CN107286199B - Binuclear aryl ruthenium metal complex and synthesis method and application thereof - Google Patents
Binuclear aryl ruthenium metal complex and synthesis method and application thereof Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title description 7
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- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 20
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- GDWGYEKGZJOUHE-UHFFFAOYSA-N 1-(3-imidazol-1-ylphenyl)imidazole Chemical compound C1=NC=CN1C1=CC=CC(N2C=NC=C2)=C1 GDWGYEKGZJOUHE-UHFFFAOYSA-N 0.000 claims abstract description 14
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- 238000006243 chemical reaction Methods 0.000 claims description 12
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- 239000012046 mixed solvent Substances 0.000 claims description 3
- SFPQFQUXAJOWNF-UHFFFAOYSA-N 1,3-diiodobenzene Chemical compound IC1=CC=CC(I)=C1 SFPQFQUXAJOWNF-UHFFFAOYSA-N 0.000 claims description 2
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- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
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- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a binuclear aryl ruthenium metal complex, and also discloses a synthetic method of the binuclear aryl ruthenium metal complex, which comprises the following steps: dissolving a certain amount of aryl ruthenium dimer in an organic solvent under an inert gas atmosphere to obtain an initial solution; adding 1, 3-di (1H-imidazole-1-yl) benzene 1, 3-bib ligand into the initial solution, and reacting for a period of time at a certain temperature to obtain a mixed solution; and adding the required anion salt into the mixed solution, stirring for a period of time at room temperature, then filtering, concentrating the filtrate, and further purifying the crude product by column chromatography to obtain the binuclear aryl ruthenium metal complex. The preparation method has simple process flow, easy operation and high product yield; the prepared binuclear aryl ruthenium metal complex has good anticancer activity, can be applied to preparation of anticancer drugs or anticancer drug components, and has good drug application prospects.
Description
Technical Field
The invention relates to a binuclear aryl ruthenium metal complex, and also relates to a synthesis method of the binuclear aryl ruthenium metal complex and application of the binuclear aryl ruthenium metal complex in preparation of anti-cancer drugs and anti-cancer drug components.
Technical Field
Metal anticancer drugs have occupied an important position in the field of bio-inorganic chemistry, wherein the clinical use rate of platinum drugs has exceeded 50%, which inhibits the proliferation of cancer cells by changing the spatial structure of DNA, but the clinical use of such drugs is hindered by the drug resistance, and in addition to this, the platinum drugs have serious side effects during the course of treatment, such as: nephrotoxicity, neurotoxicity, thrombocytopenia and neutrophilic leukocytesDecrease symptoms and the like. Therefore, the research on the low-toxicity metal anticancer drugs is of great significance. Because the ruthenium metal complex is dissolved in water, the ligand exchange rate is similar to that of the platinum drug (both are 10)-3～10-2s-1) This rate index has a greater effect on anticancer activity. Furthermore, ruthenium metal complexes have many synthesis methods and exist in a plurality of valence states in vivo (Ru)II、RuIII、RuIV). Therefore, ruthenium metal anticancer drugs attract extensive attention. The aryl ruthenium metal complex is regarded as the most promising non-platinum metal anti-cancer drug, and has the advantages of high activity, selectivity (only selectively reacting with cancer cells but not normal cells), multiple targets, low drug resistance, low toxicity and the like. Therefore, the research on the aryl ruthenium metal complex with good anticancer activity is significant.
Disclosure of Invention
The invention aims to solve the technical problem of providing a binuclear aryl ruthenium metal complex, wherein the binuclear aryl ruthenium metal complex with the structure has good anticancer activity and only has extremely low side effect on normal cells.
The technical problem to be solved by the invention is to provide the synthesis method of the binuclear aryl ruthenium metal complex, which has the advantages of simple process flow, easy operation and high yield.
