CN111072727B - Iridium complex constructed based on 8-hydroxyquinoline derivative and 2-phenylpyridine iridium dimer as well as synthetic method and application thereof - Google Patents
Iridium complex constructed based on 8-hydroxyquinoline derivative and 2-phenylpyridine iridium dimer as well as synthetic method and application thereof Download PDFInfo
- Publication number
- CN111072727B CN111072727B CN201911336068.6A CN201911336068A CN111072727B CN 111072727 B CN111072727 B CN 111072727B CN 201911336068 A CN201911336068 A CN 201911336068A CN 111072727 B CN111072727 B CN 111072727B
- Authority
- CN
- China
- Prior art keywords
- complex
- iridium
- phenylpyridine
- application
- dimer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0033—Iridium compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an iridium complex constructed based on 8-hydroxyquinoline derivatives and 2-phenylpyridine iridium dimers, and a synthesis method and application thereof. The synthesis method of the iridium complex comprises the following steps: putting the iridium 2-phenylpyridine dimer and the 8-hydroxyquinoline derivative in an organic solvent, and reacting under heating or non-heating conditions to obtain the corresponding target complex. The test results of the applicant show that the complex of the invention has significant biological activity (the activity is significantly higher than that of the ligand and cisplatin) on cervical cancer and ovarian cancer cells, and simultaneously, the toxicity of the complex to normal human liver cells is very low (IC)50> 80. mu.M); on the other hand, the complex can also perform fluorescence localization on tumor cells, and can be developed into a targeted anti-cancer drug which targets mitochondria through fluorescence localization.
Description
Technical Field
The invention relates to an iridium complex constructed based on 8-hydroxyquinoline derivatives and 2-phenylpyridine iridium dimers, and a synthesis method and application thereof, and belongs to the technical field of medicines.
Background
At present, tumors are the second most serious diseases of human death, and seriously endanger the physical and mental health of the nation. The malignant tumor is commonly of lung cancer, cervical cancer, breast cancer, liver cancer, lymph cancer, leukemia and other types. Clinically, platinum antineoplastic drugs are still one of the important chemotherapy drugs for treating tumors, and account for more than 50% of the application of clinical chemotherapy drugs. The main target of the medicine against cancer is double-stranded DNA, wherein the main action mechanism is to interfere double-stranded replication of DNA in tumor cells, thereby playing a role in restraining cell growth. Despite their important impact as anti-cancer drugs, these drugs have significant side effects, coupled with their inherent inadequate drug resistance, have prompted researchers to develop new non-platinum metal anti-tumor drugs.
Hydroxyquinoline is considered a special structure because these heterocycles are widely present in natural and synthetic bioactive molecules, interacting with different targets, inducing important functional changes in a variety of disease states. Chemical studies of quinoline derivatives have received particular attention in the last few years even up to now, and researchers have synthesized a variety of quinoline-carried antimalarial, antiallergic, antiviral, antiinflammatory, bactericidal, and the like. However, no report related to the iridium complex constructed by 8-hydroxyquinoline derivatives and 2-phenylpyridine iridium dimers, and a synthetic method and application thereof is found at present.
Disclosure of Invention
The invention aims to solve the technical problem of providing an iridium complex which has obvious inhibitory activity on various tumor cells but has low toxicity on normal human liver cells and is constructed on the basis of 8-hydroxyquinoline derivatives and 2-phenylpyridine iridium dimers, and a synthesis method and application thereof.
The iridium complex constructed based on the 8-hydroxyquinoline derivative and the 2-phenylpyridine iridium dimer is a complex with a structure shown in the following formula 1-5 and a pharmaceutically acceptable salt thereof:
the invention also provides a synthesis method of the complex compound with the structure shown in the formula 1-5, which comprises the following steps: putting a 2-phenylpyridine iridium dimer and a compound shown in a formula (I) in an organic solvent, and reacting under a heating condition or a non-heating condition to obtain a corresponding target complex;
wherein:
R1represents a hydrogen atom or a methyl group, R2Represents a hydrogen atom or a halogen atomR, R3Represents a hydrogen atom or a halogen atom;
the organic solvent is ethanol, or the combination of ethanol and one or more than two of water, acetone, dichloromethane, trichloromethane, dimethyl sulfoxide and N, N-dimethylformamide.
