CN111574568A - Cyclometalated iridium metformin complex and preparation method and application thereof - Google Patents
Cyclometalated iridium metformin complex and preparation method and application thereof Download PDFInfo
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 52
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000010668 complexation reaction Methods 0.000 title description 2
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 49
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- 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
- C07F15/0033—Iridium compounds
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Abstract
The invention discloses a cyclometalated iridium metformin complex and a preparation method and application thereof. The invention firstly provides a cyclometalated iridium metformin complex which can be rapidly taken up by tumor cells and has a phosphorescent tracing characteristic; the complex has excellent hypoxic anti-tumor activity, and compared with the normal oxygen condition, the complex has the advantages that the cytotoxicity of tumor cells is enhanced under the hypoxic condition, ROS can be better induced to be generated in the tumor cells, the HIF-1 alpha has better inhibition activity, and the apoptosis of the tumor cells is finally induced; the invention also provides a preparation method of the complex, which is simple and has lower cost; therefore, the complex has good application prospect in preparation of hypoxic anti-tumor drugs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry. More particularly, relates to a cyclometalated iridium metformin complex and a preparation method and application thereof.
Background
Hypoxia is a prominent feature of most solid tumors. Solid tumors are deficient in oxygen, nutrition and other supplies due to rapid proliferation of tumor cells, incomplete blood vessel development and uneven distribution inside tumor tissues, and finally, hypoxic regions exist in tumors. The hypoxic microenvironment can induce tumor tissues to generate drug resistance to traditional chemotherapy drugs such as cisplatin and the like, so that the chemotherapy effect is poor, the treatment effect of the photosensitizer in a hypoxic region of the tumor can be reduced, and the relapse, transfer and invasion capabilities of the tumor can be increased. Therefore, the development of novel metal antitumor drugs with different antitumor mechanisms has important significance for improving the treatment effect of hypoxic tumors.
Hypoxia inducible factor-1 alpha (HIF-1 alpha) is an important transcription factor responding to hypoxic stress and can combine with beta subunit to form a dimeric complex with transcriptional activity. HIF-1 alpha is over-expressed in more than 70% of cancers, plays an important role in the metabolism, angiogenesis and metastasis of hypoxic tumor cells, and is one of the important targets for treating cancer. HIF-1 alpha expression levels increase progressively with increasing tumor hypoxia levels. It is found that metformin can improve the treatment effect of hypoxic tumors by inhibiting the expression of HIF-1 alpha, and has attracted more and more attention.
Metformin is an oral hypoglycemic agent for clinically treating type 2 diabetes, and can also be used for treating tumors; for example, metformin can be used in combination with aspirin in the treatment of pancreatic cancer to inhibit tumor formation by inhibiting COX-1 and COX-2 activity and modulating inflammation. Metformin increases the sensitivity of breast cancer cells to radiation therapy and restores the sensitivity of breast cancer drug-resistant cells to HER2 inhibitors. In addition, the gold-biguanide complex can cause endoplasmic reticulum damage and cell cycle arrest of HeLa cells, and has an anti-tumor effect.
However, the above prior arts all show that metformin has a good antitumor effect, and its antitumor activity under hypoxic condition is not mentioned; and the complex obtained after different metals are matched with metformin has great difference on the uptake capacity, selectivity and antitumor mechanism of tumor cells under the hypoxic condition. Therefore, the further research on the complex with the anti-tumor activity under the hypoxic condition has important significance for treating hypoxic tumors.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects and shortcomings of the existing antitumor drugs in the treatment of hypoxic tumors, and provides a cyclometalated iridium metformin complex and a preparation method and application thereof.
The invention aims to provide a cyclometalated iridium metformin complex.
The invention also aims to provide a preparation method of the cyclometalated iridium metformin complex.
The invention further aims to provide application of the complex in preparation of hypoxic anti-tumor drugs.
The above purpose of the invention is realized by the following technical scheme:
the invention firstly provides a cyclometalated iridium metformin complex, the structural formula of which is shown as the formula (I):
wherein the content of the first and second substances,
is a ligand, the structural formula of the ligand is
Any one of them.
