarbazone product.1H NMR(DMSO-d6,/ppm):10.28(s,1H),8.68(d,J＝4.7Hz,1H),8.32(d,J＝8.1 Hz,2H),8.12–8.17(m,1H),7.89(td,J＝8.1,1.5Hz,1H),7.48(dd,J＝6.8,5.4Hz, 1H),2.42(d,J＝6.4Hz,3H)。13C NMR(DMSO-d6,/ppm):179.12(s),154.2(s), 148.21(s),148.43(s),136.58(s),124.01(s),121.01(s),11.99(s)。
(2) Synthesis of ligand L:
mixing the thiosemicarbazone obtained in the previous step with ethyl bromoacetate (1: 1.5) and triethylamine in a toluene solution, stirring at room temperature for 2-6h, and after the reaction is finished, carrying out reduced pressure rotary evaporation to obtain a solid substance. And recrystallizing the methanol to obtain the ligand L.1H NMR(DMSO-d6,/ppm):11.99(s,1H),8.59(d,J＝4.3Hz,1H),7.98 (d,J＝8.0Hz,1H),7.79(td,J＝7.9,1.6Hz,1H),7.53(dd,J＝6.8,5.3Hz,1H),3.79 (s,2H),2.51(s,3H)。13C NMR(DMSO-d6,/ppm):174.01(s),165.29(s),162.19(s), 156.05–154.34(s),148.81(s),136.48(s),124.19(s),120.41(s),33.02(s),13.49(s)。
(3) Synthesis of a binuclear copper complex:
dissolving a ligand L by using ethanol, preparing copper acetate into a suspension by using the ethanol, mixing the two suspensions to obtain a solution, wherein the solution is initially a mixed suspension, changing the solution into a dark green transparent clear solution after a period of time, stirring the solution at room temperature for 12 hours, placing the filtrate in a small beaker, allowing dark green rod-shaped crystals to appear after 7 days, and collecting the crystals to perform single crystal diffraction. Elemental analysis results (%), experimental values: c40.61; h3.36; n15.70; theoretical value: (C)24H24Cu2N8O6S2): c40.56; h3.41; and (6) N15.77. The crystal structure data are shown in Table 1, and the main bond lengths and bond angles of the copper complex crystals are shown in Table 2.
TABLE 1 Main data on the crystal structure of copper complexes
Figure BDA0002687241330000051
Figure BDA0002687241330000061
TABLE 2 major bond lengths and bond angles of copper complex crystals
Figure BDA0002687241330000062
Example 2
The thiazolidone binuclear copper compound prepared by the invention is subjected to an anti-tumor activity experiment,
1. concentration dependent cleavage experiments of pUC19 DNA with the complexes:
since the DNA molecule is a polyanion, it is negatively charged and moves to the positive pole in the electric field. In the moving field, due to the different configuration of DNA, under the action of two opposite forces of friction force and electric field force, the electrophoresis rates, namely the moving speeds, are different, respectively: supercoil (Form I) > linear (Form III) > open loop (Form II). In addition, the chemical nuclease activity of the complex is mainly affected by the following four aspects: the physical and chemical properties of the complex, the reaction concentration of the complex, the reaction time and whether an inducer is added. The complex was reacted with pUC19 DNA at pH 7.2 at 37 ℃ under a near physiological condition to measure the chemical nuclease activity of the copper complex.
The experimental process comprises the following steps:
in order to detect the chemonuclease activity of the novel copper complex, the complex is subjected to a pUC19 DNA cutting experiment study by an agarose gel electrophoresis method, as shown in figure 2, the complex is mixed with 100ng of pUC19 DNA under a near physiological condition environment (pH 7.2 and 37 ℃), and the copper compound concentration gradient data are as follows: blank, 50. mu.M, 150. mu.M, 250. mu.M, 350. mu.M, 550. mu.M, 650. mu.M, 750. mu.M.
The experimental results are as follows:
as shown in FIG. 2, the copper complex can cleave DNA under near physiological conditions, degrading the supercoiled plasmid pUC19 DNA (Form I) to a nicked circular Form (Form II). The research shows that the concentration of the complex is related to the breaking degree of DNA, obvious Form II is formed when the concentration of the compound is 550 mu M, and the compound needs to be at a higher concentration to show the cutting effect under the condition of not adding an inducer.
