CN115160376B - Cinnamic acid modified cyclometalated iridium (III) complex and synthetic method and application thereof - Google Patents

Cinnamic acid modified cyclometalated iridium (III) complex and synthetic method and application thereof Download PDF

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CN115160376B
CN115160376B CN202210819934.2A CN202210819934A CN115160376B CN 115160376 B CN115160376 B CN 115160376B CN 202210819934 A CN202210819934 A CN 202210819934A CN 115160376 B CN115160376 B CN 115160376B
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苏岩
杨津
苏志
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Nanjing Normal University
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Abstract

The invention discloses a cinnamic acid modified cyclometalated iridium (III) complex, which has good fat solubility, tumor cell uptake capacity, anti-tumor cell proliferation capacity, anti-tumor cell migration capacity and capability of overcoming tumor cisplatin resistance, can effectively inhibit tumor cell proliferation, induce ROS (reactive oxygen species) generation, reduce mitochondrial membrane potential, change the mitochondrial morphology of tumor cells, damage the mitochondrial function of tumor cells, induce autophagy of tumor cells (mitochondria), and can overcome the cisplatin tolerance of tumors, namely the complex has good effect of inhibiting the proliferation of cisplatin-tolerant tumor cells; therefore, the complex of the invention has better effect than cisplatin drugs on the premise of small toxic and side effects; the invention also discloses a synthesis method of the cinnamic acid modified cyclometalated iridium (III) complex and application of the cinnamic acid modified cyclometalated iridium (III) complex in preparation of antitumor drugs and cisplatin-resistant antitumor drugs.

Description

Cinnamic acid modified cyclometalated iridium (III) complex and synthetic method and application thereof
Technical Field
The invention relates to a cinnamic acid modified cyclometalated iridium (III) complex, and also relates to a synthesis method of the cinnamic acid modified cyclometalated iridium (III) complex and application of the cinnamic acid modified cyclometalated iridium (III) complex in preparation of anti-tumor drugs and anti-cisplatin resistant tumor drugs.
Technical Field
Since the discovery of cisplatin (cis-Pt), inorganic drugs have been at the front of chemotherapy studies. However, common platinum-based therapies, including cisplatin, oxaliplatin, or carboplatin, all cause a series of serious adverse effects. Nephrotoxicity is the most common specific adverse effect encountered by cisplatin patients, while myelosuppression and neurotoxicity are associated with the use of carboplatin and oxaliplatin, respectively, which motivates the study of other metallic anticancer drugs that retain the efficacy of the platinum-based drug but have fewer side effects.
The natural product or the derivative thereof has various biological activities, and the potential medicinal value thereof makes the anticancer research of the natural product gradually become a hot spot of clinical antitumor drug research. Cinnamic acid is a natural compound consisting of a benzene ring substituted with acrylic groups, usually in the form of the trans isomer. Cinnamic acid has a variety of pharmacological activities including antibacterial, anti-inflammatory and antioxidant activities. In addition, it is found that it has anti-tumor activity in vitro on various human solid tumors, but needs to be added with a large dose to have a corresponding effect, and only the dose has no significant effect on normal cells. Therefore, cinnamic acid has the defects of poor water solubility, low bioavailability, large dosage and the like, and the application of the cinnamic acid as a candidate anticancer drug or anticancer drug component is limited.
Disclosure of Invention
The invention aims to: the invention aims to provide a cinnamic acid modified cyclometalated iridium (III) complex which can solve the problems of difficult water dissolution and low bioavailability existing when cinnamic acid is used as an anti-tumor drug or an anti-tumor drug component, and can solve the problems of large toxic and side effects and cisplatin tolerance generated by tumor cells existing when a simple cyclometalated complex is used as an anti-tumor drug or an anti-tumor drug component; the invention also aims to provide a synthesis method of the cinnamic acid modified cyclometalated iridium (III) complex and application of the cinnamic acid modified cyclometalated iridium (III) complex in preparation of antitumor drugs or antitumor drug components.