When the structural formula of the ligand is
When the obtained complex has the structural formula
Is named as complex Ir 1.
When the structural formula of the ligand is
When the obtained complex has the structural formula
Is named as complex Ir 2.
When the structural formula of the ligand is
When the obtained complex has the structural formula
Is named as complex Ir 3.
The invention also provides a preparation method of the cyclometalated iridium metformin complex, which comprises the following steps:
s1, mixing and dissolving an iridium trichloride hydrate and a ligand, and carrying out a coordination reaction under reflux stirring to obtain an iridium precursor;
s2, mixing and dissolving the iridium precursor obtained in the step S1 and metformin, and adding strong base for reaction under the protection of inert gas to obtain the complex.
Preferably, the molar ratio of the iridium trichloride hydrate to the ligand in step S1 is 1: 2.2 to 3.
More preferably, the molar ratio of iridium trichloride hydrate to ligand in step S1 is 1: 2.2.
preferably, the molar ratio of the iridium precursor, the metformin and the strong base in step S2 is 1: 4: 6 to 10.
More preferably, the molar ratio of the iridium precursor, metformin and strong base in step S2 is 1: 4: 8.
preferably, the strong base in step S2 is potassium tert-butoxide.
Preferably, the temperature of the reaction of step S2 is 30 to 40 ℃.
More preferably, the temperature of the reaction of step S2 is 35 ℃.
Preferably, the reaction time of the step S2 is 20-30 h.
More preferably, the reaction time of step S2 is 25 h.
Preferably, the temperature of the coordination reaction in step S1 is 130 ℃ to 140 ℃.
More preferably, the temperature of the coordination reaction in step S1 is 135 ℃.
Preferably, the coordination reaction time in the step S1 is 22-26 h.
More preferably, the coordination reaction time of step S1 is 24 h.
Preferably, the solvent used for the dissolution in step S2 is a dichloromethane/methanol mixed solvent.
Preferably, the volume ratio of the dichloromethane to the methanol is 1-2: 1.
more preferably, the volume ratio of dichloromethane to methanol is 1.5: 1.
preferably, the solvent used for the dissolution in step S1 is a mixed solvent of ethylene glycol ethyl ether and ultrapure water.
Preferably, the volume ratio of the ethylene glycol ether to the ultrapure water is 2-4: 1.
more preferably, the volume ratio of the ethylene glycol ether to the ultrapure water is 3: 1.
preferably, the inert gas is N2。
In a preferred embodiment of the invention, the process for preparing the complex is expressed by the following equation:
step S1:
step S2:
the research of the invention finds that: the complexes Ir1, Ir2 and Ir3 can be well taken up by tumor cells, have good antitumor activity, and the antitumor activity of the complexes is independent of metformin, wherein the toxicity of the complexes Ir1 and Ir3 to the tumor cells is obviously higher than that of cisplatin; under the hypoxic condition, the complex Ir1 can induce tumor cells to generate more ROS, so that the apoptosis of the tumor cells is obviously induced, and the complex Ir1 has good inhibitory activity on HIF-1 alpha and obvious hypoxic anti-tumor activity; therefore, the following should be considered within the scope of the present invention:
the complex or the complex prepared by the method and the application thereof in preparing hypoxic anti-tumor drugs.
Preferably, the tumor is breast cancer, cervical cancer or lung cancer.
The invention has the following beneficial effects:
the invention provides a cyclometalated iridium metformin complex and a preparation method and application thereof. The cyclometalated iridium metformin complex Ir1, Ir2 and Ir3 prepared by the invention can be rapidly taken by tumor cells and has the phosphorescence tracing characteristic; in addition, compared with the normoxic condition, the complex has the advantages that the cytotoxicity of the complex on tumor cells is enhanced under the hypoxic condition, ROS can be better induced to be generated in the tumor cells, the HIF-1 alpha has better inhibition activity, and the apoptosis of the tumor cells is finally induced, so that the complex has excellent hypoxic anti-tumor activity, and the activity is even better than that of cisplatin; in addition, the preparation method of the complex is simple and feasible and has low cost; therefore, the complex prepared by the invention has good application prospect and wide development space in the preparation of hypoxic anti-tumor drugs.
