CN112062790A - 5-Fu-ruthenium (II) complex with anti-tumor and antibacterial activities and preparation method and application thereof - Google Patents
5-Fu-ruthenium (II) complex with anti-tumor and antibacterial activities and preparation method and application thereof Download PDFInfo
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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
- 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
- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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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 provides a 5-Fu-ruthenium (II) complex with antitumor and antibacterial activities, and a preparation method and application thereof, wherein the 5-Fu-ruthenium (II) complex has a structure shown in a formula I. Because the metal ions are contained and have charges, compared with the traditional organic micromolecules, the in vivo permeation and retention effects are enhanced, and the metal complex has a multi-coordination configuration, so that modification of different ligands can be carried out, and the excellent biological activity of the metal complex is realized. Experimental results show that the 5-Fu-ruthenium (II) complex provided by the invention not only has excellent anti-tumor activity, but also has certain bacteriostatic activity. The complex enters cells mainly in an energy-dependent mode, is positioned in lysosomes, causes the intracellular reactive oxygen level to be increased, and blocks the cell cycle in a concentration-dependent mode in a G0/G1 phase, and finally induces apoptosis and autophagy of cancer cells. The complex has a certain inhibiting effect on staphylococcus aureus and pseudomonas aeruginosa.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a 5-Fu-ruthenium (II) complex with antitumor and antibacterial activities, and a preparation method and application thereof.
Background
5-fluorouracil (5-Fu) is used as an antimetabolite for inhibiting thymidylate synthase, has a structure similar to that of uracil, a metabolite in tumor cells, competes with each other in the same system enzyme, blocks metabolic links, and blocks DNA synthesis, thereby inhibiting proliferation of tumor cells, but has limited therapeutic effects and long-term application due to low selectivity, significant first-pass metabolism, low lipophilicity and narrow therapeutic window. The transition metal ruthenium compound not only has good physicochemical characteristics of large Stokes shift, photobleaching resistance, long phosphorescence lifetime, high quantum yield and the like, but also has easily modified ligands, and can introduce functional groups with different characteristics into the ruthenium complex. With the continuous and intensive research, people also find that the transition metal ruthenium complex not only has excellent antitumor activity, but also has the advantages of strong drug effect, low toxicity, low drug resistance and the like, and has stronger antibacterial activity and good biocompatibility. The 5-Fu derivative is coordinated with the ruthenium metal, so that the defects of the traditional chemotherapeutic drugs are overcome, and the drugs with better biological activity can be developed.
There are two types of common pathways for apoptosis (PCD): type I PCD: apoptosis and ii PCD: autophagy. Tumor cells can cause apoptosis through a death receptor pathway or a mitochondrial pathway, for example, activation of death receptors, mitochondrial dysfunction, endoplasmic reticulum stress and the like can activate a downstream cysteine protease Caspase family, and then the cells show a series of apoptosis characteristics such as apoptotic bodies, cell volume reduction, nuclear shrinkage, fragmentation and the like. Autophagy is a catabolic pathway that maintains cell homeostasis by digesting cytoplasmic components and damaged organelles within cytoplasmic vesicles (called lysosomes) to provide energy and nutrient sources for the cell. When the cells are not sufficiently resistant to external stimuli, autophagy is excessive, a large amount of cytoplasm is decomposed, and finally autophagic death occurs. A complex relationship exists between apoptosis and autophagy, and the two can exist synergistically and mutually antagonize.
The mortality rate and chemotherapy failure caused by malignant tumor lead to the annual rise of the incidence of drug-resistant bacterial infection, and seriously threaten the survival of human beings. The situation of low immune system can not be avoided in the chemotherapy treatment process, so that how to effectively treat the tumor and the infection caused by drug-resistant bacteria becomes an urgent problem to be solved. Therefore, the design and synthesis of the novel ruthenium complex with the dual biological activities of anticancer and antibiosis undoubtedly provides a feasible strategy for future cancer treatment.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a 5-Fu-ruthenium (ii) complex with anti-tumor and anti-bacterial activities, a preparation method and an application thereof, wherein the prepared 5-Fu-ruthenium (ii) complex has both anti-tumor and anti-bacterial activities.