The technical scheme is as follows: the cinnamic acid modified cyclometalated iridium (III) complex has a chemical structural formula shown in a formula (I):
。
the cyclometalated iridium (III) complex has higher fat solubility, and can be combined with cinnamic acid to improve the uptake of cinnamic acid by tumor cells, and after entering the tumor cells, the metal complex and the cinnamic acid cooperatively play an anti-tumor role. Meanwhile, the cyclometallated iridium (III) complex has photochemical and photophysical characteristics and can be used for cell localization.
Wherein the cinnamic acid modified cyclometallated iridium (III) complex further comprises an anionic PF 6 - 。
The synthesis method of the cinnamic acid modified cyclometalated iridium (III) complex specifically comprises the following steps: heating and refluxing cinnamic acid modified dipyridine ligand and cyclometallated iridium dimer in a mixed solution of dichloromethane and methanol in an inert atmosphere to reduceThe solvent was removed by pressure distillation using NH 4 PF 6 The crude product is obtained through displacement, and cinnamic acid modified cyclometallated iridium (III) complex is obtained through separation and purification of the crude product through column chromatography;
the chemical structural formula of the cinnamic acid modified bipyridine ligand is shown as a formula (II):
the chemical structural formula of the cyclometallated iridium dimer is shown in a formula (III):
。
the preparation method of the cinnamic acid modified bipyridine ligand comprises the following steps: and (3) dissolving cinnamic acid, EDCI or DCC, HOBt, TEA and a bridging ligand 4-methyl-4 '-aminomethyl-2, 2' -bipyridine in N, N-dimethylformamide under an inert atmosphere, reacting the mixed materials at room temperature for 48 hours to obtain a crude product, and separating and purifying the crude product by a column chromatography method.
Wherein the inert atmosphere is nitrogen or argon as a shielding gas.
Wherein, the reaction mole ratio of the cinnamic acid modified dipyridine ligand to the cyclometallated iridium dimer is 2:1.
wherein, the volume ratio of dichloromethane to methanol in the mixed solution is 2:1.
wherein the reflux reaction time is 10 hours; the reaction temperature was 45 ℃.
The cinnamic acid modified cyclometalated iridium (III) complex is applied to the preparation of antitumor drugs, antitumor drug components, antitumor metastasis drugs, antitumor metastasis drug components, anti-cisplatin resistant tumor drugs and anti-cisplatin resistant tumor drug components.
Wherein the tumor refers to a human lung cancer cell.
The beneficial effects are that: the natural product cinnamic acid modified cyclometalated iridium (III) complex has good fat solubility, tumor cell uptake capacity, anti-tumor cell proliferation capacity, anti-tumor cell migration capacity and capability of overcoming tumor cisplatin resistance, can effectively inhibit tumor cell proliferation, induce ROS (reactive oxygen species) production, reduce mitochondrial membrane potential, change mitochondrial morphology of tumor cells, damage mitochondrial functions of tumor cells, induce autophagy of tumor cells (mitochondria), and overcome cisplatin tolerance of tumors, namely the complex has good effect of inhibiting the proliferation of cisplatin-tolerant tumor cells; therefore, the complex of the invention has better effect than cisplatin drugs on the premise of small toxic and side effects; the complex has the capability of inhibiting proliferation of tumor cells, inhibiting proliferation of cisplatin-resistant tumor cells, damaging mitochondrial function of tumor cells and inducing autophagy of tumor cells (mitochondria), can be used for preparing antitumor drugs, antitumor drug components, cisplatin-resistant tumor drugs and cisplatin-resistant tumor drug components, and has wide application prospect.
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FIG. 1 is a confocal fluorescence imaging of the uptake of cancer cells at different concentrations and a cell flow chart at different concentrations for example 1 of complex incubation; wherein, FIG. 1a is a confocal fluorescence imaging chart, and FIG. 1b is a cell flow chart at different concentrations;
FIG. 2 is a flow chart of the complex-induced cell production of active oxygen and confocal fluorescence imaging of example 1; wherein, FIG. 2a is a flow chart of cells at different concentrations; FIG. 2b is a confocal fluorescence imaging image;
FIG. 3 is a flow chart of the cell and confocal fluorescence imaging of the complex of example 1 inducing a change in mitochondrial membrane potential of the cell; wherein, FIG. 3a is a flow chart of cells at different concentrations; FIG. 3b is a confocal fluorescence imaging image;
FIG. 4 is a TEM image of the effect of the complex of example 1 on mitochondrial morphology;
FIG. 5 is a western blot protein diagram of the complex-induced autophagy of cancer cells (mitochondria) of example 1;
FIG. 6 is a graph showing scratch test and Transwell migration test of the complex of example 1 for inhibiting cancer cell migration; wherein, fig. 6a is a scratch experiment diagram; FIG. 6b is a graph of a Transwell migration experiment.