Drawings
FIG. 1 shows the uptake of cyclometalated iridium metformin complex by tumor cells; wherein, "Brightfield" represents the bright field, "Overlay" represents the superposition, the picture a is a bright field picture, the picture b is a picture of a complex 405nm excitation channel, and the picture c is a picture obtained by superposing the picture a and the picture b.
FIG. 2 is a result of the effect of the complex Ir1 on the apoptosis-inducing ability of MCF-7 cells under normoxic and hypoxic conditions.
FIG. 3 is a result of the effect of complex Ir1 on ROS levels in MCF-7 cells under normoxic and hypoxic conditions.
FIG. 4 is a graph showing the results of HIF-1. alpha. inhibitory activity of complex Ir1 under hypoxic conditions; wherein, Metformin represents Metformin, Hoechst represents excitation of Hoechst, Merge represents merging, a picture is an excitation channel photo of Hoechst, a picture b picture is an excitation channel photo of secondary antibody, and a picture c is a photo obtained by superposing the a picture and the b picture.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 preparation of Cyclometalated Iridium metformin Complex Ir1
The preparation method of the cyclometalated iridium metformin complex Ir1 comprises the following steps:
s1, mixing iridium trichloride hydrate and a ligand in a molar ratio of 1: 2.2 after mixing, dissolving in a mixed solvent (volume ratio is 3: 1) of ethylene glycol ethyl ether and ultrapure water, carrying out coordination reaction for 24h at 135 ℃ under reflux stirring, cooling to room temperature, carrying out suction filtration, respectively washing the obtained solid product for 3 times by using ultrapure water and diethyl ether, and carrying out vacuum drying to obtain an iridium precursor;
s2, mixing the iridium precursor (121.4mg, 0.1mmol) obtained in the step S1 with metformin (66.2mg, 0.4mmol), dissolving in a dichloromethane/methanol mixed solvent (volume ratio of 1.5: 1), and dissolving in N2Adding potassium tert-butoxide (89.8mg, 0.8mmol) under protection, reacting at 35 deg.C for 25h, rotary evaporating reaction solvent after reaction, adding 1mL methanol for dissolution, and adding saturated NH4PF6Separating out a solid from an aqueous solution, performing suction filtration, respectively washing the solid with ultrapure water and diethyl ether for 3 times to obtain a relatively pure solid, further purifying by using a column chromatography (an eluent is dichloromethane: methanol-10: 1 in a volume ratio), and performing vacuum drying to obtain the complex Ir 1;
wherein, the molar ratio of the iridium precursor, the metformin and the potassium tert-butoxide in the step S2 is 1: 4: 8, the ligand is 2- (2, 4-difluorophenyl) pyridine, and the structural formula is shown in the specification
The structural formula of the complex Ir1 is
The data are as follows:
1H NMR(400MHz,DMSO-d6)8.77(d,J＝5.4Hz,1H),8.67(d,J＝5.8Hz,1H),8.25(d,J＝4.4Hz,1H),8.06(q,J＝7.1Hz,3H),7.51(q,J＝6.2,5.6Hz,3H),6.79–6.61(m,2H),6.40(s,2H),6.35(s,1H),5.98(s,1H),5.60(dd,J＝8.7,2.2Hz,1H),5.52(dd,J＝8.6,2.2Hz,1H),2.87(s,6H).
ESI-MS: theoretical value: 701.71[ M-PF ] M/z6]+(ii) a Experimental values: 702.44[ M-PF ] M/z6]+。
Elemental analysis: the molecular formula is as follows: c26H22F10IrN7P·CH3OH·H2O, theoretical value: 36.20% of C, 3.15% of H and 10.95% of N; experimental values: c36.16%, H3.14%, N10.91%.