In order to achieve the above purpose, the invention provides a series of ruthenium (II) complexes taking 5-Fu derivatives as ligands, and the chemical general formula is [ Ru (N-N)2L](PF6)2Wherein the ligand L is 1- ((1, 10-phenanthroline-5-amino) pentyl) -5-fluorouracil (L), and N-N are respectively 2, 2-bipyridyl (bpy) and recorded as Ru 1; 1, 10-phenanthroline (phen), noted Ru 2; 4, 7-Diphenyl-1, 10-phenanthroline (dip), noted as Ru 3.
Specifically, the 5-Fu-ruthenium (II) complex has a structure shown in a formula I:
wherein,
selected from any of the following structures:
the single bond represents a connecting position.
Preferably, the 5-Fu-ruthenium (II) complex has any one of the following Ru-1-Ru-3 structures:
preferably, the anion of the 5-Fu-ruthenium (II) complex is PF6 -。
The invention discloses a preparation method of the 5-Fu-ruthenium (II) complex, which comprises the following steps:
A) reacting the 5-fluorouracil derivative shown in the formula I-a with [1,10] -phenanthroline-5-amino shown in the formula I-b to obtain a ligand shown in the formula I-c;
B) reacting the ligand shown in the formula I-c with a metal ruthenium complex shown in the formula I-d, the formula I-e or the formula I-f to obtain a 5-Fu-ruthenium (II) complex shown in the formula I;
X1、X2independently selected from halogens.
Preferred of the invention, X1Is Br.
Preferred of the invention, X2Is Cl.
The ligand (shown in formula I-c) is prepared by reacting 1- (5-bromopentyl) -5-fluorouracil (shown in formula I-a) with [1,10] -phenanthroline-5-amino (shown in formula I-b).
The sources of the above-mentioned 1- (5-bromopentyl) -5-fluorouracil and [1,10] -phenanthroline-5-amino group in the present invention are not particularly limited, and they may be generally commercially available or prepared by a method known to those skilled in the art.
The above reaction is preferably carried out under the catalytic action of a catalyst.
Specifically, 1- (5-bromopentyl) -5-fluorouracil and [1,10] -phenanthroline-5-amino are respectively dissolved in an organic solvent and react under the catalytic action of a catalyst.
The organic solvent is preferably N, N-dimethylformamide.
The catalyst is preferably tris (dibenzylideneacetone) dipalladium, tris (o-methylphenyl) phosphorus, sodium tert-butoxide and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine.
The mass ratio of the tris (dibenzylideneacetone) dipalladium, the tris (o-methylphenyl) phosphorus, the sodium tert-butoxide and the 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine is preferably (3-5): (4-6): (20-25): (8-10).
The reaction is preferably carried out in an inert atmosphere.
The inert gas atmosphere in the present invention is not particularly limited, and may be an inert gas atmosphere known to those skilled in the art, and preferably a nitrogen or argon atmosphere.
The temperature of the reaction is preferably 80-120 ℃; the time is preferably 4 to 12 hours.
After the reaction is finished, the post-treatment is carried out, preferably in the invention, the reaction solution is cooled, diluted with ether, filtered with kieselguhr, washed with ether, the organic phases are combined and concentrated to obtain the ligand.
Then the ligand reacts with the metal ruthenium complex shown in the formula I-d, the formula I-e or the formula I-f to obtain the 5-Fu-ruthenium (II) complex shown in the formula I.
Preferably, the reaction is carried out in an ethylene glycol solution under reflux.
Preferably, the reaction is carried out under protection from light.
The reaction is preferably carried out in an inert atmosphere.
The inert gas atmosphere in the present invention is not particularly limited, and may be an inert gas atmosphere known to those skilled in the art, and preferably a nitrogen or argon atmosphere.
After the reaction is completed, it is preferable to add an excess of saturated NH to the system4PF6And collecting the precipitated solid, namely the 5-Fu-ruthenium (II) complex.
Specifically, after the reaction is finished, adding the catalyst into the systemExcess saturated NH4PF6And (3) removing most of the solvent after the solution and the reaction are finished, and dripping the residual system into ether to separate out a solid, namely the 5-Fu-ruthenium (II) complex.