In the synthetic method, the raw material 2-phenylpyridine iridium dimer can be prepared by referring to the existing literature (Watts, R.J.; J.Am.chem.SOC., 1984, 106, 6647-6653), and can also be designed and synthesized by self, and the details are not described herein.
In the synthesis method of the invention, the molar ratio of the compound shown in the formula (I) and the iridium dimer 2-phenylpyridine is stoichiometric, and the amount of the iridium dimer 2-phenylpyridine can be relatively excessive in the actual operation process.
In the synthetic method, in the compound shown as the raw material formula (I), R1Preferably a hydrogen atom or a methyl group, R2Preferably a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom, R3Preferably a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom. Specifically, the method comprises the following steps:
when R is1Is methyl, R2Is a chlorine atom, R3When the compound is a chlorine atom, the compound shown in the formula (I) is chloroquindol (also referred to as H-QL1 in the application), and the correspondingly synthesized target complex is a complex with a structure shown in the formula 1 (also referred to as Ir1 or Ir1 in the application);
when R is1Is methyl, R2Is a bromine atom, R3When the compound is a bromine atom, the compound shown in the formula (I) is 5, 7-dibromo-2-methyl-8-hydroxyquinoline (also referred to as H-QL2 in the application), and a target complex obtained by corresponding synthesis is a complex with a structure shown in the formula 2 (also referred to as Ir2 or Ir2 in the application);
when formula R1Is a hydrogen atom, R2Is an iodine atom, R3When the compound is an iodine atom, the compound shown in the formula (I) is 5, 7-diiodo-8-hydroxyquinoline (also referred to as H-QL3 in the application), and a target complex obtained by corresponding synthesis is a complex with a structure shown in a formula 3 (also referred to as Ir3 or Ir3 in the application);
when formula R1Is a hydrogen atom, R2Is a chlorine atom, R3When the compound is a hydrogen atom, the compound shown in the formula (I) is 5-chloro-8-hydroxyquinoline (also referred to as H-QL6 in the application), and a target complex obtained by corresponding synthesis is a complex with a structure shown in a formula 4 (also referred to as Ir4 or Ir4 in the application);
when formula R1Is methyl, R2Is a hydrogen atom, R3When the compound is a hydrogen atom, the compound shown in the formula (I) is 8-hydroxyquinaldine (also referred to as H-QL7 in the application), and the correspondingly synthesized target complex is a complex with a structure shown in a formula 5 (also referred to as Ir5 or Ir5 in the application).
In the synthesis method of the invention, the target compound is generated only under the condition that ethanol exists in the solvent. When the organic solvent is ethanol and other selected combinations, the volume ratio of ethanol in the organic solvent is preferably more than or equal to 5 percent, more preferably more than or equal to 10 percent, and even more preferably more than or equal to 20 percent. The amount of the organic solvent is preferably such that the raw materials to be reacted can be dissolved, and in general, all the raw materials to be reacted are dissolved in 1.5 to 50mL of the organic solvent based on 1mmol of the iridium-2-phenylpyridine dimer.
In the synthesis method of the present invention, when the reaction is carried out under heating, the target compound can be obtained more quickly than when the reaction is not carried out under heating, and therefore, the reaction is preferably carried out under heating, more preferably at not less than 30 ℃, and still more preferably at 35 to 100 ℃. TLC can be adopted to track and detect whether the reaction is complete or not in the reaction process. The test result of the applicant shows that when the reaction is carried out under the condition of no heating, the target compound can be generated within the time of more than or equal to 5 days; when the reaction is carried out at 35-100 ℃, a large amount of target compounds can be generated within 8-48 h.
The invention also provides application of the complex with the structure shown in the formula 1-5 or pharmaceutically acceptable salt thereof in preparing antitumor drugs. In particular to application in preparing a medicament for resisting cervical cancer and/or ovarian cancer.
The invention further comprises a pharmaceutical composition which contains a therapeutically effective dose of the complex with the structure shown in the formulas 1-5 or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials. The dosage form of the medicine can be any pharmaceutically acceptable dosage form, such as granules, capsules, injection and the like.
In addition, the applicant also finds that the complex with the structure shown in the formula 1-5 can be used as a fluorescence imaging dye for mitochondrial membrane potential in tumor cells, and therefore, the invention also comprises the application of the complex with the structure shown in the formula 1-5 or pharmaceutically acceptable salts thereof in preparing a sensitizer.