Example 2 preparation of Cyclometalated Iridium metformin Complex Ir2
The preparation method of the cyclometalated iridium metformin complex Ir2 comprises the following steps:
s1, mixing iridium trichloride hydrate and a ligand in a molar ratio of 1: 2.5, dissolving in a mixed solvent (volume ratio is 2: 1) of ethylene glycol ethyl ether and ultrapure water, carrying out a coordination reaction for 22h at 130 ℃ under reflux stirring, cooling to room temperature, carrying out suction filtration, washing the obtained solid product with ultrapure water and diethyl ether respectively for 3 times, and carrying out vacuum drying to obtain an iridium precursor;
s2, mixing the iridium precursor (121.4mg, 0.1mmol) obtained in the step S1 with metformin (66.2mg, 0.4mmol), dissolving in a dichloromethane/methanol mixed solvent (volume ratio of 2: 1), and dissolving in N2Adding potassium tert-butoxide (89.8mg, 0.8mmol) under protection, reacting at 40 deg.C for 30h, rotary evaporating reaction solvent after reaction, adding 1mL methanol to dissolve, and adding saturated NH4PF6Separating out solid from aqueous solution, suction filtering, washing the solid with ultrapure water and diethyl ether respectively for 3 times,obtaining a relatively pure solid, further purifying by column chromatography (eluent is dichloromethane: methanol 10: 1 by volume ratio), and drying in vacuum to obtain the complex Ir 2;
wherein, the molar ratio of the iridium precursor, the metformin and the potassium tert-butoxide in the step S2 is 1: 4: 10, the ligand is 2-phenylpyridine and the structural formula is shown in the specification
The structural formula of the complex Ir2 is
The data are as follows:
1H NMR(400MHz,DMSO-d6)8.74(d,J＝6.4Hz,1H),8.64(d,J＝5.7Hz,1H),8.16(d,J＝8.2Hz,2H),7.98–7.89(m,2H),7.79–7.71(m,2H),7.40(dddd,J＝11.1,7.3,5.8,1.4Hz,2H),6.81(tdd,J＝7.5,3.9,1.3Hz,2H),6.65(t,J＝7.3Hz,2H),6.37(s,2H),6.22(s,1H),6.17(dd,J＝7.6,1.2Hz,1H),6.10(dd,J＝7.5,1.2Hz,1H),5.57(s,1H),2.84(s,6H).
ESI-MS: theoretical value: 629.75[ M-PF ] M/z6]+(ii) a Experimental values: 630.50[ M-PF ] M/z6]+。
Elemental analysis: the molecular formula is as follows: c26H26F6IrN7P·CH3OH, theoretical value: 40.25%, H3.75%, N12.17%; experimental values: c40.34%, H3.90%, N11.62%.
Example 3 preparation of Cyclometalated Iridium metformin Complex Ir3
The preparation method of the cyclometalated iridium metformin complex Ir3 comprises the following steps:
s1, mixing iridium trichloride hydrate and a ligand in a molar ratio of 1: 3, dissolving the mixture in a mixed solvent (volume ratio is 4: 1) of ethylene glycol ethyl ether and ultrapure water, carrying out a coordination reaction for 26 hours at 140 ℃ under reflux stirring, cooling to room temperature, carrying out suction filtration, washing the obtained solid product with ultrapure water and diethyl ether respectively for 3 times, and carrying out vacuum drying to obtain an iridium precursor;
s2, reacting the iridium precursor (121.4mg, 0.1mmol) obtained in the step S1 withMetformin (66.2mg, 0.4mmol) was mixed, dissolved in a mixed solvent of methylene chloride/methanol (volume ratio: 1), and dissolved in N2Adding potassium tert-butoxide (89.8mg, 0.8mmol) under protection, reacting at 30 deg.C for 20h, rotary evaporating reaction solvent after reaction, adding 1mL methanol for dissolution, and adding saturated NH4PF6Separating out a solid from an aqueous solution, performing suction filtration, respectively washing the solid with ultrapure water and diethyl ether for 3 times to obtain a relatively pure solid, further purifying by using a column chromatography (an eluent is dichloromethane: methanol-10: 1 in a volume ratio), and performing vacuum drying to obtain the complex Ir 3;
wherein, the molar ratio of the iridium precursor, the metformin and the potassium tert-butoxide in the step S2 is 1: 4: 6, the ligand is 7, 8-benzoquinoline, and the structural formula is
The structural formula of the complex Ir3 is
The data are as follows:
1H NMR(400MHz,DMSO-d6)9.16(dd,J＝5.4,1.3Hz,1H),9.04(dd,J＝5.4,1.3Hz,1H),8.56(ddd,J＝8.1,3.0,1.3Hz,2H),7.93–7.78(m,6H),7.33(ddd,J＝7.9,3.2,0.9Hz,2H),6.94(td,J＝7.5,4.5Hz,2H),6.34(d,J＝10.0Hz,3H),6.22(dd,J＝7.2,0.9Hz,1H),6.07(dd,J＝7.2,0.9Hz,1H),5.80(s,1H),2.84(s,6H).