The above reaction is shown in the following reaction scheme:
the invention detects the antitumor activity and the antibacterial activity of the cyclometalated iridium complex, and preferably specifically comprises the following operation steps:
1) the detection of the antitumor activity mainly comprises the following operation steps: when the cells grew to log phase, the cells were digested with 0.25% trypsin into single cell suspensions, viable cells were counted, 160 μ Ι _ of cells per well 4,000 were seeded in 96-well plates, and the empty wells at the edges could be filled with PBS. CO 22After 24h of culture in an incubator, 40 mu L of drugs with different concentrations diluted by the culture medium are respectively added, then the culture is incubated for 44h in the incubator, 20 mu L of MTT (dissolved by PBS) is added into each hole, the culture medium is sucked off after 4h, 150 mu L of DMSO is added into each hole, the light is kept out, the shaking table is shaken for about 10min, and the OD value at 595nm is immediately measured by a microplate reader. Calculating cell viability according to the formula, and plotting to obtain half lethal concentration (IC)50A value); the assay provides a reliable screening method based on classical MTT assays that can be used to directly determine whether a compound has anti-tumor activity.
Survival%
Therefore, the 5-Fu-ruthenium (II) complex prepared by the invention can be used for preparing antitumor drugs. Preferably, the tumor is a solid tumor. More preferably, the tumor is a Hela tumor cell.
2) Determination of antibacterial Activity by MicrometryMIC determination by double dilution method: culturing Staphylococcus aureus and Pseudomonas aeruginosa. Culturing to logarithmic phase, centrifuging, removing supernatant, washing with PBS, resuspending with LB culture medium, and diluting to 1 × 106CFU/mL. Sterile 96-well plates were taken and the complexes were serially diluted in LB medium in 100. mu.L volume on sterile 96-well plates. Diluted bacterial suspension (100 μ L) was added to 96-well plates, at which point the final drug concentration per well was, from left to right: 20, 10, 5, 2.5, 1.25, 0.625, 0.3125, 0.15625, 0.078, 0.039, 0.0195, 0.0098 uM; setting negative control (only adding blank broth without adding bacteria liquid) and positive control (adding bacteria liquid without adding liquid) at the same time, and operating the other medicines as above; after placing the 96-well plate in a 37-degree incubator for 18 hours, the results were observed. And (4) observing the turbidity of the pore plate, wherein the minimum drug concentration corresponding to the clear administration pore is MIC (minimum inhibitory concentration).
Therefore, the 5-Fu-ruthenium (II) complex prepared by the invention can be used for preparing antibacterial drugs. Preferably, the bacterial species are gram-positive bacteria and/or gram-negative bacteria, and further preferably, the bacterial species are staphylococcus aureus and/or pseudomonas aeruginosa.
The experimental result shows that the 5-Fu-ruthenium (II) complex provided by the invention can specifically target lysosome, simultaneously induce tumor cells, particularly Hela cells to generate autophagy and apoptosis, and has antibacterial activity.
Particularly, the complex Ru3 has certain selectivity on normal cells, has excellent anti-tumor activity on Hela cells, can specifically target lysosomes, induce cell death through apoptosis and autophagy, and kill Hela cells in a targeted manner, and has certain antibacterial activity on staphylococcus aureus and pseudomonas aeruginosa.
Therefore, the 5-Fu-ruthenium (II) complex provided by the invention can be used for preparing medicines with dual anti-tumor and antibacterial activities.
Experimental results show that the 5-Fu-ruthenium (II) complex provided by the invention has excellent anti-tumor activity, particularly has the best Ru3 activity, and has IC (integrated Circuit) on cervical cancer cells507.35. + -. 0.39. mu.M for normal cellsIC of5036.64 ± 2.73 μ M, selectivity factor (SI) 5. Ru3 can be seen to selectively kill tumors, and the mechanism research shows that the complex mainly plays a role through apoptosis and autophagy. It is noted that Ru3 also has some antibacterial activity, with MIC 2.5 μ M for staphylococcus aureus and MIC 10 μ M for pseudomonas aeruginosa. Therefore, Ru3 has dual activities of anti-tumor and anti-bacterial.