Compared with the prior art, the invention provides five iridium complexes with novel structures and a synthesis method thereof, and test results of the applicant show that the complexes have remarkable biological activity (the activity is remarkably higher than that of a ligand and cisplatin) on cervical cancer and ovarian cancer cells, and meanwhile, the toxicity (IC) of the complexes on normal human liver cells is extremely low (the IC is extremely low)50> 80. mu.M); on the other hand, the complexes can also perform fluorescence localization in tumor cells, and can be developed into targeted anti-cancer drugs with fluorescence localization targeting to mitochondria.
Drawings
FIG. 1 is a crystal structure diagram of a final product obtained in example 1 of the present invention.
FIG. 2 is a crystal structure diagram of the final product obtained in example 3 of the present invention.
FIG. 3 is a crystal structure diagram of the final product obtained in example 5 of the present invention.
FIG. 4 is a crystal structure diagram of the final product obtained in example 6 of the present invention.
FIG. 5 is a crystal structure diagram of the final product obtained in example 7 of the present invention.
FIG. 6 is a fluorescence imaging diagram of complex Ir1 in Experimental example 2 of the present invention acting on cervical cancer HeLa cells for 6h (1: blank control group; 2: complex Ir1 (1.22. mu.M) drug addition group).
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
The iridium-2-phenylpyridine (H-ppy) dimers involved in the following examples were prepared as follows:
2.4mmol of 2-phenylpyridine, 1.2mmol of iridium trichloride trihydrate and 6mL of ethylene glycol ethyl ether 18mL of deionized water are placed in a 50mL flask, then the flask is heated to 120 ℃ under the protection of nitrogen, condensed and refluxed for 24 hours, after the reaction is finished, the flask is naturally cooled to room temperature, 200mL of deionized water is poured into the reaction liquid, a large amount of yellow precipitate is separated out by stirring, the yellow precipitate is filtered, a filter cake is sequentially washed by water and ethanol, and then the yellow precipitate is dried in vacuum at 45 ℃ to obtain a yellow solid, namely the 2-phenylpyridine iridium dimer.
Example 1: synthesis of Complex Ir1
In a 100.0mL round bottom flask, 2.0mmol of chloroquinadol (H-QL1) and 1.0mmol of iridium-2-phenylpyridine dimer were added, followed by 16.5mL of an organic solvent (consisting of 15.0mL of ethanol and 1.5mL of water), stirred to dissolve, the reaction was carried out at 70 ℃ until completion (about 12H), the reaction was stopped, cooled to room temperature, reddish brown crystals precipitated, collected, and dried to obtain a reddish brown solid product. The yield was 90.21%.
The product obtained in this example was characterized:
(1) single crystal X-ray diffraction
The reddish brown crystals with intact surface structures were measured by single crystal diffraction to determine the crystal structures thereof, and the resulting crystallographic and structure correction data are shown in the following Table 1, and the partial bond length and bond angle data are shown in the following tables 2 and 3, respectively, and the crystal structures of the resulting reddish brown crystals are shown in FIG. 1.
TABLE 1 crystallography and Structure correction data for complexes Ir1-Ir3
aR1＝Σ||Fo|–|Fc||/Σ|Fo|；bwR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 2 bond Length of Complex Ir1
TABLE 3 bond angles [ ° ] of the complexes Ir1
(2) Elemental analysis (C)32H22Cl2IrN3O) results, as shown in Table 4.
TABLE 4 elemental analysis results for complexes Ir1-Ir3
(3) Infrared spectra, the infrared data of which are shown below.
IR(KBr):3449,1635,1604,1542,1425,1357,1263,1158,1030,936,844,756,731,466,418cm-1.
(4) Electrospray mass spectrometry, which was analyzed as follows.
ESI-MS m/z:727.7[M+H]+Wherein M is the molecular weight of the complex Ir 1.
Therefore, the product obtained in this example was determined to be the target complex Ir1 with the molecular formula [ Ir (QL1) (ppy)2](wherein QL1 represents a dehydroxy hydrogen atom of chloroquinalder, and has a negative charge unitPpy represents that 2-phenylpyridine has one unit negative charge without one hydrogen atom), and the chemical structural formula is as follows:
example 2: synthesis of Complex Ir1
Example 1 was repeated, except that the organic solvent was changed to ethanol and the amount used was unchanged; the reaction was carried out at 100 ℃ instead (reaction to completion for about 6 h).