Detailed Description
The technical scheme of the invention is further described below with reference to specific embodiments.
Example 1
The preparation method of the cinnamic acid modified cyclometalated iridium (III) complex (Ir-CA for short) comprises the following steps:
step 1, preparing cinnamic acid modified bipyridine ligands: cinnamic acid (37.0 mg,0.25 mmol) and EDCI (57.5 mg,0.3 mmol) were weighed into a two-necked flask under an argon atmosphere, evacuated, argon was introduced, and then anhydrous DMF (2 mL) and Et were added under ice-bath conditions 3 N (100. Mu.L) was stirred for 20min, then added with DMF solution containing HOBt (0.2 mmol,27 mg), stirred for 15min, then the ice bath was removed and the temperature was restored to room temperature, then added with DMF solution containing 4-methyl-4 '-aminomethyl-2, 2' -bipyridine (0.3 mmol,59.8 mg) and the reaction was continued for 48h; after the reaction was completed, 20mL of distilled water was added, extraction was performed with methylene chloride (3×30 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the crude product was further purified by flash chromatography to give a beige solid (65 mg, 80.0%). 1 H NMR(400MHz,Chloroform-d)δ8.63(d,J＝5.0Hz,1H),8.54(d,J＝4.9Hz,1H),8.36–8.30(m,1H),8.26–8.20(m,1H),7.72(d,J＝15.6Hz,1H),7.55–7.50(m,2H),7.38(dd,J＝5.0,2.0Hz,3H),7.17(dt,J＝4.9,1.4Hz,1H),6.52(d,J＝15.6Hz,1H),6.38(s,1H),4.69(d,J＝6.0Hz,2H),2.46(s,3H).
Step 2: cinnamic acid modified bipyridine ligand (26.352 mg,0.08 mmol) and cyclometallated iridium dimer (42.884 mg,0.04 mmol) are dissolved in a mixed solvent of anhydrous dichloromethane and anhydrous methanol (the volume ratio of the anhydrous dichloromethane to the anhydrous methanol is 2:1) under the protection of argon, and the mixture is heated, refluxed and stirred for 10 hours at 45 ℃; reaction completionThe solvent is distilled off under reduced pressure and saturated NH is added 4 PF 6 After stirring for 2h, the solid was collected by centrifugation and the crude product was further purified by column chromatography to give Ir-CA as a yellow solid (30 mg, 77% yield). 1 H NMR(400MHz,DMSO-d 6 )δ8.76(d,J＝18.1Hz,2H),8.26(dd,J＝8.1,4.7Hz,2H),7.97–7.87(m,5H),7.79(d,J＝5.6Hz,1H),7.69(d,J＝5.6Hz,1H),7.62(d,J＝5.8Hz,2H),7.60–7.56(m,2H),7.54(dt,J＝6.3,3.1Hz,2H),7.49(s,1H),7.46–7.40(m,3H),7.16(tdd,J＝6.1,3.2,1.7Hz,2H),7.05–6.97(m,2H),6.92–6.85(m,2H),6.70(d,J＝15.9Hz,1H),6.19(dt,J＝7.5,1.5Hz,2H),4.66–4.59(m,2H),2.53(s,3H)。ESI-MS(in CH 3 OH, +) and: theoretical value: [ Ir-CA-PF 6 - ]m/z 830.2, experimental values: 830.4.
complex Ir-NH without cinnamic acid modification 2 The structural formula is as follows:
Ir-CA, a complex of Ir-NH, which is prepared in example 1, and Ir-NH, which is a complex of cyclometallated iridium (III) free of cinnamic acid, are prepared 2 The following experiments were performed:
example 1 cytotoxicity of the complex against human lung cancer cell a549 and cisplatin-resistant strain a 549R:
analysis of cinnamic acid modified cyclometallated iridium (III) complexes Ir-CA, trans-CA, cinnamic acid free cyclometallated iridium (III) complexes Ir-NH Using MTT colorimetry 2 Anti-proliferation effect of cisplatin cis-Pt on human lung cancer cells A549 and cisplatin resistant strains A549R. MTT (thiazole blue) is a tetrazolium salt which is reduced by succinate dehydrogenase in the mitochondria of living cells to form a blue-violet product, formazan (the product is soluble in DMSO) and has an absorption peak at 570nm, so A can be used 570nm To analyze the proliferation of cells.