2. In the inducer H2O2Concentration-dependent cleavage experiments of pUC19 DNA with the complexes:
the experimental process comprises the following steps:
the complex is added with pUC19 DNA and 500 mu M H under the environment of near physiological condition (pH 7.2,37 ℃), and2O2then, the gradient copper compound was mixed with 100ng of pUC19 DNA, and the gradient data of the copper compound were as follows: blank group, H2O2Control, 50. mu.M, 150. mu.M, 250. mu.M, 400. mu.M, 550. mu.M, 650. mu.M.
The experimental results are as follows:
as shown in FIG. 3, the copper complex was under near physiological conditions and in inducer H2O2In the presence of the DNA fragment, the DNA fragment can effectively cleave the supercoiled plasmid pUC19 DNA (Form I) to a nicked open circular Form (Form II). The research shows that the concentration of the complex is correlated with the breaking degree of DNA, when the concentration of the compound is 250 mu M, the Form II is obviously formed, and as the concentration is increased, when the concentration reaches 400 mu M, the Form I is almost completely converted into the Form II.
3. Carrying out the addition of H2O2Thereafter, the cleavage mechanism of pUC19 DNA by the copper complex was examined:
to investigate the mechanism of DNA cleavage by dinuclear complexes, we used singlet oxygen (C: (A))1O2) Inhibitor NaN3And L-his, hydroxyl radical (OH. cndot.) quencher DMSO, superoxide anion radical quencher SOD, metal ion chelating agent EDTA, hydrogen peroxide scavenger KI, and determining the presence of active oxygen species based on the effect on DNA cleavage activity.
The experimental process comprises the following steps:
in the agarose gel electrophoresis apparatus, the lanes are: a control DNA; DNA + 500. mu. M H2O2+ 400. mu.M of the complex; lanes 3-8 are studies of cleavage mechanism: DNA + 400. mu.M Complex + 500. mu. M H2O2+ DMSO; DNA + 400. mu.M Complex + 500. mu. M H2O2+NaN3(ii) a DNA + 400. mu.M Complex + 500. mu. M H2O2+ SOD; DNA + 400. mu.M Complex + 500. mu. M H2O2+ EDTA; DNA + 400. mu.M Complex + 500. mu. M H2O2+ KI; DNA + 400. mu.M Complex + 500. mu. M H2O2+ L-his. The results of the experiment are shown in FIG. 4.
The experimental results are as follows:
as can be seen from FIG. 4, in the study of the DNA cleavage activity by the copper complex, DMSO (lane 3) has a certain inhibitory effect, which indicates that hydroxyl radicals may be generated during the process, hydrogen peroxide scavenger KI (lane 7) has a significant inhibition, and NaN3(lane 4) and L-his (lane 8) showed inhibition, indicating that singlet oxygen species may be generated during the reaction. The SOD (lane 5) was not significantly inhibited, indicating that superoxide anion radicals were not produced. In the presence of the metal chelator EDTA, the complex has reduced DNA fragmentation, suggesting that the metal cation plays an important role in the complex DNA fragmentation process. The cleavage mechanism of pUC19 DNA by the compound is oxidative cleavage.
4. Drug sensitivity experiments of copper complexes on five tumor cells:
the MTT method (3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazole bromide, thiazole blue) is a conventional method for detecting cell survival and growth, and is widely applied to the activity screening of antitumor drugs: a) determining the toxicity of the medicine to the cells cultured in vitro; b) cell proliferation and cell activity were measured. Thiazole blue permeates a live cell membrane to enter a cell, succinate dehydrogenase exists in mitochondria of the live cell, exogenous MTT can be reduced into water-insoluble blue-purple formazan and is remained in the cell, and dead cells do not have the function. Dimethyl sulfoxide was able to lyse formazan in cells and its light absorption (OD value) was determined with a microplate reader at a wavelength of 570 nm. A larger OD value indicates a relatively stronger cell activity and less drug toxicity. The method is commonly used for screening antitumor drugs, cytotoxicity test, determination of tumor drug resistance, and the like. Has the advantages of high sensitivity, economy and the like.