As a result, reddish brown crystals were obtained. The yield was 85.31%.
And (3) performing single crystal diffraction analysis, elemental analysis, infrared analysis and mass spectrometry on the product obtained in the embodiment, and determining that the obtained reddish brown crystal is the target complex Ir 1.
Example 3: synthesis of Complex Ir2
In a 100.0mL round bottom flask, 2.0mmol of 5, 7-dibromo-2-methyl-8-hydroxyquinoline (H-QL2) and 1.0mmol of iridium 2-phenylpyridine dimer were added, followed by 16.5mL of an organic solvent (composed of 3.5mL of ethanol and 10.5mL of chloroform) and stirred to dissolve, and the reaction was carried out at 65 ℃ until completion (about 27 hours), and the reaction was stopped, cooled to room temperature, and reddish brown crystals precipitated, collected and dried to obtain a reddish brown solid product. The yield was 80.46%.
The product obtained in this example was characterized:
(1) single crystal X-ray diffraction
The reddish brown crystals with intact surface structures were measured by single crystal diffraction to determine the crystal structures thereof, and the resulting crystallographic and structure correction data are shown in the above Table 1, and the partial bond length and bond angle data are shown in the following tables 5 and 6, respectively, and the crystal structures of the resulting reddish brown crystals are shown in FIG. 2.
TABLE 5 bond Length of Complex Ir2
TABLE 6 bond angles [ ° of complex Ir2
(2) Elemental analysis (C)32H22Br2IrN3O) results, as shown in Table 4 above.
(3) Infrared spectra, the infrared data of which are shown below.
IR(KBr):3462,1637,1604,1539,1476,1423,1352,1266,1158,1116,1029,924,841,755,731cm-1.
(4) Electrospray mass spectrometry was analyzed as follows.
ESI-MS m/z:815.8[M+H]+Wherein M is the molecular weight of the complex Ir 2.
Therefore, the product obtained in this example was determined to be the target complex Ir2 with the molecular formula [ Ir (QL2) (ppy)2](wherein QL2 represents that 5, 7-dibromo-2-methyl-8-hydroxyquinoline removes hydroxyl hydrogen atoms and has a unit negative charge, ppy represents that 2-phenylpyridine removes a hydrogen atom and has a unit negative charge), and the chemical structural formula is as follows:
example 4: synthesis of Complex Ir2
Example 1 was repeated, except that the organic solvent was instead composed of 1.0mL of ethanol, 10.0mL of acetone, and 9.0mL of dichloromethane; the reaction was carried out at 40 ℃ instead (reaction time was about 30h to completion).
As a result, reddish brown crystals were obtained. The yield was 74.06%.
And (3) performing single crystal diffraction analysis, elemental analysis, infrared analysis and mass spectrometry on the product obtained in the embodiment, and determining that the obtained reddish brown crystal is the target complex Ir 2.
Example 5: synthesis of Complex Ir3
In a 100.0mL round bottom flask, 2.0mmol of 5, 7-diiodo-8-hydroxyquinoline (H-QL3) and 1.0mmol of iridium 2-phenylpyridine dimer were added, followed by 25.0mL of an organic solvent (consisting of 20.0mL of ethanol and 5.0mL of DMF), stirred to dissolve, and the reaction was carried out at 100 ℃ until completion (about 72H), the reaction was stopped, cooled to room temperature, reddish brown crystals precipitated, the crystals were collected and dried to obtain a reddish brown solid product. The yield was 90.54%.
The product obtained in this example was characterized:
(1) single crystal X-ray diffraction
The reddish brown crystals with intact surface structures were measured by single crystal diffraction to determine the crystal structures thereof, and the resulting crystallographic and structure correction data are shown in the above Table 1, and the partial bond length and bond angle data are shown in the following tables 7 and 8, respectively, and the crystal structures of the resulting reddish brown crystals are shown in FIG. 3.
TABLE 7 bond Length of Complex Ir3
TABLE 8 bond angles [ ° of complex Ir3
(2) Elemental analysis (C)31H20I2IrN3O) results, as shown in Table 4 above.
(3) Infrared spectra, the infrared data of which are shown below.
IR(KBr):3452,1637,1476,1385,1040,645cm-1.