ESI-MS: theoretical value: 677.79[ M-PF ] M/z6]+(ii) a Experimental values: 678.36[ M-PF ] M/z6]+。
Elemental analysis: the molecular formula is as follows: c30H26F6IrN7P·2CH3OCH3The theoretical value is as follows: c44.68%, H4.19%, N10.73%; experimental values: 44.81% of C, 4.05% of H and 10.73% of N.
Application example 1 determination of hypoxic antitumor Activity of Cyclometalated Irmetformin Complex
1. Experimental methods
The cyclometalated iridium metformin complexes Ir1, Ir2 and Ir3 prepared in the embodiments 1, 2 and 3 of the invention are used as experimental groups, metformin and cisplatin are used as control groups, and the cytotoxicity of the cyclometalated iridium metformin complexes Ir1, Ir2 and Ir3 on tested tumor cells (MCF-7 (human breast cancer cell line), HeLa (human cervical cancer cell line) or A549 (human lung cancer cell line)) is respectively determined, and the specific determination method is as follows:
measuring with tetrazolium salt (MTT) colorimetric method, digesting the tumor cells with pancreatin to obtain single cell suspension, counting with blood counting plate, and adjusting cell concentration to 5 × 104/mL, inoculating in 96-well plate, culturing for 24 hr, adding medicines (cyclometalated iridium-metformin complex Ir1, Ir2, Ir3, metformin or cisplatin) with different concentrations, and placing in oxygen (cells containing 5% CO)2Cultured in an incubator) or hypoxic (cells at 1% O)2、5％CO2、94％N2Under hypoxic conditions) was incubated at 37 ℃ for 48h and MTT 20 μ L/well was added 4h before the end of incubation. After 4h, the supernatant was discarded, DMSO was added in an amount of 150. mu.L/well, and after shaking for 5 minutes, the OD value was measured with a microplate reader at 595 nm.
The survival rate of the tested tumor cells was calculated according to the following formula, and the IC was determined by plotting50Value, evaluation of the hypoxic antitumor activity of cyclometalated iridium metformin complexes.
2. Results of the experiment
The cyclometalated iridium metformin complex prepared by the invention has IC effect on tumor cells under the normoxic condition50The values are shown in table 1, and it can be seen that the complexes Ir1, Ir2 and Ir3 all have good antitumor activity, wherein the toxicity of the complexes Ir1 and Ir3 to tumor cells is significantly higher than that of cisplatin, and metformin has almost no toxicity to tumor cells.
The results show that: the cyclometalated iridium metformin complex Ir1, Ir2 and Ir3 prepared by the invention have good anti-tumor activity.
TABLE 1 IC of cyclometalated iridium metformin complex prepared according to the present invention on tumor cells under normoxic conditions50Value of
The cyclometalated iridium metformin complex Ir1 prepared by the invention has IC effect on tumor cells under the conditions of normal oxygen and hypoxia50The values are shown in table 2, and it can be seen that the complexes Ir1, Ir2 and Ir3 all have good antitumor activity, wherein the toxicity of the complex Ir1 to tumor cells is significantly higher than that of cisplatin, and the complex Ir1 is in hypoxic condition (1% O)2) Is obviously higher than that of the product under the normal oxygen condition (21 percent of O)2) Cytotoxicity to tumor cells.
