CN112062790A - A kind of 5-Fu-ruthenium (II) complex with antitumor and antibacterial activity and its preparation method and application - Google Patents

Abstract

The present invention provides a 5-Fu-ruthenium(II) complex with antitumor and antibacterial activities, a preparation method and application thereof, and the 5-Fu-ruthenium(II) complex has the structure shown in formula I. Due to the inclusion of metal ions and charges, compared with traditional organic small molecules, the in vivo penetration and retention effects are enhanced, and the metal complexes have a multi-coordination configuration, which can be modified with different ligands to achieve their excellent biological properties. active. The experimental results show that the 5-Fu-ruthenium (II) complex provided by the present invention not only has excellent antitumor activity, but also has certain antibacterial activity. The complexes enter cells mainly in an energy-dependent manner and localize to lysosomes, causing an increase in the level of intracellular reactive oxygen species, and arresting the cell cycle in the G0/G1 phase in a concentration-dependent manner, ultimately inducing the growth of cancer cells. Apoptosis and autophagy. The complex has a certain inhibitory effect on Staphylococcus aureus and Pseudomonas aeruginosa.

Description

A 5-Fu-ruthenium(Ⅱ) complex with antitumor and antibacterial activity and its preparation methods and applications

technical field

The invention relates to the technical field of medicine, in particular to a 5-Fu-ruthenium (II) complex with anti-tumor and antibacterial activities and a preparation method and application thereof.

Background technique

5-Fluorouracil (5-Fu) is an antimetabolite that inhibits thymidylate synthase. Its structure is similar to the metabolite uracil in tumor cells. It competes with each other in the same system of enzymes to block metabolic links and hinder DNA synthesis. , thereby inhibiting the proliferation of tumor cells, but its therapeutic effect and long-term application are limited due to its low selectivity, significant first-pass metabolism, low lipophilicity and narrow therapeutic window. The transition metal ruthenium compounds not only have good physical and chemical properties such as large Stokes shift, resistance to photobleaching, long phosphorescence lifetime and high quantum yield, but also the ligands are easy to modify, and functional groups with different characteristics can be introduced into the ruthenium complexes . With the deepening of research, it has been found that transition metal ruthenium complexes not only have excellent antitumor activity, but also have the advantages of strong efficacy, low toxicity and low drug resistance, and have strong antibacterial activity and good biocompatibility. sex. The coordination of 5-Fu derivatives with metal ruthenium can overcome the defects of traditional chemotherapeutic drugs and enable the development of drugs with better biological activity.

There are two common pathways of programmed cell death (PCD): type I PCD: apoptosis and II PCD: autophagy. Tumor cells can induce apoptosis through the death receptor pathway or the mitochondrial pathway. For example, the activation of death receptors, mitochondrial dysfunction, endoplasmic reticulum stress, etc. will activate the downstream cysteine protease Caspase family, and then the cells will undergo apoptosis. A series of apoptotic features such as corpuscle, cell size reduction, nuclear shrinkage, fragmentation and so on. Autophagy is a catabolic pathway that maintains cellular homeostasis by digesting cytoplasmic components and damaged organelles within cytoplasmic vesicles (called lysosomes) to provide cells with a source of energy and nutrients. When cells are insufficiently resistant to external stimuli, excessive autophagy occurs, a large amount of cytoplasm is decomposed, and finally autophagic death occurs. There is a complex relationship between apoptosis and autophagy, which can coexist and antagonize each other.

The mortality rate and chemotherapy failure caused by malignant tumors have led to an increase in the incidence of drug-resistant bacterial infections year by year, which seriously threatens the survival of human beings. In the course of chemotherapy treatment, the immune system is inevitably weakened. Therefore, how to effectively treat tumors and infections caused by drug-resistant bacteria has become an urgent problem to be solved. It can be seen that the design and synthesis of novel ruthenium complexes with dual anticancer and antibacterial biological activities will undoubtedly provide a feasible strategy for future cancer treatment.

SUMMARY OF THE INVENTION

In view of this, the technical problem to be solved by the present invention is to provide a 5-Fu-ruthenium (II) complex with anti-tumor and antibacterial activity and its preparation method and application. The prepared 5-Fu-ruthenium (II) complex is It has both antitumor activity and bacteriostatic activity.