(4) Electrospray mass spectrometry, which was analyzed as follows.
ESI-MS m/z:897.3[M+H]+Wherein M is the molecular weight of the complex Ir 3.
Therefore, the product obtained in this example was determined to be the target complex Ir3 with the molecular formula [ Ir (QL3) (ppy)2](wherein QL2 represents that 5, 7-diiodo-8-hydroxyquinoline removes a hydroxyl hydrogen atom and has a negative unit charge, ppy represents that 2-phenylpyridine removes a hydrogen atom and has a negative unit charge), and the chemical structural formula is as follows:
example 6: synthesis of Complex Ir4
In a 100.0mL round bottom flask, 2.0mmol of 5-chloro-8-hydroxyquinoline (H-QL6) and 1.0mmol of iridium 2-phenylpyridine dimer were added, followed by 15.5mL of an organic solvent (composed of 15.0mL of ethanol and 0.5mL of dimethyl sulfoxide), stirred to dissolve, and the reaction was carried out at 55 ℃ until completion (about 36H), the reaction was stopped, cooled to room temperature, reddish brown crystals precipitated, the crystals were collected and dried to obtain a reddish brown solid product. The yield was 80.00%.
The product obtained in this example was characterized:
(1) single crystal X-ray diffraction
The reddish brown crystals with intact surface structures were measured by single crystal diffraction to determine the crystal structures thereof, and the resulting crystallographic and structure correction data are shown in the following Table 9, and the partial bond length and bond angle data are shown in the following tables 10 and 11, respectively, and the crystal structures of the resulting reddish brown crystals are shown in FIG. 4.
TABLE 9 crystallographic and structural correction data for complexes Ir4-Ir5
aR1＝Σ||Fo|–|Fc||/Σ|Fo|；bwR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 10 bond Length of Complex Ir4
TABLE 11 bond angles [ ° of complex Ir4
(2) Elemental analysis (C)31H21ClIrN3O) results, as shown in Table 12.
TABLE 12 elemental analysis results for complexes Ir4-Ir5
(3) Infrared spectra, the infrared data of which are shown below.
IR(KBr):3450,1634,1577,1538,1426,1352,1117,1037,937,782,731,666cm-1.
(4) Electrospray mass spectrometry was analyzed as follows.
ESI-MS m/z:845.5[M+DMSO+H]+Wherein M is the molecular weight of the complex Ir 4.
Therefore, the product obtained in this example was determined to be the target complex Ir4 with the molecular formula [ Ir (QL6) (ppy)2](wherein QL6 represents that 5-chloro-8-hydroxyquinoline removes a hydroxyl hydrogen atom and has a single negative charge, ppy represents that 2-phenylpyridine removes a hydrogen atom and has a single negative charge), and the chemical structural formula is as follows:
example 7: synthesis of Complex Ir5
In a 100.0mL round bottom flask, 2.0mmol of 8-hydroxyquinaldine (H-QL7) and 1.0mmol of iridium 2-phenylpyridine dimer were added, followed by 22.5mL of an organic solvent (consisting of 2.5mL of ethanol and 20mL of water), stirred to dissolve, the reaction was carried out at 80 ℃ until completion (about 6H), the reaction was stopped, cooled to room temperature, reddish brown crystals precipitated, collected, and dried to give a reddish brown solid product. The yield was 80.33%.
The product obtained in this example was characterized:
(1) single crystal X-ray diffraction
The reddish brown crystals with intact surface structures were measured by single crystal diffraction to determine the crystal structures thereof, and the resulting crystallographic and structure correction data were as shown in the above Table 9, and the partial bond length and bond angle data were as shown in the following tables 13 and 14, respectively, and the crystal structures of the resulting reddish brown crystals were as shown in FIG. 5.
TABLE 13 bond Length of Complex Ir5
TABLE 14 bond angles [ ° of complex Ir5
(2) Elemental analysis (C)32H24IrN3O) results, as shown in table 12 above.
(3) Infrared spectra, the infrared data of which are shown below.
IR(KBr):3452,1638,1605,1581,1555,1452,1424,1385,1159,1109,1059,829,760,737,668,472cm-1.
(4) Electrospray mass spectrometry, which was analyzed as follows.
ESI-MS m/z:657.7[M+H]+Wherein M is the molecular weight of the complex Ir 5.