The specific experimental steps are as follows:
(1) Firstly, resuscitating a tube of tumor cells, culturing with fresh culture solution (wherein, A549 cells use DMEM culture medium+10% foetus calf serum+1% penicillin and streptomycin; A549R cells use RPMI-1640 culture medium+10% foetus calf serum+1% penicillin and streptomycin), and carrying out passage for 2 times for use;
(2) When the cells reached the logarithmic phase, they were inoculated into 96-well plates (100. Mu.L of culture medium per well) at a cell density of 5000 cells/well, followed by placing in an incubator (37 ℃,5% CO) 2 ) Culturing in medium;
(3) After the cells are attached, 100 mu L of compound Ir-CA with different concentration gradients, trans-CA with different concentration gradients and compound Ir-NH with different concentration gradients are respectively added into each hole 2 And fresh culture solution containing cis-platinum cis-Pt with different concentration gradients, and then placing the culture solution in an incubator for continuous incubation;
(4) After 48 hours of incubation, 20. Mu.L MTT (5 mg/mL) was added to each well and incubation was continued for 4 hours at 37℃in an incubator, the supernatant was aspirated, 150. Mu.L dimethyl sulfoxide (DMSO) was added to each well, and A was detected using an ELISA 570nm Calculating the cell proliferation inhibition ratio and obtaining IC 50 Value (drug concentration corresponding to inhibition equal to 50%). Ir-CA, trans-CA and Ir-NH 2 And the MTT test results of cis-Pt are shown in Table 1.
Table 1 shows the compounds Ir-CA, ir-NH 2 IC of cis-platinum cis-Pt 50 Value (mu M)
a RF＝resistance factor＝IC 50,A549R /IC 50,A549 .
The results show that: the proliferation inhibition activity of the complex Ir-CA on A549 and A549R is higher than that of natural product cinnamic acid and compound Ir-NH 2 And cis-Pt, which shows that the anti-tumor activity of the complex Ir-CA modified by cinnamic acid is improved; meanwhile, the complex Ir-CA has lower RF value (RF, resistance Factor, equivalent IC) 50 (A549R)/IC 50 (A549) Shows that the complex Ir-CA modified by cinnamic acid also has good inhibition effect on cisplatin-tolerant lung cancer cells A549R.
Example 1 cellular uptake of the complex Ir-CA:
method 1: confocal microscopy examined uptake of cells over different time periods. A549R cells were inoculated into 35mm Corning laser confocal dishes, and when the cell density grew to 70%, cell culture media containing the complex Ir-CA at a concentration of 10. Mu.M were added, the incubation times were 0.5h, 1h, 2h, 4h and 6h, respectively, the media were discarded, washed three times with PBS, and observed by confocal microscopy, the excitation wavelength was 405nm.
Method 2: flow cytometry detects the uptake of drug by tumor cells. Cell cultures containing Ir-CA at concentrations of 2.5, 5, 10 and 15. Mu.M were added to 6-well plates inoculated with well-formed and normal growth A549R cells, respectively, after 24h of drug treatment, the cells were harvested, washed twice with PBS, resuspended in 500. Mu.l of PBS, and the fluorescence intensity was measured using a flow cytometer.
The uptake of the complex Ir-CA in A549R cells is shown in FIG. 1. Confocal microscopy results showed that: the uptake of intracellular drugs showed a time-dependent increase with prolonged incubation time. Compared with a control group, the flow cytometry results show that the fluorescence intensity of the dosing group is obviously improved, and the dosage dependence is increased, so that tumor cells show good uptake effect on the complex Ir-CA, and the complex Ir-CA has good cell uptake capacity.