In order to achieve the above object, the present invention provides a series of ruthenium (II) complexes with 5-Fu derivatives as ligands, the general chemical formula is [Ru(NN) ₂ L](PF ₆ ) ₂ , wherein the ligand L is 1-((1,10-o-phenanthroline-5-amino)pentyl)-5-fluorouracil (L), NN are 2,2-bipyridine (bpy), denoted as Ru1; 1,10- phenanthroline (phen), denoted as Ru2; 4,7-diphenyl-1,10-phenanthroline (dip), denoted as Ru3.

Specifically, the 5-Fu-ruthenium (II) complex has the structure shown in formula I:

选自以下任一结构：in,

Choose from any of the following structures:

The above single bond indicates the connection position.

Preferably in the present invention, the 5-Fu-ruthenium (II) complex has any of the following structures of Ru-1 to Ru-3:

Preferably in the present invention, the anion of the 5-Fu-ruthenium (II) complex is PF ₆ ⁻ .

The invention discloses a preparation method of the above-mentioned 5-Fu-ruthenium (II) complex, including:

A) The 5-fluorouracil derivative shown in formula I-a is reacted with [1,10]-phenanthroline-5-amino group shown in formula I-b to obtain the ligand shown in formula I-c;

B) The ligand represented by formula I-c is reacted with the metal ruthenium complex represented by formula I-d, formula I-e or formula I-f to obtain 5-Fu-ruthenium (II) complex represented by formula I;

X ₁ and X ₂ are independently selected from halogen.

Preferably in the present invention, X ₁ is Br.

Preferably in the present invention, X ₂ is Cl.

The present invention reacts with 1-(5-bromopentyl)-5-fluorouracil (shown in formula I-a) and [1,10]-phenanthroline-5-amino (shown in formula I-b) to prepare a ligand (shown in formula I-b). shown in I-c).

The present invention has no particular limitation on the sources of the above-mentioned 1-(5-bromopentyl)-5-fluorouracil and [1,10]-phenanthroline-5-amino, and they can be generally commercially available, or according to those skilled in the art Prepared by well-known methods.

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 the reaction is carried out 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, tris(o-methylphenyl)phosphorus, sodium tert-butoxide and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine is preferably (3-5): (4-6): (20-25): (8-10).

The reaction is preferably carried out in an inert atmosphere.

The inert atmosphere is not particularly limited in the present invention, and can be an inert atmosphere well known to those skilled in the art, preferably a nitrogen or argon atmosphere.

The temperature of the reaction is preferably 80-120°C; the time is preferably 4-12h.

After the reaction is completed, post-treatment is performed. Preferably, the reaction solution is cooled, diluted with ether, filtered with celite, washed with celite, and the organic phases are combined and concentrated to obtain the ligand.

The ligand is then reacted with a metal ruthenium complex represented by formula I-d, formula I-e or formula I-f to obtain a 5-Fu-ruthenium(II) complex represented by formula I.

Preferably in the present invention, the reaction is carried out under reflux in an ethylene glycol solution.

Preferably, in the present invention, the reaction is carried out under the condition of avoiding light.

The reaction is preferably carried out in an inert atmosphere.

The inert atmosphere is not particularly limited in the present invention, and can be an inert atmosphere well known to those skilled in the art, preferably a nitrogen or argon atmosphere.

After the reaction is completed, preferably, an excess saturated NH ₄ PF ₆ solution is added to the system, and the precipitated solid is collected, which is the 5-Fu-ruthenium (II) complex.

Specifically, after the reaction is completed, an excess saturated NH ₄ PF ₆ solution is added to the system, and after the reaction is completed, most of the solvent is removed, and the remaining system is added dropwise to ether to precipitate a solid, which is 5-Fu-ruthenium ( II) Complexes.

The above reaction is shown in the following reaction scheme:

The present invention detects the antitumor activity and antibacterial activity of the above-mentioned cyclic metal iridium complex, preferably through the following operation steps:

1) The detection of anti-tumor activity is mainly carried out through the following steps: when the cells grow to the log phase, the cells are digested with 0.25% trypsin to form a single cell suspension, the viable cells are counted, and 4,000 cells per well are inoculated in 160 μL In a 96-well plate, the empty wells at the edges can be filled with PBS. After culturing for 24h in a _CO2 incubator, 40μL of different concentrations of drugs diluted with medium were added, and after 44h incubation in the incubator, 20μL of MTT (dissolved in PBS) was added to each well, and the medium was then aspirated after 4h. , add 150 μL of DMSO to each well, protect from light, shake on a shaker for about 10 min, and immediately measure the OD value at 595 nm with a microplate reader. The cell viability was calculated according to the formula and plotted to obtain the median lethal concentration (IC ₅₀ value); this assay provides a reliable screening method based on the classical MTT assay, which can be used to directly determine whether a compound has anti-tumor properties active ability.

