CN110950914A - Iridium complex and synthesis method and application thereof - Google Patents
Iridium complex and synthesis method and application thereof Download PDFInfo
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- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 24
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title abstract description 14
- 238000001308 synthesis method Methods 0.000 title abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- WZJYKHNJTSNBHV-UHFFFAOYSA-N benzo[h]quinoline Chemical compound C1=CN=C2C3=CC=CC=C3C=CC2=C1 WZJYKHNJTSNBHV-UHFFFAOYSA-N 0.000 claims abstract description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000000539 dimer Substances 0.000 claims abstract description 10
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- CTQMJYWDVABFRZ-UHFFFAOYSA-N cloxiquine Chemical compound C1=CN=C2C(O)=CC=C(Cl)C2=C1 CTQMJYWDVABFRZ-UHFFFAOYSA-N 0.000 claims abstract description 8
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- 210000004027 cell Anatomy 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 7
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 5
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- 230000004071 biological effect Effects 0.000 abstract description 4
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- 238000004949 mass spectrometry Methods 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002503 iridium Chemical class 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229910021638 Iridium(III) chloride Inorganic materials 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
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- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- LNJXVUXPFZKMNF-UHFFFAOYSA-K iridium(3+);trichloride;trihydrate Chemical compound O.O.O.Cl[Ir](Cl)Cl LNJXVUXPFZKMNF-UHFFFAOYSA-K 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- DANYXEHCMQHDNX-UHFFFAOYSA-K trichloroiridium Chemical compound Cl[Ir](Cl)Cl DANYXEHCMQHDNX-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- 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 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an iridium complex and a synthesis method and application thereof, wherein the synthesis method of the complex comprises the following steps: placing 5-chloro-8-hydroxyquinoline and 7, 8-benzoquinoline iridium dimer in an organic solvent, and reacting under heating or non-heating conditions to obtain a target compound; wherein the organic solvent is ethanol, or the combination of ethanol and one or more than two of water, acetone, dichloromethane, chloroform, dimethyl sulfoxide and N, N-dimethylformamide. The test results of the applicant show that the complex has remarkable biological activity (the activity is obviously higher than that of cisplatin) on cervical cancer and ovarian cancer cells, and meanwhile, the toxicity (IC) of the complex on normal human liver cells is extremely low50＞80μM)。
Description
Technical Field
The invention relates to an iridium complex and a synthesis method and application thereof, belonging to the technical field of medicines.
Background
Cancer is currently one of the most serious malignant diseases threatening human life and health. At present, more than three hundred and more than ten thousand people die of cancer every year in China, and the life health safety of the people in China is seriously threatened. Platinum complexes such as cisplatin are one of the most widely used chemotherapeutic drugs at present and are one of the first choice drugs for treating many cancers (Lippard, s.j.; et al. chem.sci.,2015,6, 1189-1193.). However, clinical use of platinum drugs such as cisplatin in large quantities is likely to cause drug resistance and severe toxic side effects such as nephrotoxicity, neurotoxicity and myelosuppression, which greatly limits their therapeutic effects and long-term use (Lippard, s.j.; et al chem.sci.,2015,6, 1189-1193.). Therefore, the development of novel metal-targeting antitumor drugs is highly urgently required.
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. The 8-hydroxyquinoline is used as a medical intermediate, but no related report that the iridium complex obtained by construction by using 5-chloro-8-hydroxyquinoline and 7, 8-benzoquinoline iridium dimer as ligands has obvious biological activity on tumor cells and low toxicity on normal human liver cells exists at present.
Disclosure of Invention
The invention aims to solve the technical problem of providing an iridium complex which has obvious biological activity on tumor cells and low toxicity on normal human liver cells, a synthetic method and application thereof.
The iridium complex is a compound shown as the following formula (I) or a pharmaceutically acceptable salt thereof:
the invention also provides a synthesis method of the compound shown in the formula (I), which comprises the following steps: placing 5-chloro-8-hydroxyquinoline and 7, 8-benzoquinoline iridium dimer in an organic solvent, and reacting under heating or non-heating conditions to obtain a target compound; wherein the organic solvent is ethanol, or the combination of ethanol and one or more than two of water, acetone, dichloromethane, chloroform, dimethyl sulfoxide and N, N-dimethylformamide.