The experimental process comprises the following steps:
the invention uses MTT method to determine the complexes on external cervical cancer HeLa, liver cancer HepG2, gastric cancer cell 7901 and breast cancerThe inhibition ability of MCF-7 and non-small cell lung cancer A549 cell growth. The method comprises the following basic steps: cancer cells in the logarithmic growth phase were collected, conventionally trypsinized, blown up into single cells, adjusted for cell seeding concentration and seeded in 96-well plates (3000-. Cells were incubated at 37 ℃ with 5% CO2Under constant conditions, overnight in an incubator, the final concentrations of the complexes were 0, 1.25, 2.5, 5 and 10. mu.M, respectively, and the drug duration was 24 or 48h, respectively, after which 10. mu.L of 5mg mL was added-1MTT prepared by PBS and protected from light are cultured for 4 hours. Then, the original culture broth was discarded, and 100. mu.L of DMSO was added to each well. After formazan crystals were dissolved, the OD value of the sample at 570nm was measured by an enzyme-labeling instrument. After the test is finished, the following equation can be obtained: cell survival (%) ═ (OD)treated–ODblank)/(ODcontrol–ODblank) X 100%. Half inhibition IC for sensitivity of cells to drugs50And expressing the value. And (4) performing data processing by using Graphpad software and drawing a growth curve graph.
As shown in Table 3, after the two complexes respectively act on cervical cancer HeLa, liver cancer HepG2, gastric cancer cell 7901, breast cancer MCF-7 and non-small cell lung cancer A549 cells for 48 hours, the two complexes are found to have obvious inhibition effects on four cells, and the copper complexes are shown to have good anti-tumor activity on five cells and can be used as potential anti-cancer drugs.
TABLE 3 half Inhibition (IC) of the copper complexes against five tumor cell lines50) Value of
Figure BDA0002687241330000101
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. While the invention has been described with respect to the above embodiments, it will be understood by those skilled in the art that the invention is not limited to the above embodiments, which are described in the specification and illustrated only to illustrate the principles of the invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (3)

1. The preparation method of the anti-tumor compound thiazolidone binuclear copper compound comprises the following steps:
1) firstly, synthesizing a ligand precursor compound, namely putting sodium methoxide into a single-neck flask of absolute methanol, and adding 2-cyanopyridine and thiosemicarbazide according to a molar ratio of 4: 1:1 feeding. Heating and refluxing the mixed solution for 4-8h, and recrystallizing with ethanol to obtain thiosemicarbazone product;
2) synthesis of ligand L: mixing the thiosemicarbazone obtained in the previous step with ethyl bromoacetate (1: 1.5) and triethylamine in a toluene solution, stirring at room temperature for 2-6h, after the reaction is finished, carrying out reduced pressure rotary evaporation to obtain a solid substance, and recrystallizing with methanol to obtain a ligand L;
3) dissolving an equimolar ligand L in ethanol, adding a copper acetate solution dissolved in the ethanol in an equimolar proportion, regulating the pH value by using triethylamine, stirring for 12h at room temperature, standing the filtrate for 7 days to separate out crystals, collecting dark green rod-shaped crystals, washing with diethyl ether, and washing with cold methanol to obtain the thiazolidone binuclear copper compound, and performing single crystal diffraction on the collected crystals.
2. The method for preparing a thiazolinone binuclear copper compound as an antitumor compound according to claim 1, wherein the thiazolinone binuclear copper compound has a chemical formula of [ CuLAc]2Wherein L is (Z) -2- ((E) - (1- (pyridine-2-yl) ethylidene) hydrazono) thiazolidin-4-one, Ac is an acetate group, the crystal of the binuclear copper complex is a triclinic system, the space point group is P1, and the unit cell parameters are as follows:
Figure FDA0002687241320000011
Figure FDA0002687241320000012
α is 61.86(3) °, β is 75.48(3) °, γ is 87.94(3) °, unit cell volume
Figure FDA0002687241320000013
3. The method for preparing thiazolidone binuclear copper compound according to claim 1, wherein the ligand precursor compound is synthesized by replacing sodium methoxide, which is a dangerous metal, with sodium methoxide, thereby eliminating the dangerous operation step of using sodium metal in the reaction.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113801100A (en) * 2021-10-26 2021-12-17 四川省产品质量监督检验检测院 Tetranuclear copper complex and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Title
JIA SHAO等: ""Thiosemicarbazone Cu(II) and Zn(II) complexes as potential anticancer agents: Syntheses,crystal structure,DNA cleavage,cytotoxicity and apoptosis induction activity"", 《JOURNAL OF INORGANIC BIOCHEMISTRY》 *
XUE-QING SONG等: ""Rapid induction of apoptosis in tumor cells treated with a new platinum(II) complex based on amino-thiazolidinone"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113801100A (en) * 2021-10-26 2021-12-17 四川省产品质量监督检验检测院 Tetranuclear copper complex and preparation method and application thereof

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