Survival rate % = average OD value of drug-added wells/average OD value of control wells × 100%

This proves that the 5-Fu-ruthenium (II) complex prepared by the present invention can be used for preparing antitumor drugs. Preferably, the tumor is a solid tumor. More preferably, the tumor is Hela tumor cells.

2) Determination of antibacterial activity MIC was determined by micro-dilution method: Staphylococcus aureus and Pseudomonas aeruginosa were cultured. After culturing to logarithmic growth phase, the bacterial liquid was centrifuged, the supernatant was removed, washed with PBS, then resuspended in LB medium, and diluted to 1×10 ⁶ CFU/mL. Take a sterile 96-well plate, and serially dilute the complex with LB medium in a sterile 96-well plate in a volume of 100 μL. Then add the diluted bacterial suspension (100 μL) to the 96-well plate. At this time, the final drug concentration of each well is from left to right: 20, 10, 5, 2.5, 1.25, 0.625, 0.3125, 0.15625, 0.078, 0.039, 0.0195, 0.0098uM; set up negative control (only blank broth without bacterial liquid) and positive control (add bacterial liquid without adding medicinal liquid), and the rest of the drug operations are the same as above; put the 96-well plate into a 37-degree constant temperature culture After 18h in the box, observe the results. The turbidity of the orifice plate was observed, and the lowest drug concentration corresponding to the clear dosing well was MIC (minimum inhibitory concentration).

This proves that the 5-Fu-ruthenium (II) complex prepared by the present 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 results show that the 5-Fu-ruthenium(II) complex provided by the present invention can specifically target lysosomes, and at the same time induce tumor cells, especially Hela cells, to undergo autophagy and apoptosis, and have antibacterial activity.

In particular, the complex Ru3 has certain selectivity for normal cells, excellent anti-tumor activity against Hela cells, can specifically target lysosomes and induce cell death through apoptosis and autophagy pathways, and target and kill Hela cells , and has certain antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa.

Therefore, the 5-Fu-ruthenium (II) complex provided by the present invention can be used to prepare a drug with dual antitumor and antibacterial activities.

The experimental results show that the 5-Fu-ruthenium (II) complex provided by the present invention has excellent anti-tumor activity, especially Ru3 has the best activity, IC ₅₀ =7.35±0.39 μM for cervical cancer cells, IC for normal cells ₅₀ = 36.64±2.73 μM, selectivity coefficient (SI)=5. It can be seen that Ru3 can selectively kill tumors, and the mechanism study shows that the complex mainly acts through apoptosis and autophagy. It is worth noting that Ru3 also has certain antibacterial activity, with MIC=2.5 μM against Staphylococcus aureus and MIC=10 μM against Pseudomonas aeruginosa. It can be seen that Ru3 has both anti-tumor and antibacterial activities.

Based on this, the present invention provides the application of the above 5-Fu-ruthenium (II) complex or the 5-Fu-ruthenium (II) complex prepared by the above preparation method in the preparation of antitumor drugs or antibacterial drugs.

The present invention provides the above-mentioned 5-Fu-ruthenium (II) complex or the 5-Fu-ruthenium (II) complex prepared by the above-mentioned preparation method, which can simultaneously induce autophagy and apoptosis of tumor cells and has antibacterial activity. Application in functional medicine.

In the present invention, the tumor cells are preferably solid tumor cells, more preferably Hela cells.

The bacterial species against which the antibacterial activity is directed are preferably Gram-positive bacteria and/or Gram-negative bacteria.

The Gram-positive bacteria are preferably Staphylococcus aureus.

The Gram-negative bacteria are preferably Pseudomonas aeruginosa.