Therefore, the product obtained in this example was determined to be the target complex Ir5 with the molecular formula [ Ir (QL7) (ppy)2](wherein QL7 represents 8-hydroxyquinaldine with one negative charge per hydroxyl group and ppy represents 2-phenylpyridine with one negative charge per hydroxyl group), the chemical formula is as follows:
example 8: synthesis of Complex Ir5
Example 7 was repeated except that the reaction was carried out at ordinary temperature (to completion for about 4 days).
As a result, reddish brown crystals were obtained. The yield was 86.32%.
And (3) performing single crystal diffraction analysis, elemental analysis, infrared analysis and mass spectrometry on the product obtained in the embodiment, and determining that the obtained reddish brown crystal is the target complex Ir 5.
Experimental example 1: experiments on proliferation inhibition activity of the complex Ir1-Ir5 on various human tumor cell strains:
1. cell lines and cell cultures
The experiment selects human cervical carcinoma HeLa, human ovarian cancer cis-platinum-resistant SK-OV-3/DDP cell strain and human normal liver cell HL-7702.
All cell lines were cultured in RPMI-1640 medium containing 10 wt% calf blood, 100U/mL penicillin and 100U/mL streptomycin, and placed at 37 ℃ in a volume concentration of 5% CO2Culturing in an incubator.
2. Preparation of test Compounds
The purity of each compound to be tested is more than or equal to 95 percent, the DMSO stock solution is diluted by physiological buffer solution to prepare a final solution with the concentration of 20 mu mol/L, wherein the final concentration of the cosolvent DMSO is less than or equal to 1 percent, and the inhibition degree of the compound to be tested on the growth of various tumor cells under the concentration is tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking tumor cells in logarithmic growth phase, digesting by trypsin, preparing cell suspension with the number concentration of 5000/mL by using culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate, and enabling the cell density to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);
(2)5％CO2incubating for 6.0h at 37 ℃ until a cell monolayer is paved on the bottom of each well, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 compound wells in each concentration gradient;
(3)5％CO2incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4 h;
(5) terminating the culture, carefully removing the culture solution in the wells, adding 150 μ L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, a drug dissolving medium with the same concentration, a culture solution, MTT, DMSO) are arranged.
(7) The number of living cells was judged from the measured optical density values (OD values), and the larger the OD value, the stronger the cell activity.
The inhibition rate of the drug on the growth of tumor cells is calculated by the formula, and then the IC of the iridium complex on the cell strains is calculated by a Bliss method50The value is obtained. The results are shown in Table 15.
TABLE 15 IC of complexes Ir1-Ir5 for different tumor cell lines50Value (μ M, 6.0h)
From IC of table 1550The results show that the complex of the invention has certain proliferation inhibition effect on 3 human cell strains, especially has the most obvious HeLa inhibition effect on human cervical carcinoma cells, and the activity of the complex is obviously higher than that of cisplatin and IrCl3·6H2O and the corresponding ligands H-QL1, H-QL2, H-QL3, H-QL6, H-QL7 and H-ppy; and the toxicity of the complexes to normal cells HL-7702 is small (IC)50Greater than 80 μ M) with better cytotoxicity selectivity. Therefore, the complex has good potential medicinal value and is expected to be used for preparing various antitumor medicaments.
Experimental example 2: imaging experiment of complex Ir1 on target positioning mitochondria of HeLa cell
1. Experimental procedure
(1) The complex Ir1(1.22 mu M) acts on the HeLa cell for 6 h;
(2) mitochondrial staining solution was diluted with serum-free medium at a final concentration of 50nM at a ratio of 1:1000, and after removal of the cell culture medium, the diluted mitochondrial staining solution was added in an appropriate volume, preferably sufficient to cover the cells.
(3) Incubate at 37 ℃ for 20min in a cell culture box.
(4) Washing the cells with serum-free cell culture solution for 3 times to sufficiently remove mitochondrial staining solution which does not enter the cells;
(5) staining with DAPI (staining for nucleus) and Mito-green (staining for mitochondrial membrane) for 10min, respectively, and washing the cells with serum-free cell culture solution for 3 times;
(6) the intracellular mitochondria were observed.