Based on the above, the invention provides the application of the 5-Fu-ruthenium (II) complex or the 5-Fu-ruthenium (II) complex prepared by the preparation method in preparing an anti-tumor drug or an antibacterial drug.
The invention provides the application of the 5-Fu-ruthenium (II) complex or the 5-Fu-ruthenium (II) complex prepared by the preparation method in preparing a multifunctional medicine which can simultaneously induce autophagy and apoptosis of tumor cells and has antibacterial activity.
In the present invention, the tumor cell is preferably a solid tumor cell, and more preferably a Hela cell.
The species against which the antimicrobial activity is directed is preferably a gram-positive and/or gram-negative bacterium.
The gram positive bacterium is preferably staphylococcus aureus.
The gram-negative bacteria are preferably pseudomonas aeruginosa.
Compared with the prior art, the invention provides a 5-Fu-ruthenium (II) complex which has a structure shown in a formula I. The metal complex has a multi-coordination configuration, and can be modified by different ligands to realize excellent biological activity. Experimental results show that the 5-Fu-ruthenium (II) complex provided by the invention not only has excellent anti-tumor activity, but also has certain bacteriostatic activity. The anti-tumor action mechanism of the complex is further intensively studied, and the complex is found to enter cells mainly in an energy-dependent mode, is positioned on lysosomes, causes the increase of intracellular active oxygen level, blocks the cell cycle in a concentration-dependent mode in G0/G1, and finally induces the apoptosis and autophagy of cancer cells. In addition, antibacterial activity experiments show that the complex has a certain inhibiting effect on staphylococcus aureus and pseudomonas aeruginosa. Therefore, the 5-Fu-ruthenium (II) complex provided by the invention has certain potential in the aspects of tumor resistance and bacteriostasis.
Drawings
FIG. 1 is a graph of the dose-dependent effect of complex Ru3 on LC3 protein in example 2;
FIG. 2 is a graph of the dose-dependent effect of complex Ru3 on related apoptotic proteins in example 2;
FIG. 3 is a graph of the MIC determination of ligand L and complex Ru1-Ru3 against Staphylococcus aureus in example 3;
FIG. 4 is a graph of the MIC determination of ligand L and complex Ru1-Ru3 for Pseudomonas aeruginosa in example 3.
Detailed Description
In order to further illustrate the present invention, the following examples are given to describe the 5-Fu-ruthenium (ii) complex with antitumor and antibacterial activities, and the preparation method and application thereof.
Example 1 preparation example
(1) Preparation of ligand L:
take 0.128g of [1,10]]Dissolving phenanthroline-5-amino (0.66mmol) in an appropriate amount of N, N-dimethylformamide, heating and stirring for 30min, and then taking 1- (5-bromopentyl) -5-fluorouracil (0.194g,0.66mmol), tris (dibenzylideneacetone) dipalladium (0.006g,0.007mmol) as a catalyst, and tris (o-tolylene) phosphorus (abbreviation: P (o-tolyl)30.008g, 0.026mmol), sodium tert-butoxide (abbreviation: NaOt-Bu, 0.041g, 0.43mmol) and 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (0.016g, 0.026mmol), adding 10mL of N, N-dimethylformamide under the protection of Ar, refluxing at 100 ℃ for 12h, after the reaction solution is cooled, diluting with a proper amount of diethyl ether, filtering with diatomite, washing with diethyl ether, combining the organic phases, and concentrating as much as possible. Yield: 32.5 percent.
Elemental analysis C21H20FN5O2(molecular weight 393.41), theoretical value: c64.11%, H5.12%, N17.80%; experimental values: c64.43%, H5.01%, N17.50%.
ESI-MS：[(M+H)]+Theoretical value: m/z 394.41, experimental value: 394.1.