The results show that: the cyclometalated iridium metformin complex Ir1 prepared by the invention has good anti-tumor activity under the hypoxic condition, namely the complex Ir1 has obvious hypoxic anti-tumor activity.
TABLE 2 IC of cyclometalated iridium metformin complex Ir1 prepared by the present invention on tumor cells under normoxic and hypoxic conditions50Value of
The above results show that: the cyclometalated iridium metformin complex Ir1, Ir2 and Ir3 prepared by the invention have obvious antitumor activity, and the complex Ir1 has obvious hypoxic antitumor activity.
Application example 2 uptake of Cyclometalated Iridium metformin Complex by tumor cells
1. Experimental methods
Preparing 3 clean and sterilized 35mm Corning laser/confocal culture dishes, digesting human breast cancer cells (MCF-7 cells) with good growth state with pancreatin, transferring to the confocal culture dishes, and culturing in normal oxygen (the cells contain 5% CO)2Cultured in an incubator) at 37 ℃. When MCF-7 cells are cultured to 70%, cyclometalated iridium metformin complex Ir1, Ir2 and Ir3 prepared by the method are respectively added, the final concentration is 10 mu M, the cells are continuously cultured for 10min, then a culture medium is removed, PBS is used for washing twice, the cells are immediately observed by a laser confocal microscope, excitation with 405nm is adopted, and the complexes Ir1, Ir2 and Ir3 are respectively measured to be 500 +/-20 nm and 530 +/-20 nm580. + -.20 nm fluorescence intensity.
2. Results of the experiment
The uptake condition of the cyclometalated iridium metformin complex by a tumor cell is shown in fig. 1, and it can be seen that the complexes Ir1, Ir2 and Ir3 are mainly enriched in the cytoplasm of the tumor cell, which indicates that the complexes Ir1, Ir2 and Ir3 can be well taken up by the tumor cell and have the phosphorescence tracing characteristic.
Application example 3 study on hypoxic anti-tumor effect of cyclometalated iridium metformin complex
The embodiment explains the mechanism of the hypoxic anti-tumor effect of the cyclometalated iridium metformin complex prepared by the invention from multiple aspects, and determines the capacity of the complex Ir1 in inducing MCF-7 cell apoptosis and the influence of the ROS level in MCF-7 cells by a flow cytometer, and determines the inhibitory activity of the complex Ir1 on HIF-1 alpha by an immunofluorescence experiment. The specific experimental methods and results are as follows:
1. ability to induce apoptosis of MCF-7 cells
(1) Experimental methods
MCF-7 cells in good growth state were digested with trypsin, diluted with DMEM medium to form a single cell suspension, and plated in a Corning six-well plate at 200. mu.L per well. After culturing for 24h under the condition of normal oxygen or hypoxia at 37 ℃, the complex Ir1 with the concentration of 2 mu M, 5 mu M and 10 mu M is respectively added for cell apoptosis stimulation. After 24h incubation, cells were trypsinized and harvested, 195. mu.L Annexin V-FITC binding solution was added to gently resuspend the cells, then 5. mu.L Annexin V-FITC and 10. mu.L propidium iodide staining solution were added and gently mixed. Incubating for 10-20 min at room temperature in the dark, then placing in an ice bath, and keeping out of the light with aluminum foil. And then detected by a flow cytometer.
(2) Results of the experiment
The results of the effect of the complex Ir1 on the cell apoptosis inducing capability of MCF-7 cells under the normoxic and hypoxic conditions are shown in FIG. 2, and it can be seen that the proportion of the MCF-7 cell apoptosis is gradually increased along with the increase of the concentration of the complex Ir1 after the complex Ir1 is treated; the proportion of MCF-7 apoptosis induced by complex Ir1 under hypoxic conditions was further increased compared to normoxic conditions, consistent with the data in table 2.