Compared with the prior art, the present invention provides a 5-Fu-ruthenium (II) complex, which has the structure shown in formula I. Due to the inclusion of metal ions, which are charged themselves, compared with traditional small organic molecules, the in vivo penetration and retention effects are enhanced, and the metal complexes have a multi-coordination configuration, which can be modified with different ligands to achieve its Excellent biological activity. The experimental results show that the 5-Fu-ruthenium (II) complex provided by the present invention not only has excellent antitumor activity, but also has certain antibacterial activity. The anti-tumor mechanism of the complex was further studied, and it was found that the complex entered the cell mainly in an energy-dependent manner, and was located in the lysosome, causing an increase in the level of intracellular reactive oxygen species, and in a concentration-dependent manner. Cell cycle arrest in G0/G1 phase eventually induces apoptosis and autophagy in cancer cells. In addition, the antibacterial activity experiments showed that the complexes had certain inhibitory effects on Staphylococcus aureus and Pseudomonas aeruginosa. It can be seen that the 5-Fu-ruthenium (II) complex provided by the present invention has certain potential in anti-tumor and antibacterial.

Description of drawings

Fig. 1 is the dose-dependent effect diagram of complex Ru3 on LC3 protein in Example 2;

Figure 2 is a graph of the dose-dependent effect of complex Ru3 on related apoptotic proteins in Example 2;

Fig. 3 is the MIC determination diagram of ligand L and complex Ru1-Ru3 to Staphylococcus aureus in Example 3;

4 is a graph of the MIC determination of ligand L and complex Ru1-Ru3 in Example 3 against Pseudomonas aeruginosa.

Detailed ways

In order to further illustrate the present invention, the 5-Fu-ruthenium(II) complex with antitumor and antibacterial activity provided by the present invention and its preparation method and application are described in detail below with reference to the examples.

Example 1 Preparation Example

(1) Preparation of ligand L:

Dissolve 0.128g [1,10]o-phenanthroline-5-amino (0.66mmol) in an appropriate amount of N,N-dimethylformamide, heat and stir for 30min, and then take an equivalent amount of 1-(5 -Bromopentyl)-5-fluorouracil (0.194g, 0.66mmol), catalyst tris(dibenzylideneacetone)dipalladium (0.006g, 0.007mmol), tris(o-methylphenyl)phosphorus (abbreviation: P( o-tolyl) ₃ , 0.008 g, 0.026 mmol), sodium tert-butoxide (abbreviation: NaOt-Bu, 0.041 g, 0.43 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.016 g, 0.026 mmol), 10 mL of N,N-dimethylformamide was added, under the protection of Ar, refluxed at 100 °C for 12 h, after the reaction solution was cooled, diluted with an appropriate amount of ether, filtered through celite, and washed with ether. diatomaceous earth, combine the organic phases and concentrate as much as possible. Yield: 32.5%.

Elemental analysis C ₂₁ H ₂₀ FN ₅ O ₂ (molecular weight 393.41), theoretical: C 64.11%, H 5.12%, N 17.80%; experimental: C 64.43%, H 5.01%, N 17.50%.

ESI-MS: [(M+H)] ⁺ theoretical: m/z=394.41, experimental: m/z=394.1.

(2) Preparation of complex Ru1

The ligand L (0.125mmol, 1equiv) and the precursor cis-Ru(bpy) ₂ Cl ₂ ·2H ₂ O (0.125mmol, 1 equiv) were placed in a three-necked flask, 10 mL of ethylene glycol solvent was added, and the solution was evacuated under argon protection. Light refluxed for 6h, after the reaction was completed, it was allowed to stand to cool to room temperature, and excess NH ₄ PF ₆ was added to stir to form a large amount of red-brown precipitate, which was filtered, separated and purified by silica gel column chromatography, and dried to obtain the complex Ru1 with a yield of 56.6%.

Elemental analysis C ₄₁ H ₃₆ F ₁₃ N ₉ O ₂ P ₂ Ru (molecular weight 1096.78), theoretical: C 44.90%, H 3.31%, N 11.49%; experimental: C 44.65%, H 3.21%, N 11.66 %.

ESI-MS: [(M-PF ₆ )] ⁺ theoretical value: m/z=951.82, experimental value: m/z=951.7; [(M-2PF ₆ )] ²⁺ theoretical value: m/z=403.43, Experimental value: m/z=403.7.