(2) Preparation of the Complex Ru1
Ligand L (0.125mmol,1equiv) and precursor cis-Ru (bpy)2Cl2·2H2Placing O (0.125mmol,1equiv) in a three-neck flask, adding 10mL of glycol solvent, refluxing for 6h in the dark under the protection of argon, standing and cooling to room temperature after the reaction is finished, and adding excessive NH4PF6Stirring to generate a large amount of reddish brown precipitate, filtering, separating and purifying by silica gel column chromatography, and drying to obtain the complex Ru1 with the yield of 56.6%.
Elemental analysis C41H36F13N9O2P2Ru (molecular weight 1096.78), theoretical value: 44.90% of C, 3.31% of H and 11.49% of N; experimental values: c44.65%, H3.21%, N11.66%.
ESI-MS：[(M–PF6)]+Theoretical value: m/z 951.82, experimental value: 951.7; [ (M-2 PF)6)]2+Theoretical value: m/z 403.43, experimental value: 403.7.
(3) Preparation of the Complex Ru2
Ligand L (0.125mmol,1equiv) and precursor cis-Ru (phen)2Cl2·2H2Placing O (0.125mmol,1equiv) in a three-neck flask, adding 10mL of glycol solvent, refluxing for 6h in the dark under the protection of argon, standing and cooling to room temperature after the reaction is finished, and adding excessive NH4PF6Stirring to generate a large amount of reddish brown precipitate, filtering, separating and purifying by silica gel column chromatography, and drying to obtain the complex Ru2 with the yield of 54.2%.
Elemental analysis C45H36F13N9O2P2Ru (molecular weight 1144.82), theoretical value: 47.21% of C, 3.17% of H and 11.01% of N; experimental values: 47.56% of C, 3.34% of H and 10.88% of N.
ESI-MS：[(M–PF6)]+Theoretical value: m/z 999.86, experimental value: m/z is 1000.0; [ (M-2 PF)6)]2+Theoretical value: m/z 427.45, experimental value: m/z is 427.4。
(4) Preparation of the Complex Ru3
Ligand L (0.125mmol,1equiv) and precursor cis-Ru (dip)2Cl2·2H2Placing O (0.125mmol,1equiv) in a three-neck flask, adding 10mL of glycol solvent, refluxing for 6h in the dark under the protection of argon, standing and cooling to room temperature after the reaction is finished, and adding excessive NH4PF6Stirring to generate a large amount of reddish brown precipitate, filtering, separating and purifying by silica gel column chromatography, and drying to obtain the complex Ru3 with the yield of 50.7%.
Elemental analysis C69H52F13N9O2P2Ru (molecular weight 1449.21), theoretical value: c57.19%, H3.62%, N8.70%; experimental values: c56.90%, H3.75%, N8.92%.
ESI-MS：[(M–PF6)]+Theoretical value: m/z 1305.24, experimental value: m/z is 1305.8; [ (M-2 PF)6 -)]2+Theoretical value: m/z 579.64, experimental value: 579.8.
Example 2 in vitro antitumor Activity assay
(1) Antitumor activity test (MTT method): the antitumor capacity of the 5-Fu-ruthenium (II) complex is mainly determined by the MTT method: the MTT method is a classical method for determining drug toxicity, and the procedure is roughly as follows, 4,000 Hela cells, CO are added to 96-well culture plates2After 24h of culture in an incubator, drugs with different concentrations diluted by the culture medium are respectively added, then the culture is incubated for 44h in the incubator, MTT is added, the culture medium is sucked off after 4h, DMSO is added, and the OD value at 595nm is measured after shaking up.
The test results are shown in table 1 below:
TABLE 15 results of in vitro antitumor Activity of Fu-ruthenium (II) Complex
aIC50The concentration of the corresponding complex at which tumor Hela is inhibited by 50%. The experimental data are three parallel experimentsMean values obtained after the experiment.bSI is a selectivity index, which is numerically equal to the IC of normal cells50Specific IC of tumor cells50The value is obtained.
As can be seen from the experimental results, the complex Ru3 not only has excellent antitumor activity and IC50It is only 7.35 +/-0.39 mu M and has certain selectivity.