Use of the complex Ir-CA prepared in example 1 for inducing intracellular reactive oxygen species:
method 1: confocal microscopy detects ROS within cancer cells. A549R cells were seeded in 35mm Corning laser confocal dishes and when the cell density was grown to 70%, ir-CA was added at concentrations of 5. Mu.M and 10. Mu.M, respectively, and treated for 24h, then the cells were treated with a solution containing 10. Mu. M H 2 Serum-free culture of DCFH-DA was stained for 30min at 37℃in the absence of light, immediately followed by confocal microscopy, excitation at 488nm and emission at 530.+ -. 20nm.
Method 2: flow cytometry detects ROS within tumor cells. After A549R cells were treated with Ir-CA at concentrations of 2.5, 5, 10 and 15. Mu.M, respectively, for 24h, they were treated with a solution containing 10. Mu.M M H 2 DCFH-DA freeSerum culture is based on shading for 30min at 37deg.C, centrifuging, discarding supernatant, washing with serum-free medium three times, and removing H not entering cells 2 DCFH-DA; measuring green fluorescence intensity by a flow cytometer within the second half hour of collecting the cells; the excitation wavelength was 488nm and the emission wavelength was 530.+ -.20 nm. The average fluorescence intensity of green light was analyzed using FlowJo 7.6 (Tree Star, OR, USA) software.
The results of the complex Ir-CA on the induction of intracellular reactive oxygen species are shown in FIG. 2. The results show that compared with the control group, the flow cytometry and confocal results after Ir-CA treatment show that the green fluorescence is obviously enhanced, and the complex Ir-CA effectively induces the increase of the intracellular active oxygen content.
Example 1 use of Ir-CA prepared to induce changes in intracellular mitochondrial membrane potential:
method 1: confocal microscopy detects changes in mitochondrial membrane potential within tumor cells. A549R cells were inoculated into 35mm Corning laser confocal dishes, and when the cell density grew to 70%, ir-CA was added at 5. Mu.M and 10. Mu.M respectively for 24 hours, and then the cells were stained with pre-prepared JC-1 working solution at 37℃for 30 minutes in the dark, and immediately observed with confocal microscopy.
Method 2: flow cytometry detects changes in mitochondrial membrane potential within tumor cells. Adding cell culture solutions containing Ir-CA with concentrations of 2.5, 5, 10 and 15 mu M into 6-well plates inoculated with A549R cells with good morphology and normal growth vigor respectively, carrying out drug treatment for 24 hours, collecting cells, washing with PBS, and then adding the prepared JC-1 working solution for dyeing for 30 minutes; cells were washed with buffer and resuspended, and samples tested were immediately examined using a BD FACS verse Flow cytometer and the results were processed with Flow Jo 7.6 software and analyzed. Detection of fluorescent channel as lambda ex ＝488nm，λ em ＝530±30nm；λ ex ＝488nm，λ em ＝590±30nm。
The results of the complex Ir-CA on inducing changes in intracellular mitochondrial membrane potential are shown in FIG. 3. The results show that: compared with the control group, the complex can be used for treating the mitochondrial membrane, the green fluorescence can be obviously enhanced, the red fluorescence can be obviously reduced, and the complex Ir-CA can effectively induce the mitochondrial membrane potential to be reduced. The same results are also shown by flow cytometry.
Example 1 effect of the complex Ir-CA produced on mitochondrial morphology:
mitochondrial morphology of the a549R cells after complex Ir-CA treatment was observed by transmission through a Transmission Electron Microscope (TEM). Adding a pre-prepared cell culture solution containing 10 mu M of complex Ir-CA into a 100mm culture dish inoculated with A549R cells for drug treatment, after incubating for 24 hours, collecting the cells, washing with PBS, fixing with 2.5% glutaraldehyde, gradient dehydrating with alcohol, embedding with resin, ultrathin slicing, staining with uranyl acetate and lead citrate, preparing a sample to be observed on a copper wire, and observing the mitochondrial morphology by using a Hitachi H-7650 transmission microscope.