2. Experimental results and discussion
As shown in FIG. 6, after the complex Ir1(1.22 μ M) is acted on HeLa cells for 6h, the complex Ir1 is mainly distributed on mitochondrial membrane potential, overlaps with fluorescent dye (Mito-Green) for detecting membrane potential on the market, is red on mitochondrial membrane parts, and is a good fluorescent dye. Furthermore, it can also be seen from the figure that there is little distribution of the drug in the nucleus, indicating that the drug targets the mitochondrial membrane, thereby inducing apoptosis of tumor cells.
In conclusion, the complex Ir1-Ir5 generally shows obvious in-vitro antitumor activity and toxicity selectivity, has good potential medicinal value, is a targeted anticancer medicament with fluorescence localization targeting to mitochondria, and is expected to be used for preparing various antitumor medicaments.
Claims (1)
1. The application of the complex with the structure shown in the following formula 1-5 and the pharmaceutically acceptable salt thereof in preparing a targeted anticancer drug targeting mitochondria by fluorescence localization,
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110326515.0A CN113072591B (en) | 2019-12-23 | 2019-12-23 | Iridium complex and synthesis method and application thereof |
| CN201911336068.6A CN111072727B (en) | 2019-12-23 | 2019-12-23 | Iridium complex constructed based on 8-hydroxyquinoline derivative and 2-phenylpyridine iridium dimer as well as synthetic method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911336068.6A CN111072727B (en) | 2019-12-23 | 2019-12-23 | Iridium complex constructed based on 8-hydroxyquinoline derivative and 2-phenylpyridine iridium dimer as well as synthetic method and application thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110326515.0A Division CN113072591B (en) | 2019-12-23 | 2019-12-23 | Iridium complex and synthesis method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111072727A CN111072727A (en) | 2020-04-28 |
| CN111072727B true CN111072727B (en) | 2021-04-30 |
Family
ID=70316665
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110326515.0A Active CN113072591B (en) | 2019-12-23 | 2019-12-23 | Iridium complex and synthesis method and application thereof |
| CN201911336068.6A Active CN111072727B (en) | 2019-12-23 | 2019-12-23 | Iridium complex constructed based on 8-hydroxyquinoline derivative and 2-phenylpyridine iridium dimer as well as synthetic method and application thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110326515.0A Active CN113072591B (en) | 2019-12-23 | 2019-12-23 | Iridium complex and synthesis method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN113072591B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679549B (en) * | 2020-12-24 | 2022-09-20 | 玉林师范学院 | 8-hydroxyquinoline derivative iridium (III) complex and preparation method and application thereof |
| CN112661795B (en) * | 2020-12-24 | 2022-09-20 | 玉林师范学院 | Human ovarian cancer cell inhibitor, preparation method and application thereof |
| CN112608341B (en) * | 2020-12-24 | 2022-09-20 | 玉林师范学院 | Mixed quinoline derivative iridium (III) complex and preparation method and application thereof |
| CN113683644B (en) * | 2021-08-26 | 2022-05-20 | 玉林师范学院 | Bis-quinoline iridium complex for treating cisplatin-resistant cancer cells and preparation method and application thereof |
| CN113527370B (en) * | 2021-08-26 | 2022-07-15 | 玉林师范学院 | Quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells and synthesis method and application thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4154145B2 (en) * | 2000-12-01 | 2008-09-24 | キヤノン株式会社 | Metal coordination compound, light emitting device and display device |
| CN101003730B (en) * | 2006-11-07 | 2010-05-12 | 南昌大学 | Electronic phosphorescence material of heavy metal complexes by using octa-hydroxy quinoline as assistant ligand and synthetic method thereof |
| CN101891627B (en) * | 2009-05-22 | 2015-04-29 | 中国科学院化学研究所 | Ruthenium-containing coordination compound and preparation method thereof |
| CN102516309B (en) * | 2011-10-25 | 2014-07-02 | 暨南大学 | Ruthenium complex capable of inhibiting tumor angiogenesis and preparation method and application thereof |
| CN106905372A (en) * | 2017-01-24 | 2017-06-30 | 中山大学 | A kind of Ir (III) complex and preparation method thereof and the application in electroluminescent device is prepared |