The invention finally aims to solve the technical problem of providing the application of the binuclear aryl ruthenium metal complex in preparing anti-cancer drugs and anti-cancer drug components.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a binuclear aryl ruthenium metal complex has the following structural general formula:
wherein: r is p-cymene or biphenyl, X is Cl-、Br-Or I-Y is Cl-、Br-、I-、CF3SO3 -、NO3 -、PF6 -、BF4 -Or SbF6 -One kind of (1).
The binuclear aryl ruthenium metal complex has a bowl-shaped structure, and the water solubility of anions contained in the complex can be adjusted, namely, the types of the anions contained in the complex are different, and the water solubility of the complex is also different.
The synthesis method of the binuclear aryl ruthenium metal complex comprises the following steps:
step 1, dissolving a certain amount of aryl ruthenium dimer in an organic solvent under an inert gas atmosphere to obtain an initial solution;
and 3, adding the required anion salt into the mixed solution obtained in the step 2, stirring for a period of time at room temperature, filtering, concentrating the filtrate, and further purifying the crude product through column chromatography to obtain the binuclear aryl ruthenium metal complex.
Wherein the aryl ruthenium dimer is dichloro aryl ruthenium dimer, dibromo aryl ruthenium dimer or diiodo aryl ruthenium dimer.
Wherein the organic solvent is one or more mixed solvents of methanol, ethanol, dichloromethane, acetonitrile or chloroform according to any proportion.
Wherein the reaction molar ratio of the aryl ruthenium dimer to the 1, 3-bis (1H-imidazole-1-yl) benzene 1, 3-bib ligand is 1: 20-10: 1.
Wherein the reaction time is 25-80 ℃, and the reaction time is 1-80 h.
Wherein the anion salt is NaCl or AgCF3SO3、AgNO3、AgBF4、AgPF6、LiCF3COO、KI、LiSbF6LiBr or KBr.
The application of the binuclear aryl ruthenium metal complex in preparing anticancer drugs and anticancer drug components.
The application of the binuclear aryl ruthenium metal complex in preparing medicines for resisting cervical cancer, breast cancer, liver cancer and lung cancer and preparing components of the medicines for resisting cervical cancer, breast cancer, liver cancer and lung cancer.
The preparation method of the 1, 3-di (1H-imidazole-1-yl) benzene 1, 3-bib ligand in the synthetic method comprises the following steps: dissolving required amounts of 1, 3-diiodobenzene, imidazole, potassium hydroxide and cuprous oxide in dimethyl sulfoxide (DMSO) under an argon environment, reacting for 48 hours at 120 ℃, cooling the mixed solution to room temperature after the reaction is finished, pouring the cooled mixed solution into a mixed solvent of water and ethyl acetate with the volume ratio of 1:3, carrying out suction filtration, extracting the filtrate with ethyl acetate, drying, concentrating, and carrying out column chromatography purification to obtain the 1, 3-bis (1H-imidazol-1-yl) benzene 1, 3-bib ligand.
The reaction chain of the synthesis method of the binuclear aryl ruthenium metal complex is as follows:
compared with the prior art, the technical scheme of the invention has the beneficial effects that:
the preparation method has simple process flow, easy operation and high product yield; the prepared binuclear aryl ruthenium metal complex has good anticancer activity, can react with DNA (deoxyribonucleic acid), can be applied to preparation of anticancer drugs or anticancer drug components, and has high selectivity on cancer cells and normal cells, so that the binuclear aryl ruthenium metal complex has low toxic and side effects and high drug research value.
Drawings
FIG. 1 is a crystal structure diagram of a binuclear arylruthenium metal complex 3 obtained in example 3;
FIG. 2 is a crystal structure diagram of a binuclear aryl ruthenium metal complex 4 obtained in example 4;
FIG. 3 is a crystal structure diagram of a binuclear arylruthenium metal complex 6 obtained in example 6;
FIG. 4 is a circular dichroism diagram of the interaction between the binuclear aryl ruthenium metal complex 2 prepared in example 2 and DNA.
Detailed Description
The technical solutions of the present invention are further described below with reference to the drawings and the specific embodiments, but the scope of the present invention is not limited thereto.