The effect of the Ir-CA complex on mitochondrial morphology is shown in FIG. 4. The results show that: compared with the complete mitochondrial cristae structure of the control group, the mitochondrial swelling of the A549R cells treated by the complex Ir-CA becomes round, and the cristae structure disappears, which indicates that the complex Ir-CA can destroy the structural morphology of mitochondria.
Use of Ir-CA prepared in example 1 for inducing autophagy of A549R cells:
autophagic protein content changes were detected using Western Blotting (WB). Adding a pre-prepared cell culture solution containing a complex Ir-CA (2.5, 5, 10 and 15 mu M) into a 100mm culture dish for adherent growth of A549R cells, centrifuging to collect cells after the drug is treated for 24 hours, washing with PBS to remove serum in the residual culture solution, adding a strong lysis solution of Biyun RIPA containing PMSF, and performing whole cell lysis for 20 minutes, wherein a low-temperature environment at 4 ℃ is ensured in the whole process to ensure protein invariance. Centrifuging at 13400rpm for 20min under low temperature condition, and sucking supernatant obtained by centrifugation to obtain cell whole protein sample required by experiment; determining the protein concentration in the protein sample using a BCA protein content assay kit; and detecting the expression content of different proteins in the sample by SDS-PAGE gel electrophoresis. After the gel is prepared, adding protein samples with the same volume into each hole for gel electrophoresis experiments, and immediately stopping electrophoresis after proper separation; the target protein was transferred onto PVDF membrane using a wet method, and after the completion, the membrane was blocked in 5% nonfat milk powder for 2 hours. Diluting the primary antibody with skimmed milk powder according to the corresponding proportion according to the instruction of the antibody, and placing the sealed membrane in a primary antibody incubation liquid for incubation for a period of time at room temperature so as to enable the membrane to be specifically combined with the target protein. After completion, the cells were washed with PBST (5X 6 min/time). The washed membrane was incubated in a pre-formulated secondary antibody incubation for a period of time to bind to the primary antibody, again washed with PBST. An equal volume of ECL developer is prepared, covered on a PVDF film, and photographed by a chemiluminescent imaging system after 2min of treatment.
The experimental results of the complex Ir-CA on the A549R cells to induce the autophagy-related protein expression are shown in FIG. 5. The results show that: compared with a control group which is not treated by adding medicine, after the cells are treated by the complex Ir-CA, the expression of the mitochondrial autophagy related protein PINK1 is obviously up-regulated, and meanwhile, the content of autophagy marker protein LC3-II is increased in a concentration-dependent manner, which indicates that the death mode of the complex Ir-CA induced A549R cells is autophagy.
Use of Ir-CA prepared in example 1 to inhibit migration of A549R cells:
method 1: the effect of Ir-CA on the ability of A549R cells to migrate was determined using wound healing. The cells were grown at 5X 10 5 The cells/well were inoculated into 6-well cell culture plates and incubated at 37℃for 12 hours until 90% confluence. The cell monolayer was scratched with a pipette tip and then washed with PBS. Cells were treated with 5. Mu.M 1% DMSO and Ir-CA complex in RPMI 1640 medium with 1% FBS. The extent of wound healing was monitored using an inverted microscope at 0, 24 and 48 hours. Wound healing area was quantified using Image J software and percent inhibition was calculated based on total cell area as 100.
Method 2: the effect of Ir-CA on the ability of A549R cells to migrate was determined using a Transwell migration assay. A chamber with a pore size of 8 mu M and a 24-well cell culture plate special for a Transwells migration experiment are adopted. Starving the cells for 24h before preparing the cell suspension, then centrifuging the cells to discard the medium, washing twice with PBS, and resuspension with serum-free mediumCells were adjusted to 2.5X10 5 Per ml of cells. 200 μl of cell culture solution prepared to contain Ir-CA complexes at concentrations of 5 and 10 μM was inoculated into the upper chamber of the chamber, and 600 μl of medium containing 20% FBS was added to the lower chamber, and the mixture was stirred at 37deg.C with 5% CO 2 Incubation in incubator was for 24 hours. After that, the mixture was washed twice with PBS, fixed with 4% paraformaldehyde for 20 minutes, and stained with 0.1% crystal violet for 10 minutes. The non-migrated cells in the upper chamber were gently scraped off using a cotton swab. Cells migrated in the cells were photographed in five random fields with an inverted microscope, and the number of migrated cells was measured using Image J.