The above results show that: under the condition of hypoxia, the complex Ir1 prepared by the invention can obviously induce tumor cell apoptosis and has obvious capacity of inducing MCF-7 cell apoptosis.
2. Effect on ROS levels in MCF-7 cells
(1) Experimental methods
Mitochondria are the major site of ROS (reactive oxygen species) production, and mitochondrial dysfunction and abnormal production of ROS are important causes of apoptosis in cancer cells induced by many anticancer drugs.
MCF-7 cells with good growth state are taken, trypsinized and diluted into single cell suspension by adding a culture medium, the single cell suspension is inoculated into a six-hole plate, 200 mu L of each hole is inoculated, and the single cell suspension is cultured under the condition of normal oxygen or anaerobic condition at 37 ℃. When the cells grow to the density of about 80%, the complexes Ir1 with the concentrations of 2. mu.M, 5. mu.M and 10. mu.M are respectively added for incubation for 6h, and the cells which are not added with the complexes Ir1 are used as a control group. The cells were trypsinized and collected, incubated with 10 μ M DCFH-DA in serum-free medium at 37 ℃ for 20min in the absence of light, and mixed by inversion every 5min to bring the probe into intimate contact with the cells. The supernatant was removed by centrifugation and the cells were washed three times with serum-free cell culture medium to remove DCFH-DA well without entering the cells. Thereafter, the fluorescence intensity was measured using an excitation wavelength of 488nm and an emission wavelength of 525 nm. Data were analyzed using FlowJo 10(Tree Star, OR, USA) software.
(2) Results of the experiment
The results of the effect of the complex Ir1 on the ROS level in MCF-7 cells under the normoxic and hypoxic conditions are shown in FIG. 3, and it can be seen that the fluorescence intensity (MFI value) of DCF in MCF-7 cells is gradually increased along with the increase of the concentration of the complex Ir1, which indicates that the ROS level in the cells is gradually increased; and in hypoxic conditions, the ROS level in the cells is obviously increased compared with that in the normal oxygen condition after the complex Ir1 is treated.
The above results show that: the complex Ir1 prepared by the invention can induce MCF-7 cells to generate more ROS under the hypoxic condition, and better induce the apoptosis of the MCF-7 cells.
3. Inhibitory Activity on HIF-1 alpha
(1) Experimental methods
Antibodies were purchased from Abcam and manipulated according to the protocol described herein. MCF-7 cells in good growth state are digested by pancreatin and inoculated in a confocal dish. After the cells are attached to the wall, 40uM metformin and 6uM complex Ir1 are added respectively, and the cells are incubated for 48h under the hypoxic condition, and the cells which are not added with the complex treatment are used as a control group. Removing the culture medium, adding 4% paraformaldehyde to fix the cells, permeabilizing with 0.2% TrintonX-100 for 15min, and washing with PBS; sealing the cells with sealing solution for 30 min; the blocking solution was removed, washed with washing solution, and then incubated overnight at 4 ℃ with the addition of primary antibody (rabbit anti-HIF-1. alpha. antibody). After removing the primary antibody, the cells were washed three times with a washing solution, and a horseradish peroxidase (HRP) -labeled secondary antibody (goat anti-rabbit IgG H & L) was added and incubated for 1H at room temperature in the dark. Rinsing with PBS, followed by addition of Hoechst to stain nuclei. And then observed under a laser confocal microscope.
(2) Results of the experiment
The inhibitory activity result of the complex Ir1 on HIF-1 alpha under the hypoxic condition is shown in FIG. 4, and it can be seen that under the hypoxic condition, the fluorescence of the excitation channel of the secondary antibody treated by the complex Ir1 almost disappears, and the cell treated by the metformin still has fluorescence; the complex Ir1 shows that the complex Ir1 has better inhibitory activity on HIF-1 alpha.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (8)
1. A cyclometalated iridium metformin complex is characterized in that the structural formula of the complex is shown as a formula (I):
wherein the content of the first and second substances,
is a ligand, the structural formula of the ligand is
Any one of them.