Example 1
Dissolving 0.06mmol of dichloro (p-methylisopropylphenyl) ruthenium (II) dimer in acetonitrile under an argon atmosphere to prepare an initial solution; adding 0.4mmol of 1, 3-di (1H-imidazole-1-yl) benzene 1, 3-bib ligand into acetonitrile solution of dichloroaryl ruthenium dimer, reacting at 80 ℃ for 72H, and adding 1mmol of a required anion salt AgCF (ammonium dihydrogen phosphate) into the reaction solution3SO3Stirring for 4 hours at room temperature; filtering, concentrating the filtrate, and separating and purifying the crude product by column chromatography to obtain yellow powder binuclear aryl ruthenium metal complex 1 with the yield of 92.1 percent.
Elemental analysis: theoretical value (%): ru2C46H48Cl2N8F6S2O6·(C2H6O)1.5: c44.28, H4.32, N8.43; experimental values: c44.28, H4.04, N8.28.1H NMR(CDCl3-d，400MHz)：7.69(2H，m，Hbz，1，3-bib)，7.65(4H，s，Him)，7.47(4H，dd，J＝8.2Hz，J＝2.0Hz，Him)，7.36(4H，s，Hbz，1，3-bib)，7.24(6H，s，Hbz，1，3-bib)，5.94(4H，d，J＝5.7Hz，Hbz，p-cymene)，5.85(4H，d，J＝5.3Hz，Hbz，p-cymene)，2.45(2H，m，CH)，1.93(6H，s，CH3)，1.18(12H，d，J＝6.9Hz，CH3). ESI-MS (+): theoretical value: [1-CF ]3SO3]+m/z: 1111.03, Experimental value: m/z 1111.17.
Example 2
Dissolving 0.06mmol of dichloro (p-methylisopropylphenyl) ruthenium (II) dimer in chloroform under an argon atmosphere to prepare an initial solution; adding 0.2mmol of 1, 3-bis (1H-imidazole-1-yl) benzene 1, 3-bib ligand into a chloroform solution of dichloroaryl ruthenium dimer, reacting at 60 ℃ for 10 hours, adding 1mmol of needed anion salt KI into the reaction solution, and stirring at room temperature for 48 hours; filtering, concentrating the filtrate, and separating and purifying the crude product by column chromatography to obtain yellow powder binuclear aryl ruthenium metal complex 2 with the yield of 54.7%.
Elemental analysis: theoretical value (%): ru2(C20H28)(C24H20N8Cl2)I2·(C2H6O)1.5: c43.93, H4.47, N8.72; experimental values: c43.58, H4.60, N8.25.1H NMR(DMSO-d6，400MHz)：9.76(4H，s，Him)，8.71(2H，s，Hbz，1，3-bib)，8.06(4H，s，Him)，7.79(6H，d，J＝6.9Hz，Hbz，1，3-bib)，7.54(4H，s，Hbz，1，3-bib)，6.11(8H，s，Hbz，p-cymene)，2.56(2H，m，CH)，1.85(6H，s，CH3)，1.14(12H，d，J＝6.9Hz，CH3). ESI-MS (+): theoretical value: [2-I ]-]+m/z: 1090.75, Experimental value: m/z 1090.7, theoretical value: [2-2I ]-]2+m/z: 481.0, Experimental value: m/z 481.17.
Example 3
Dissolving 0.2mmol of dichloro (p-methylisopropylphenyl) ruthenium (II) dimer in dichloromethane under an argon atmosphere to prepare an initial solution; adding 0.05mmol of 1, 3-di (1H-imidazole-1-yl) benzene 1, 3-bib ligand into dichloromethane solution of dichloroaryl ruthenium dimer, reacting at 25 ℃ for 24H, and adding 1mmol of a required anion salt AgNO into the reaction solution3Stirring for 24 hours at room temperature; filtering, concentrating the filtrate, and separating and purifying the crude product by column chromatography to obtain yellow powder binuclear aryl ruthenium metal complex 3 with a yield of 55.4% and a crystal structure diagram shown in figure 1.