In the synthetic method, the raw material 7, 8-benzoquinoline 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, the molar ratio of the 5-chloro-8-hydroxyquinoline to the 7, 8-benzoquinoline iridium dimer is stoichiometric, and the amount of the 7, 8-benzoquinoline iridium dimer can be relatively excessive in the actual operation process.
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 5-chloro-8-hydroxyquinoline.
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 compound shown in the formula (I) 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 compound shown in the formula (I) 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.
Compared with the prior art, the invention provides an iridium complex with a novel structure and a synthesis method thereof, and test results of the applicant show that the complex has remarkable biological activity (the activity is obviously higher than that of a ligand and cisplatin) on cervical cancer and ovarian cancer cells, and simultaneously has extremely low toxicity (IC) on normal human liver cells50＞80μM)。
Drawings
FIG. 1 is a crystal structure diagram of a final product obtained in example 1 of the present invention.
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 7, 8-benzoquinoline iridium dimers referred to in the following examples were prepared as follows:
taking 2.4mmol of 7, 8-benzoquinoline, 1.2 mmol of iridium trichloride trihydrate and 6mL of ethylene glycol ethyl ether 18mL of deionized water, placing the mixture in a 50mL flask, heating the mixture to 120 ℃ under the protection of nitrogen, condensing and refluxing for 24h, naturally cooling the mixture to room temperature after the reaction is finished, pouring 200mL of deionized water into reaction liquid, stirring the mixture to separate out a large amount of yellow precipitate, filtering the yellow precipitate, washing a filter cake with water and ethanol in sequence, and then drying the yellow precipitate in vacuum at 45 ℃ to obtain a yellow solid, namely the 7, 8-benzoquinoline iridium dimer.
Example 1
In a 100.0mL round bottom flask, 2.0mmol of 5-chloro-8-hydroxyquinoline and 1.0mmol of 7, 8-benzoquinoline iridium dimer were added, followed by 15.5mL of an organic solvent (consisting of 15.0mL of ethanol and 0.5mL of dimethyl sulfoxide), stirred to dissolve, the reaction was carried out at 55 ℃ until completion (about 8h), 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 79.99%.
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 Iridium complexes
R1＝Σ||Fo|–|Fc||/Σ|Fo|；bwR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 2 bond lengths of Iridium complexes
TABLE 3 bond angles [ ° ] of iridium complexes
(2) The results of elemental analysis are shown in Table 4.
TABLE 4 elemental analysis (C) of Iridium complexes35H21ClIrN3O) result
(3) Infrared spectra, the infrared data of which are shown below.
IR(KBr):3450,1626,1563,1495,1448,1401,1324,1087,829,780,747,675cm-1.
(4) Electrospray mass spectrometry, which was analyzed as follows.
ESI-MS m/z:725.7[M+H]+Wherein M is the molecular weight of the iridium complex.
Therefore, it was confirmed that the product obtained in this example was the objective compound having the molecular formula [ Ir (QL6) (bzql)2](wherein QL6 represents that 5-chloro-8-hydroxyquinoline has a single negative charge except hydroxyl hydrogen atom, and bzql represents that 7, 8-benzoquinoline has a single negative charge except hydrogen atom), the chemical structural formula is shown in the following (I):
example 2
Example 1 was repeated, except that the organic solvent was instead composed of 1.0mL of ethanol and 15mL of dichloromethane and the reaction was instead carried out at 35 deg.C (reaction was completed for about 50 h).
As a result, reddish brown crystals were obtained. The yield was 91.24%.
The product obtained in this example was subjected to single crystal diffraction analysis, elemental analysis, infrared analysis, and mass spectrometry, and the reddish brown crystal obtained was determined to be the target compound.
Example 3
Example 1 was repeated, except that the organic solvent was instead composed of 3.0mL of ethanol, 5.0mL of water and 12.0mL of acetone and the reaction was instead carried out at 80 deg.C (reaction was completed for about 35 h).
As a result, reddish brown crystals were obtained. The yield was 80.55%.
The product obtained in this example was subjected to single crystal diffraction analysis, elemental analysis, infrared analysis, and mass spectrometry, and the reddish brown crystal obtained was determined to be the target compound.
Example 4
Example 1 was repeated except that the organic solvent was changed to consist of 10.0mL of ethanol, 5.0mL of chloroform and 5.0mL of N, N-dimethylformamide and the reaction was changed to be carried out at normal temperature (reaction was completed for about 5 days).
As a result, reddish brown crystals were obtained. The yield was 92.02%.