(2) Western Blot analysis: hela cells are cultured in a tissue culture dish with the thickness of 60mm, when the cell density reaches 70%, the complex Ru3 with the specified concentration is added, a protein sample is collected after incubation for 24h, the prepared protein sample is denatured at the high temperature of 95 ℃, then SDS-PAGE gel electrophoresis is used for separating the needed protein, membrane transfer, blocking, primary antibody incubation (the primary antibodies are respectively PARP, Caspase35/17, Bax, Bcl-2 and LC3A/B), secondary antibody incubation and protein detection are carried out.
The results are shown in FIGS. 1 and 2, and Ru3 up-regulated Caspase17 and poly ADP ribose polymerase PARP by activating Caspase activity and fragmented in a dose-dependent manner. Meanwhile, the expression of an anti-apoptotic protein Bcl-2 is down-regulated and the expression of a pro-apoptotic protein Bax is up-regulated, which indicates that the complex Ru3 induces apoptosis in a Caspase-dependent mode. The complex Ru3 can realize the conversion of LC3-I to LC3-II in the aspect of inducing autophagy, remarkably down-regulates the expression of LC3-I and up-regulates the expression of LC3-II protein compared with a blank control, and presents obvious concentration dependence. Further indicates that the complex Ru3 can induce apoptosis and autophagy of cells.
(3) Determining MIC by a micro double dilution method: culturing Staphylococcus aureus and Pseudomonas aeruginosa. Bacteria were cultured overnight to logarithmic growth phase. The bacterial solution was centrifuged, the supernatant was removed, washed with PBS, then resuspended in LB medium and diluted to 1 × 106CFU/mL. Sterile 96-well plates were taken and the complexes were serially diluted in LB medium in 100. mu.L volume on sterile 96-well plates. Diluted bacterial suspension (100 μ L) was added to 96-well plates, at which point the final drug concentration per well was, from left to right: 20, 10, 5, 2.5, 1.25, 0.625, 0.3125, 0.15625, 0.078, 0.039, 0.0195 and 0.0098 mu M. Setting negative control (only adding blank broth without adding bacteria liquid) and positive control (adding bacteria liquid without adding liquid), and adding other medicinesThe operation of the materials is the same as the above; the 96-well plate was placed in a 37 ℃ incubator for 18 hours. And (4) observing the turbidity of the pore plate, wherein the minimum drug concentration corresponding to the clear administration pore is MIC (minimum inhibitory concentration). The results are shown in FIGS. 3 and 4, wherein FIG. 3 is a graph of MIC determination of ligand L and complex Ru1-Ru3 against Staphylococcus aureus. FIG. 4 is a graph showing MIC determination of ligand L and complex Ru1-Ru3 for Pseudomonas aeruginosa.
In fig. 3 and 4, the bacteriostatic effect of the ligand L and the complex Ru1-Ru3 on staphylococcus aureus and pseudomonas aeruginosa was judged by observing the turbidity degree of the well plate, wherein the lowest drug concentration corresponding to the clear administration well was the MIC-minimum inhibitory concentration.
The test result shows that the ligand L, the ligand Ru1 and the ligand Ru2 have poor antibacterial activity, while the ligand Ru3 has obvious antibacterial activity, and the MIC of the ligand L, the ligand Ru1 and the ligand Ru2 is 2.5 mu M for staphylococcus aureus and 10 mu M for pseudomonas aeruginosa, which indicates that the ligand Ru3 has certain antibacterial activity.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A5-Fu-ruthenium (II) complex having the structure shown in formula I:
wherein,
selected from any of the following structures:
2. the 5-Fu-ruthenium (ii) complex of claim 1, having any of the following Ru-1 to Ru-3 structures:
3. the 5-Fu-ruthenium (II) complex of claim 1, wherein the anion is PF6 -。
4. The process for preparing a 5-Fu-ruthenium (ii) complex according to any of claims 1 to 3, comprising:
A) reacting the 5-fluorouracil derivative shown in the formula I-a with [1,10] -phenanthroline-5-amino shown in the formula I-b to obtain a ligand shown in the formula I-c;
B) reacting a ligand shown as a formula I-c with a metal ruthenium complex shown as a formula I-d, a formula I-e or a formula I-f to obtain a 5-Fu-ruthenium (II) complex shown as a formula I;
X1、X2independently selected from halogens.