Elemental analysis: theoretical value (%): ru2C44H48Cl2N10O6·CH2Cl2: c46.16, H4.30, N11.96; experimental values: c46.60, H4.55, N11.98.1H NMR(DMSO-d6，400MHz)：10.34(4H，s，Him)，9.09(2H，s，Hbz，1，3-bib)，8.08(4H，t，J＝1.6Hz，Him)，7.77(4H，m，Hbz，1，3-bib)，7.73(2H，m，Hbz，1，3-bib)，7.48(4H，s，Hbz，1，3-bib)，6.09(8H，m，Hbz，p-cymene)，2.53(2H，m，CH)，1.82(6H，s，CH3)，1.14(12H，d，J＝1.9Hz，CH3). ESI-MS (+): theoretical value: [3-NO ]3 -]+m/z: 1023.96, Experimental value: m/z1023.23, theoretical value: [3-2NO ]3 -]2+m/z: 480.98, Experimental value: m/z 481.25.
Example 4
Dissolving 0.06mmol of dichloro (p-methylisopropylphenyl) ruthenium (II) dimer in methanol under an argon atmosphere to prepare an initial solution; adding 0.6mmol of 1, 3-di (1H-imidazole-1-yl) benzene 1, 3-bib ligand into methanol solution of dichloroaryl ruthenium dimer, reacting at 70 ℃ for 40H, and adding 1mmol of a required anion salt AgBF into the reaction solution4Stirring for 2 hours at room temperature; filtering, concentrating the filtrate, and separating and purifying the crude product by column chromatography to obtain yellow powder binuclear aryl ruthenium metal complex 4 with yield of 80.3%, wherein the crystal structure diagram is shown in figure 2.
Elemental analysis: theoretical value (%): ru2C44H48C14N8B2F8·C2H6O·(CH2Cl2)2: c42.66, H4.33, N8.29; experimental values: c42.42, H4.37, N8.28.1H NMR(DMSO-d6，400MHz)：10.24(4H，d，J＝1.4Hz，Him)，8.91(2H，d，J＝1.9Hz，Hbz，1，3-bib)，7.82(4H，t，J＝1.7Hz，Him)，7.70(4H，m，Hbz，1，3-bib)，7.65(6H，m，Hbz，1，3-bib)，6.06(8H，m，Hbz，p-cymene)，2.55(2H，m，CH)，1.94(6H，s，CH3)，1.23(12H，d，J＝6.9Hz，CH3). ESI-MS (+): theoretical value: [4-BF ]4 -]+m/z: 1048.76, Experimental value: m/z1049.08, theoretical value: [4-2BF ]4 -]2+m/z: 481.0, Experimental value: m/z 481.25.
Example 5
Dissolving 0.05mmol of dichloro (p-methylisopropylphenyl) ruthenium (II) dimer in ethanol under an argon atmosphere to prepare an initial solution; adding 1.0mmol of 1, 3-di (1H-imidazole-1-yl) benzene 1, 3-bib ligand into an ethanol solution of dichloroaryl ruthenium dimer, reacting at 80 ℃ for 30H, and adding 1mmol of a required anion salt AgPF into the reaction solution6Stirring for 16h at room temperature; filtering, concentrating the filtrate, and separating and purifying the crude product by column chromatography to obtain the yellow powder binuclear aryl ruthenium metal complex 5 with the yield of 89.2 percent.
Elemental analysis: theoretical value (%): ru2C44H48N8Cl2P2F12·H2O: c41.62, H3.97, N8.83; experimental values: c41.40, H3.18, N8.38.1H NMR(DMSO-d6，400MHz)：9.05(4H，s，Him)，8.14(2H，s，Hbz，1，3-bib)，7.81(4H，m，Him)，7.74(7H，m，Hbz，1，3-bib)，7.66(3H，m，Hbz，1，3-bib)，5.90(8H，dd，J＝6.29Hz，J＝6.0Hz，Hbz，p-cymene)，2.55(2H，m，CH)，1.88(6H，s，CH3)，1.23(12H，d，J＝6.9Hz，CH3). ESI-MS (+): theoretical value: [5-PF6 -]+m/z: 1106.9, Experimental value: m/z 1108.0, theoretical value: [5-2PF6 -]2+m/z: 481.0, Experimental value: m/z 481.25.