2. A process for the preparation of a cyclometalated iridium metformin complex according to claim 1, comprising the steps of:
s1, mixing and dissolving iridium trichloride hydrate and the ligand of claim 1, and performing a coordination reaction under reflux stirring to obtain an iridium precursor;
s2, mixing and dissolving the iridium precursor obtained in the step S1 and metformin, and adding strong base for reaction under the protection of inert gas to obtain the complex.
3. The method of claim 2, wherein the molar ratio of the iridium precursor, the metformin, and the strong base in step S2 is 1: 4: 6 to 10.
4. The method according to claim 2, wherein the temperature of the reaction of step S2 is 30 ℃ to 40 ℃; the reaction time of the step S2 is 20-30 h.
5. The method according to claim 2, wherein the solvent used for the dissolving in step S2 is a mixed solvent of dichloromethane and methanol; the volume ratio of the dichloromethane to the methanol is 1-2: 1.
6. the complex as defined in claim 1 or the complex prepared by the method as defined in any one of claims 2 to 5.
7. The use of the complex of claim 6 in the preparation of hypoxic antitumor drugs.
8. The use according to claim 7, wherein the tumor is breast cancer, cervical cancer or lung cancer.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021194420A1 (en) * | 2020-03-23 | 2021-09-30 | National University Of Singapore | Gold(iii)-biguanide prodrugs, methods of preparation and uses thereof |
| CN114409711A (en) * | 2022-01-27 | 2022-04-29 | 南方海洋科学与工程广东省实验室(湛江) | Aptamer-cyclometalated iridium conjugate and preparation method and application thereof |
| CN114957340A (en) * | 2022-05-06 | 2022-08-30 | 湖南科技大学 | Preparation method and application of binuclear iridium complex for inducing iron death |
| CN115246862A (en) * | 2021-12-17 | 2022-10-28 | 昆明理工大学 | Cyclometalated platinum metformin complex and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278956A (en) * | 2016-08-04 | 2017-01-04 | 山西大学 | A kind of sulphation metformin closes Cr (III) acid potassium complexes and preparation method thereof |
-
2020
- 2020-04-13 CN CN202010286209.4A patent/CN111574568B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278956A (en) * | 2016-08-04 | 2017-01-04 | 山西大学 | A kind of sulphation metformin closes Cr (III) acid potassium complexes and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| FENG CHEN等: "Biguanide Iridium(Ⅲ) Complexes with Potent Antimicrobial Activity", 《J. MED. CHEM.》 * |
| S.P.GHOSH等: "Diacidobis(biguanidinium) Ir(Ⅲ) complexes", 《INDIAN JOURNAL OF CHEMISTRY》 * |
| 何良等: "磷光环金属化铱(Ⅲ) 配合物在癌症治疗方面的应用", 《化学进展》 * |
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| WO2021194420A1 (en) * | 2020-03-23 | 2021-09-30 | National University Of Singapore | Gold(iii)-biguanide prodrugs, methods of preparation and uses thereof |
| CN115246862A (en) * | 2021-12-17 | 2022-10-28 | 昆明理工大学 | Cyclometalated platinum metformin complex and preparation method and application thereof |
| CN115246862B (en) * | 2021-12-17 | 2024-03-22 | 昆明理工大学 | Cyclometalated platinum metformin complex and preparation method and application thereof |
| CN114409711A (en) * | 2022-01-27 | 2022-04-29 | 南方海洋科学与工程广东省实验室(湛江) | Aptamer-cyclometalated iridium conjugate and preparation method and application thereof |
| CN114409711B (en) * | 2022-01-27 | 2024-02-09 | 南方海洋科学与工程广东省实验室(湛江) | Aptamer-cyclometalated iridium conjugate and preparation method and application thereof |
| CN114957340A (en) * | 2022-05-06 | 2022-08-30 | 湖南科技大学 | Preparation method and application of binuclear iridium complex for inducing iron death |
| CN114957340B (en) * | 2022-05-06 | 2023-12-26 | 湖南科技大学 | Preparation method and application of binuclear iridium complex for inducing iron death |
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