5. The method according to claim 4, wherein the reaction temperature in step A) is 80-120 ℃; the time is 4-12 h;
the step A) is carried out under the action of a catalyst;
the catalyst is tris (dibenzylideneacetone) dipalladium, tris (o-methylphenyl) phosphorus, sodium tert-butoxide and 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine.
6. The preparation method according to claim 4, wherein the reaction of step B) is specifically:
the reaction was carried out under reflux in an ethylene glycol solution.
7. The method of claim 4, further comprising, after step B):
after the reaction is completed, excess saturated NH is added to the system4PF6And (4) collecting precipitated solid.
8. Use of the 5-Fu-ruthenium (ii) complex according to any one of claims 1 to 3 or the 5-Fu-ruthenium (ii) complex prepared by the preparation method according to any one of claims 4 to 7 in the preparation of an antitumor drug or an antibacterial drug.
9. Use of the 5-Fu-ruthenium (ii) complex according to any one of claims 1 to 3 or the 5-Fu-ruthenium (ii) complex prepared by the preparation method according to any one of claims 4 to 7 for the preparation of a multifunctional medicament capable of simultaneously inducing autophagy and apoptosis in tumor cells and having antibacterial activity.
10. The use of claim 8 or 9, wherein the tumor cell is a solid tumor cell;
the bacterial species against which the antimicrobial activity is directed are gram-positive bacteria and/or gram-negative bacteria.
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|---|---|---|---|---|
| CN113336797A (en) * | 2021-04-06 | 2021-09-03 | 江西科技师范大学 | Ruthenium polypyridine complex with triphenylphosphine structure and preparation method and application thereof |
| CN118373857A (en) * | 2024-04-30 | 2024-07-23 | 广东医科大学 | Biguanide-ruthenium complex and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275077A (en) * | 2013-01-29 | 2013-09-04 | 中山大学 | Ruthenium complex and preparation method thereof and purpose of product as histone deacetylase inhibitor |
| US20160347779A1 (en) * | 2015-05-29 | 2016-12-01 | University Of Macau | Method for antagonizing stat3 dimerization and compounds for use therein |
-
2020
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275077A (en) * | 2013-01-29 | 2013-09-04 | 中山大学 | Ruthenium complex and preparation method thereof and purpose of product as histone deacetylase inhibitor |
| US20160347779A1 (en) * | 2015-05-29 | 2016-12-01 | University Of Macau | Method for antagonizing stat3 dimerization and compounds for use therein |
Non-Patent Citations (5)
| Title |
|---|
| AOI SON 等: "Phosphorescent Ruthenium Complexes with a Nitroimidazole Unit that Image Oxygen Fluctuation in Tumor Tissue", 《CHEM. EUR. J.》 * |
| LELI ZENG 等: "Ruthenium(II) Complexes with 2-Phenylimidazo[4,5-f][1,10] phenanthroline Derivatives that Strongly Combat Cisplatin-Resistant Tumor Cells", 《SCIENTIFIC REPORTS》 * |
| NAN-LIAN PAN 等: "Lysosome-targeted ruthenium(II) complexes induce both apoptosis and autophagy in HeLa cells", 《JOURNAL OF INORGANIC BIOCHEMISTRY》 * |
| YAN ZHANG 等: "Synthesis, characterization and anticancer activity of dinuclear ruthenium( II ) complexes linked by an alkyl chain", 《NEW J. CHEM.》 * |
| ZUANDI LUO 等: "Ruthenium polypyridyl complexes as inducer of ROS-mediated apoptosis in cancer cells by targeting thioredoxin reductase", 《METALLOMICS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336797A (en) * | 2021-04-06 | 2021-09-03 | 江西科技师范大学 | Ruthenium polypyridine complex with triphenylphosphine structure and preparation method and application thereof |
| CN113336797B (en) * | 2021-04-06 | 2022-09-27 | 江西科技师范大学 | Ruthenium polypyridine complex with triphenylphosphine structure and preparation method and application thereof |
| CN118373857A (en) * | 2024-04-30 | 2024-07-23 | 广东医科大学 | Biguanide-ruthenium complex and preparation method and application thereof |
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