(3) Preparation of complex Ru2

The ligand L (0.125mmol, 1equiv) and the precursor cis-Ru(phen) ₂ Cl ₂ ·2H ₂ O (0.125mmol, 1 equiv) were placed in a three-necked flask, 10 mL of ethylene glycol solvent was added, and the solution was evacuated under argon protection. Light refluxed for 6 h, after the reaction was completed, it was allowed to stand and cooled to room temperature, and excess NH ₄ PF ₆ was added to stir to form a large amount of red-brown precipitate, which was filtered, separated and purified by silica gel column chromatography, and dried to obtain the complex Ru2 with a yield of 54.2%.

Elemental analysis C ₄₅ H ₃₆ F ₁₃ N ₉ O ₂ P ₂ Ru (molecular weight 1144.82), theoretical: C 47.21%, H 3.17%, N 11.01%; experimental: C 47.56%, H 3.34%, N 10.88 %.

ESI-MS: [(M-PF ₆ )] ⁺ theoretical value: m/z=999.86, experimental value: m/z=1000.0; [(M-2PF ₆ )] ²⁺ theoretical value: m/z=427.45, Experimental value: m/z=427.4.

(4) Preparation of complex Ru3

The ligand L (0.125mmol, 1 equiv) and the precursor cis-Ru(dip) ₂ Cl ₂ ·2H ₂ O (0.125 mmol, 1 equiv) were placed in a three-necked flask, 10 mL of ethylene glycol solvent was added, and the solution was evacuated under argon protection. Light refluxed for 6 h, after the reaction was completed, it was allowed to stand and cooled to room temperature, and excess NH ₄ PF ₆ was added to stir to form a large amount of red-brown precipitate, which was filtered, separated and purified by silica gel column chromatography, and dried to obtain complex Ru3 with a yield of 50.7%.

Elemental analysis C ₆₉ H ₅₂ F ₁₃ N ₉ O ₂ P ₂ Ru (molecular weight 1449.21), theoretical value: C 57.19%, H 3.62%, N 8.70%; experimental value: C 56.90%, H 3.75%, N 8.92 %.

ESI-MS: [(M-PF ₆ )] ⁺ theoretical value: m/z=1305.24, experimental value: m/z=1305.8; [(M-2PF ₆ ^- )] ^{2 +} theoretical value: m/z=579.64 , experimental value: m/z=579.8.

Example 2 In vitro antitumor activity test

(1) Anti-tumor activity test (MTT method): The anti-tumor ability of 5-Fu-ruthenium (II) complexes is mainly determined by MTT method: MTT method is a classic method for measuring drug toxicity. The operation steps are roughly as follows, in 96 4,000 Hela cells were added to the well culture plate, and after culturing in a CO ₂ incubator for 24 hours, different concentrations of drugs diluted with medium were added respectively, then after 44 hours of incubation in the incubator, MTT was added, and the medium was aspirated after 4 hours. DMSO was added, and the OD value at 595 nm was measured after shaking.

The test results are shown in Table 1 below:

Table 1 In vitro antitumor activity results of 5-Fu-ruthenium(Ⅱ) complexes

^a _IC50 is the concentration of complex that inhibits tumor Hela by 50%. The experimental data are the average values obtained after three parallel experiments. ^bSI is the selectivity index, numerically equal to the _IC50 value of normal cells versus the _IC50 value of tumor cells.

It can be seen from the experimental results that the complex Ru3 not only has excellent anti-tumor activity with an IC ₅₀ of only 7.35±0.39 μM, but also has a certain selectivity.

(2) Western Blot analysis: Hela cells were cultured in a 60mm tissue culture dish, when the cell density reached 70%, the specified concentration of complex Ru3 was added, and the protein samples were collected after incubation for 24 hours, and the prepared protein samples were 95 ℃. High temperature denaturation, followed by SDS-PAGE gel electrophoresis, separation of desired proteins, membrane transfer, blocking, primary antibody incubation (primary antibodies are PARP, Caspase35/17, Bax, Bcl-2 and LC3A/B), secondary antibody incubation , protein detection.