Example 6
Dissolving 0.06mmol of dichloro (biphenyl) ruthenium (II) dimer in chloroform under an argon atmosphere to prepare an initial solution; adding 0.2mmol of 1, 3-bis (1H-imidazole-1-yl) benzene 1, 3-bib ligand (1, 3-bib for short) into a chloroform solution of dichloroaryl ruthenium dimer, reacting at 70 ℃ for 10 hours, adding 1mmol of needed anion salt NaCl into a reaction solution, stirring at room temperature for 2 hours, filtering, concentrating a filtrate, and separating and purifying a crude product through column chromatography to obtain a yellow powder binuclear aryl ruthenium metal complex 6, wherein the yield is 78.9%, and the crystal structure diagram is shown in figure 3.
Elemental analysis: theoretical value (%): ru2C48H44N8Cl4·C5H12·(H2O)0.5: c, 43.69; h, 2.44; n, 5.66; experimental values: c, 43.82; h, 2.49; and N, 5.59.1H NMR(DMSO-d6，400MHz)：10.37(4H，s，Him)，9.09(2H，s，Hbz，1，3-bib)，8.11(4H，t，Him)，7.80(4H，m，Hbz，1，3-bib)，7.74(2H，m，Hbz，1，3-bib)，7.50(4H，s，Hbz，1，3-bib)，6.11(4H，d，Hbz，p-cymene)，6.07(4H，d，Hbz，p-cymene)，2.57(2H，m，CH)，1.84(6H，s，CH3)，1.16(12H，d，CH3).ESI-MS(+)：calcd.for[2-Cl-]+m/z：997.42，foundm/z 998.92，calcd.for[6-2C1-]2+m/z：480.98，found m/z 475.55。
Table 1 shows X-ray single crystal diffraction detection data of the dinuclear aryl ruthenium metal complex crystals obtained in example 3, example 4 and example 6.
TABLE 1 data sheet for X-ray single crystal diffraction detection of crystals
With the increase of the reaction time and the increase of the reaction temperature in the embodiments 1 to 6, the yield of the product is in an increasing trend, and meanwhile, the difference of the reaction raw materials also has a certain influence on the yield.
The binuclear aryl ruthenium metal complex has the following effects on tumor cells and normal human body cells:
the method comprises the following steps: MTT colorimetric method, which is used for measuring the in vitro anticancer activity of human cancer cell lines (Hela (cervical cancer), MCF7 (breast cancer), HepG2 (hepatocellular carcinoma), A549 (non-small cell lung cancer)) and the in vitro toxic and side effects of human normal cells L02 (liver cells). Hela, MCF7, HepG2, A549 and L02 cells in the presence of 10% fetal bovine serumAnd 1% penicillin-streptomycin solution in DMEM medium at 37 deg.C and 5% CO2Culturing in a cell culture box. Cells were seeded at an initial density of 5000 cells/well in 96-well cell culture plates, the medium was removed after 24 hours of culture, eight parallel control experiments were performed, complexes 1-6, 1, 3-bib and Cisplatin (CDDP) at the same concentrations were added to the eight experiments, and incubation was continued for 48 hours. Thereafter, 10. mu.L of 5mg/mL MTT was added to each well, incubated for 4h, and finally the medium was removed, 150mL DMSO was added, and the absorbance at 490nm was read on an ELIASA (TecanInfinite M1000 Pro) plate reader.