| CN107021974B (en) * | 2017-04-21 | 2019-02-05 | 广西师范大学 | Using 2- methyl -5,7- dibromc-8-hydroxyquinoline as monokaryon dysprosium complex of ligand and its preparation method and application |
| CN107602621A (en) * | 2017-09-22 | 2018-01-19 | 南京工业大学 | A kind of organometallic complex, its preparation method and its application |
| CN108191918A (en) * | 2018-04-04 | 2018-06-22 | 桂林师范高等专科学校 | Halogenated 8-hydroxyquinoline platinum (II) complex and its synthetic method and application |
| CN110330533B (en) * | 2019-07-26 | 2021-05-28 | 广西师范大学 | 2-methyl-8-hydroxyquinoline and tropolone mixed platinum complex and preparation method and application thereof |
-
2019
- 2019-12-23 CN CN202110326515.0A patent/CN113072591B/en active Active
- 2019-12-23 CN CN201911336068.6A patent/CN111072727B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111072727A (en) | 2020-04-28 |
| CN113072591B (en) | 2021-11-23 |
| CN113072591A (en) | 2021-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111072727B (en) | Iridium complex constructed based on 8-hydroxyquinoline derivative and 2-phenylpyridine iridium dimer as well as synthetic method and application thereof | |
| CN111039990B (en) | Low-toxicity iridium complex and synthesis method and application thereof | |
| CN110950914B (en) | Iridium complex and synthesis method and application thereof | |
| Hong et al. | Organotin (IV) complexes derived from Schiff base N′-[(1E)-(2-hydroxy-3-methoxyphenyl) methylidene] pyridine-4-carbohydrazone: Synthesis, in vitro cytotoxicities and DNA/BSA interaction | |
| CN111116667B (en) | Iridium complex constructed based on 8-hydroxyquinoline derivative and 1-phenylpyrazole iridium dimer as well as synthetic method and application thereof | |
| CN107746418B (en) | Synthesis and application of 9-chloro-1, 2,3, 4-tetrahydroacridine-platinum (II) complex targeting liver cancer | |
| CN107955042B (en) | Platinum complex with anticancer activity, preparation method and application | |
| CN108774270B (en) | Sorafenib antitumor platinum (II) complex targeting drug-resistant cells of human lung cancer and preparation method and application thereof | |
| CN112679549B (en) | 8-hydroxyquinoline derivative iridium (III) complex and preparation method and application thereof | |
| CN108774269B (en) | Novel targeted benzimidazole derivative antitumor platinum (II) and ruthenium (II) complex and preparation method and application thereof | |
| CN103524564A (en) | Synthesis method and application of platinum (II) complex of 6-amino oxoisoaporphine | |
| CN104208061A (en) | Medical application of berberine derivative | |
| Liu et al. | Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property | |
| CN107827934B (en) | Tetravalent platinum complex with anticancer activity, preparation method and application | |
| CN112608341B (en) | Mixed quinoline derivative iridium (III) complex and preparation method and application thereof | |
| CN111704634B (en) | Metal complex containing tridentate ligand and xanthine derivative ligand as well as preparation method and medical application of metal complex | |
| CN108148080B (en) | Organic golden (III) complex of metal and its synthetic method and application | |
| CN110590778B (en) | 3, 10 di-p-methoxyphenyl 6, 12 diaza tetracubane compound, synthetic method and pharmaceutical composition | |
| CN105440085A (en) | 9-benzothianthrene hydrazine-ruthenium (II) complex as well as synthetic method and application thereof | |
| CN106883271B (en) | ONS tridentate ligand Pt (II) complex with antitumor activity as well as preparation method and application thereof | |
| CN104327064B (en) | Acridine-1,3,4-oxadiazole compound having anti-tumor activity, preparation method and uses thereof | |
| CN108997436A (en) | A kind of novel Rui Gefeini anti-tumor platinum (II) complex and the preparation method and application thereof | |
| CN112661795B (en) | Human ovarian cancer cell inhibitor, preparation method and application thereof | |
| US11571430B2 (en) | Platinum(II) ammine selenourea complexes and methods of treating cancer | |
| CN113683645B (en) | Binuclear Pt (II) complex with anti-tumor activity and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221230 Address after: Room 801, No. 1719-8, Huishan Avenue, Huishan District, Wuxi City, Jiangsu Province, 214000 Patentee after: Huangtu Pharmaceutical (Wuxi) Co.,Ltd. Address before: 541004 No. 15 Yucai Road, Qixing District, Guilin, the Guangxi Zhuang Autonomous Region Patentee before: Guangxi Normal University |