The results are shown in Figure 1 and Figure 2, Ru3 upregulates Caspase17 and poly ADP ribose polymerase PARP by activating Caspase activity, and cleaved in a dose-dependent manner. At the same time, the expression of anti-apoptotic protein Bcl-2 was down-regulated and the expression of pro-apoptotic protein Bax was up-regulated, indicating that complex Ru3 induces apoptosis in a Caspase-dependent manner. In terms of inducing autophagy, the complex Ru3 can realize the conversion of LC3-I to LC3-II, significantly down-regulate LC3-I and up-regulate the protein expression of LC3-II compared with the blank control, and show obvious concentration-dependent characteristics. It is further demonstrated that the complex Ru3 can induce both apoptosis and autophagy.

(3) Determination of MIC by micro-dilution method: Staphylococcus aureus and Pseudomonas aeruginosa were cultured. Bacteria were grown overnight to log phase. The bacterial solution was centrifuged, the supernatant was removed, washed with PBS, and then resuspended in LB medium and diluted to 1×10 ⁶ CFU/mL. Take a sterile 96-well plate, and serially dilute the complex with LB medium in a sterile 96-well plate in a volume of 100 μL. Then add the diluted bacterial suspension (100 μL) to the 96-well plate. At this time, the final drug concentration of each well is 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 μM. At the same time, a negative control (only blank broth without bacteria solution) and a positive control (bacteria solution without drug solution) were set, and the rest of the drug operations were the same as above; the 96-well plate was placed in a 37°C constant temperature incubator for 18h. The turbidity of the orifice plate was observed, and the lowest drug concentration corresponding to the clear dosing well was MIC (minimum inhibitory concentration). The results are shown in Figures 3 and 4, wherein Figure 3 is a graph of the MIC determination of the ligand L and the complex Ru1-Ru3 against Staphylococcus aureus. Figure 4 is a graph showing the MIC determination of ligand L and complex Ru1-Ru3 against Pseudomonas aeruginosa.

In Figures 3 and 4, the bacteriostatic effect of ligand L and complex Ru1-Ru3 on Staphylococcus aureus and Pseudomonas aeruginosa was judged by observing the turbidity of the orifice plate. The lowest drug concentration is the MIC-minimum inhibitory concentration.

The test results showed that ligand L and Ru1 and Ru2 had poor antibacterial activity, while Ru3 showed obvious antibacterial activity, and its MIC=2.5μM against Staphylococcus aureus, MIC=10μM against Pseudomonas aeruginosa, It shows that Ru3 has certain antibacterial activity.

The descriptions of the above embodiments are only used to help understand the method and the core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can also be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (10)

1. A 5-Fu-ruthenium (II) complex having the structure shown in formula I:

in,

Choose from any of the following structures:

2. The 5-Fu-ruthenium (II) complex according to claim 1, characterized in that it has any of the following structures of Ru-1 to Ru-3:

3 . The 5-Fu-ruthenium (II) complex according to claim 1 , wherein the anion is PF ₆ ⁻ . 4 . 4. The preparation method of 5-Fu-ruthenium (II) complex according to any one of claims 1 to 3, characterized in that, comprising: A) The 5-fluorouracil derivative represented by the formula I-a is reacted with the [1,10]-phenanthroline-5-amino group represented by the formula I-b to obtain the ligand represented by the formula I-c; B) The ligand represented by formula I-c is reacted with the metal ruthenium complex represented by formula I-d, formula I-e or formula I-f to obtain 5-Fu-ruthenium (II) complex represented by formula I ;

X ₁ and X ₂ are independently selected from halogen. 5. preparation method according to claim 4, is characterized in that, in described step A), the temperature of reaction is 80-120 ℃; Time is 4-12h; Described step A) is carried out under the action of catalyst; The catalyst is tris(dibenzylideneacetone)dipalladium, tris(o-methylphenyl)phosphorus, sodium tert-butoxide and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine. 6. preparation method according to claim 4 is characterized in that, the reaction of described step B) is specially: The reaction was carried out at reflux in ethylene glycol solution. 7. preparation method according to claim 4 is characterized in that, also comprises after step B): After the reaction was completed, excess saturated NH ₄ PF ₆ solution was added to the system, and the precipitated solid was collected. 8. 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 is in Application in the preparation of antitumor drugs or antibacterial drugs. 9. 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 is in Preparation of multifunctional drugs that can simultaneously induce autophagy and apoptosis of tumor cells and have antibacterial activity. 10. The application according to claim 8 or 9, wherein the tumor cells are solid tumor cells; The bacterial species against which the antibacterial activity is directed are Gram-positive bacteria and/or Gram-negative bacteria.

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