TABLE 2 IC of complexes 1-6, 1, 3-bib and Cisplatin (CDDP)50Value of (. mu.M)
The results show that complex 2 shows higher anticancer activity, shows moderate antiproliferative activity on A549 cancer cells, and has relatively lower cytotoxicity (IC) on normal cells L0250215.9 μ M), cell activity selective factor for complex 2 (IC of SF L02 normal cells)50IC of A549 cells50) 7.0, higher than CDDP (SF ═ 3.3). The anticancer drug prepared by the complex has high selectivity on cancer cells and normal cells, so that the potential side effects of patients are reduced, and the low toxic and side effects and the drug research value of the anticancer drug are reflected.
The application of the binuclear aryl ruthenium metal complex 2 prepared in the embodiment 2 of the invention in the action of DNA is as follows:
the method comprises the following steps: circular dichroism chromatography. The interaction of the complex with CT-DNA was studied by CD spectroscopy in PBS buffer (50mM, pH 7.2). Preparation of [ complexes ] containing different molar ratios]/[CT-DNA]And incubated at 37 ℃ for 24 hours. Initial concentration of CT-DNA was set to 100. mu.M, and [ Complex ] was prepared]/[CT-DNA]A series of samples to be tested with the molar ratio of 0.01-0.07 increasing continuously. CD spectra were recorded in cuvettes with 1cm path, scan range set at 200-350nm, scan rate at 100 nm-min-1The slit width was 1 nm.
The effect of the binuclear aryl ruthenium metal complex 2 prepared in example 2 on DNA is shown in FIG. 4, and the intensity of the positive and negative signals of the complex 2 gradually decreases without shifting with the increase of the molar ratio of [ complex ]/[ CT-DNA ], which further confirms that the aryl ruthenium (II) complex can bind to CT-DNA. The complex 2-induced conformational change in DNA can be clearly seen from the CD spectrum, where the intensity of the positive and negative peaks decreases with increasing concentration of complex 2, indicating that an extended benzene ring is inserted into the DNA.
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious variations or modifications which fall within the spirit of the invention are intended to be covered by the scope of the present invention.
Claims (4)
1. A binuclear aryl ruthenium metal complex is characterized by having the following structural general formula:
wherein:
is p-cymene, X is Cl-Y is I-；
The binuclear aryl ruthenium metal complex is prepared by the following method, and specifically comprises the following steps:
step 1, dissolving 0.06mmol of dichloro (p-methylisopropylphenyl) ruthenium (II) dimer in chloroform under an argon atmosphere to prepare an initial solution;
step 2, 0.2mmol of 1, 3-bis (1H-imidazol-1-yl) benzene 1,3-Adding the bib ligand into a chloroform solution of dichloroaryl ruthenium dimer, and reacting at 60 ℃ for 10 hours to obtain a mixed solution;
step 3, adding 1mmol of anion salt KI into the mixed solution in the step 2, and stirring for 48 hours at room temperature; filtering, concentrating the filtrate, and separating and purifying the crude product by column chromatography to obtain the binuclear aryl ruthenium metal complex.
2. The dinuclear aryl ruthenium metal complex according to claim 1, wherein: the 1, 3-di (1H-imidazol-1-yl) benzene 1,3-The preparation of the bib ligand is as follows: dissolving required amounts of 1, 3-diiodobenzene, imidazole, potassium hydroxide and cuprous oxide in dimethyl sulfoxide under an argon environment, reacting for 48 hours at 120 ℃, cooling the mixed solution to room temperature after the reaction is finished, pouring the cooled mixed solution into a mixed solvent of water and ethyl acetate with a volume ratio of 1:3, performing suction filtration, extracting the filtrate with ethyl acetate, drying, concentrating, and performing column chromatography purification to obtain 1, 3-bis (1H-imidazol-1-yl) benzene 1,3-A bib ligand.
3. The use of the dinuclear ruthenium arylcomplex of claim 1 for the preparation of anticancer drugs and anticancer drug components.
4. The use of the dinuclear ruthenium aryl complex of claim 3 for the preparation of anticancer drugs and anticancer drug components, characterized in that: including cervical cancer, breast cancer, liver cancer and lung cancer.
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