The results of the complex Ir-CA on inhibiting the ability of A549R cells to migrate are shown in FIG. 6. The results show that: compared with a control group, the healing area of scratches after the Ir-CA complex treatment is small, and likewise, the result of a Transwell migration experiment shows that the number of cells migrating to a cell in a dosing group is obviously smaller than that of the control group, and the Ir-CA complex can effectively inhibit the migration of tumor cells.

Claims (9)

1. Cinnamic acid modified cyclometallated iridium (III) complex is characterized in that the chemical structural formula of the complex is shown as formula (I):
；
the cinnamic acid modified cyclometallated iridium (III) complex also comprises an external anion PF 6 - 。
2. The method for synthesizing cinnamic acid modified cyclometallated iridium (III) complex according to claim 1, wherein the method is specifically characterized by comprising the following steps: heating and refluxing cinnamic acid modified dipyridine ligand and cyclometallated iridium dimer in a mixed solution of dichloromethane and methanol under inert atmosphere, distilling under reduced pressure to remove solvent, and using NH 4 PF 6 The crude product is obtained through displacement, and cinnamic acid modified cyclometallated iridium (III) complex is obtained through separation and purification of the crude product through column chromatography;
the chemical structural formula of the cinnamic acid modified bipyridine ligand is shown as a formula (II):
the chemical structural formula of the cyclometallated iridium dimer is shown as a formula (III):
。
3. the method for synthesizing a cinnamic acid-modified cyclometallated iridium (III) complex according to claim 2, wherein the preparation method of the cinnamic acid-modified bipyridine ligand is as follows: and (3) dissolving cinnamic acid, EDCI or DCC, HOBt, TEA and a bridging ligand 4-methyl-4 '-aminomethyl-2, 2' -bipyridine in N, N-dimethylformamide under an inert atmosphere, reacting the mixed materials at room temperature to obtain a crude product, and separating and purifying the crude product by a column chromatography method.
4. The method for synthesizing cinnamic acid-modified cyclometallated iridium (III) complex according to claim 2, wherein: the inert atmosphere is protected by nitrogen or argon.
5. The method for synthesizing cinnamic acid-modified cyclometallated iridium (III) complex according to claim 2, wherein: the reaction mole ratio of the cinnamic acid modified bipyridine ligand to the cyclometalated iridium dimer is 2:1.
6. the method for synthesizing cinnamic acid-modified cyclometallated iridium (III) complex according to claim 2, wherein: in the mixed solution, the volume ratio of dichloromethane to methanol is 2:1.
7. the method for synthesizing cinnamic acid-modified cyclometallated iridium (III) complex according to claim 2, wherein: the reflux reaction time is 10-10.5 hours; the reaction temperature is 45-50 ℃.
8. Use of the cinnamic acid modified cyclometallated iridium (III) complex of claim 1 in the preparation of an antitumor drug.
9. The use of cinnamic acid modified cyclometallated iridium (III) complex in the preparation of an antitumor drug according to claim 8, characterized in that: the tumor refers to a human lung cancer cell.
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Publication number Priority date Publication date Assignee Title
WO2016127681A1 (en) * 2015-02-09 2016-08-18 中山大学 Use of 4,4'-bipyridine bridged tetranuclear platinum complex in preparation of anti-telomerase negative tumour medicine
CN111377975A (en) * 2020-02-28 2020-07-07 中山大学 Novel mitochondrion-targeted iridium complex and preparation method and application thereof
WO2021023290A1 (en) * 2019-08-08 2021-02-11 厦门大学 Application of zinc pyrithione in treatment of lung cancer

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016127681A1 (en) * 2015-02-09 2016-08-18 中山大学 Use of 4,4'-bipyridine bridged tetranuclear platinum complex in preparation of anti-telomerase negative tumour medicine
WO2021023290A1 (en) * 2019-08-08 2021-02-11 厦门大学 Application of zinc pyrithione in treatment of lung cancer
CN111377975A (en) * 2020-02-28 2020-07-07 中山大学 Novel mitochondrion-targeted iridium complex and preparation method and application thereof

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