The product obtained in this example was subjected to single crystal diffraction analysis, elemental analysis, infrared analysis, and mass spectrometry, and the reddish brown crystal obtained was determined to be the target compound.
Experimental example 1: proliferation inhibition activity experiments of the iridium complex 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 5.
TABLE 5 IC of Iridium complexes on different tumor cell lines50Value (μ M, 6.0h)
From IC of Table 550The 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-QL6 and H-bzql; and the complex has little toxicity (IC) to normal cell HL-770250Greater 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.
Claims (8)
1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
2. a method of synthesizing the compound of claim 1, wherein: placing 5-chloro-8-hydroxyquinoline and 7, 8-benzoquinoline iridium dimer in an organic solvent, and reacting under heating or non-heating conditions to obtain a target compound; wherein the organic solvent is ethanol, or the combination of ethanol and one or more than two of water, acetone, dichloromethane, chloroform, dimethyl sulfoxide and N, N-dimethylformamide.
3. The method of synthesis according to claim 2, characterized in that: when the organic solvent is ethanol and other selected combinations, the volume ratio of the ethanol in the organic solvent is more than or equal to 5 percent.
4. The method of synthesis according to claim 2, characterized in that: the reaction is carried out at a temperature of more than or equal to 30 ℃.
5. The method of synthesis according to claim 2, characterized in that: the reaction is carried out at 35-100 ℃.
6. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-neoplastic drug.
7. Use according to claim 6, characterized in that: is an application in preparing the medicine for resisting cervical cancer and/or ovarian cancer.
8. A pharmaceutical composition characterized by: comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608341A (en) * | 2020-12-24 | 2021-04-06 | 玉林师范学院 | Mixed quinoline derivative iridium (III) complex and preparation method and application thereof |
| CN112661795A (en) * | 2020-12-24 | 2021-04-16 | 玉林师范学院 | Human ovarian cancer cell inhibitor, preparation method and application thereof |
| CN112679549A (en) * | 2020-12-24 | 2021-04-20 | 玉林师范学院 | 8-hydroxyquinoline derivative iridium (III) complex and preparation method and application thereof |
| CN113527370A (en) * | 2021-08-26 | 2021-10-22 | 玉林师范学院 | Quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells and synthesis method and application thereof |
| CN113683644A (en) * | 2021-08-26 | 2021-11-23 | 玉林师范学院 | Bis-quinoline iridium complex for treating cisplatin-resistant cancer cells and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516309A (en) * | 2011-10-25 | 2012-06-27 | 暨南大学 | Ruthenium complex capable of inhibiting tumor angiogenesis and preparation method and application thereof |
| 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 |
| CN108409799A (en) * | 2018-03-03 | 2018-08-17 | 广西师范大学 | It can be used for the complex and preparation method thereof of optical dynamic therapy |
-
2019
- 2019-12-23 CN CN201911336628.8A patent/CN110950914B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516309A (en) * | 2011-10-25 | 2012-06-27 | 暨南大学 | Ruthenium complex capable of inhibiting tumor angiogenesis and preparation method and application thereof |
| CN108409799A (en) * | 2018-03-03 | 2018-08-17 | 广西师范大学 | It can be used for the complex and preparation method thereof of optical dynamic therapy |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| AMIT MAITY等，: "Photo induced trans/cis isomerism studies of heteroleptic iridium complex with 8-quinolinol-5-phenylazo ligand: Photophysical and electrochemical studies and it"s theoretical investigations", 《JOURNAL OF MOLECULAR STRUCTURE》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608341A (en) * | 2020-12-24 | 2021-04-06 | 玉林师范学院 | Mixed quinoline derivative iridium (III) complex and preparation method and application thereof |
| CN112661795A (en) * | 2020-12-24 | 2021-04-16 | 玉林师范学院 | Human ovarian cancer cell inhibitor, preparation method and application thereof |
| CN112679549A (en) * | 2020-12-24 | 2021-04-20 | 玉林师范学院 | 8-hydroxyquinoline derivative iridium (III) complex and 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 |
| 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 |
| CN113527370A (en) * | 2021-08-26 | 2021-10-22 | 玉林师范学院 | Quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells and synthesis method and application thereof |
| CN113683644A (en) * | 2021-08-26 | 2021-11-23 | 玉林师范学院 | Bis-quinoline iridium complex for treating cisplatin-resistant cancer cells 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 |
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