CN116217477A - 5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity, and synthetic method and application thereof - Google Patents
5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity, and synthetic method and application thereof Download PDFInfo
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- CN116217477A CN116217477A CN202310070905.5A CN202310070905A CN116217477A CN 116217477 A CN116217477 A CN 116217477A CN 202310070905 A CN202310070905 A CN 202310070905A CN 116217477 A CN116217477 A CN 116217477A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D215/24—Oxygen atoms attached in position 8
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Abstract
The invention discloses a 5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity, and a synthesis method and application thereof. The invention takes 5-bromo-8-hydroxyquinoline as an active ligand to synthesize the 5-bromo-8-hydroxyquinoline cobalt complex [ Co (BrQ) with high anticancer activity 3 ]·CH 3 OH, and the activity and toxicity experiments of the strain on human ovarian cancer drug-resistant strain cells SK-OV-3/DDP and normal HL-7702 cells are examined. Experimental results show that [ Co (BrQ) 3 ]·CH 3 The OH has obvious effect of inhibiting SK-OV-3/DDP of ovarian cancer drug-resistant strain cells, and IC 50 The value is as low as 0.27+/-0.09 mu M, which is far higher than H-BrQ and CoCl 2 ·6H 2 O and clinical medicine cisplatin, and has small toxicity to normal HL-7702 cells, which shows that the complex has good tumor selectivity to tumor cells.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a 5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity, and a synthesis method and application thereof.
Background
Cancer is generally treated by various methods such as radiation therapy, operation, chemotherapy and the like, but only the operation therapy and the radiation therapy are one of the important means of local treatment, while platinum drugs inhibit the growth of tumor cells during the chemotherapy, and simultaneously have toxic effects to various cells which normally proliferate in the organism to different degrees. Therefore, development and treatment of the targeting non-platinum drugs have shown a better prospect in recent years (Guo, Z.; et al chem. Soc. Rev.; 2013, 42:202-224.; however, at present, in the clinical trial stage, clinical use needs further deep observation and accumulation, so that the development and treatment have a larger gap from large-scale clinical popularization and use.
Cobalt (Co), which is a metal element in the fourth and eighth groups of the periodic table, has been studied more in the fields of sterilization, anticancer, chemical catalysis, etc., and compared with the traditional cisplatin anticancer drugs, the complex has the advantages of smaller side effects, safer, etc. (Guo, Z.; et al chem. Soc. Rev.; 2013,42:202-224; ji Yanhua, etc. chemical reagents, 2021,43 (10): 1348-1352).
The 8-hydroxyquinoline cobalt complex was reported to have good anticancer activity (Ling, f.—p.; et al acs med.chem.lett..2019, 10:1603-1608; qin, q..p.; et al acs med.lett..2019, 10:1603-1608.inorg.chem.Commun..2020, 115:107854), however, the anticancer activity of the 5-bromo-8-hydroxyquinoline cobalt complex remained blank.
Disclosure of Invention
The invention aims to provide a 5-bromo-8-hydroxyquinoline cobalt complex with higher anticancer activity.
Specifically, the invention provides a 5-bromo-8-hydroxyquinoline cobalt complex, which is chemicalIs [ Co (BrQ) 3 ]·CH 3 OH, its chemical structural formula is shown as the following formula:
the second purpose of the invention is to provide a synthesis method of the 5-bromo-8-hydroxyquinoline cobalt complex, which comprises the following steps: in a thick-walled, 15.0cm long resistant tube, 0.300mmol of 5-bromo-8-hydroxyquinoline (H-BrQ) and 0.100mmol of CoCl were weighed, respectively 2 ·6H 2 O, add 2.5mL MeOH, 0.5mL CH 2 Cl 2 And 0.5mL triethylamine, vacuumizing, sealing the pipe orifice, and carrying out coordination reaction at 80 ℃ for 3 days to obtain a target product [ Co (BrQ) of reddish brown bulk crystals 3 ]·CH 3 OH。
The synthetic route is as follows:
another object of the present invention is to provide the use of the above-mentioned 5-bromo-8-quinolinolato cobalt complex.
In particular to an application of a 5-bromo-8-hydroxyquinoline cobalt complex in preparing a drug for targeted treatment of ovarian cancer. Further relates to application of the 5-bromo-8-hydroxyquinoline cobalt complex in preparing a drug for targeted treatment of ovarian cancer of drug-resistant strains.
Compared with the prior art, the invention takes 5-bromo-8-hydroxyquinoline (H-BrQ) as an active ligand to synthesize the 5-bromo-8-hydroxyquinoline cobalt complex [ Co (BrQ) with high anticancer activity 3 ]·CH 3 OH, and the activity and toxicity experiments of the strain on human ovarian cancer drug-resistant strain cells SK-OV-3/DDP and normal HL-7702 cells are examined. Experimental results show that [ Co (BrQ) 3 ]·CH 3 The OH has obvious effect of inhibiting SK-OV-3/DDP of ovarian cancer drug-resistant strain cells, and IC 50 The value is as low as 0.27+/-0.09 mu M, which is far higher than H-BrQ and CoCl 2 ·6H 2 O and clinical medicine cisplatin, and has small toxicity to normal HL-7702 cells, which shows that the complex has good tumor selectivity to tumor cells. In conclusion, 5-bromo-8-The cobalt hydroxyquinoline complex has excellent anti-tumor activity and potential medicinal value, and is expected to be used for preparing various anti-tumor medicaments.
Drawings
FIG. 1 is a view showing the structure of an X-ray single crystal of the complex prepared in example 1 of the present invention.
Detailed Description
The present invention will be further illustrated by the following specific examples, but the present invention is not limited to these examples.
Example 1
0.300mmol of 5-bromo-8-hydroxyquinoline (H-BrQ) and 0.100mmol of CoCl were weighed into a 15.0cm thick-walled drug-resistant tube, respectively 2 ·6H 2 O, add 2.5mL MeOH, 0.5mL CH 2 Cl 2 And 0.5mL triethylamine, vacuumizing, sealing the pipe orifice, and carrying out coordination reaction at 80 ℃ for 3 days to obtain a target product [ Co (BrQ) of reddish brown bulk crystals 3 ]·CH 3 OH. The yield was 87.9%.
The product obtained was identified:
(1) The structure diagram of the X-ray single crystal of the complex is shown in figure 1.
(2) The elemental analysis results are shown in table 1.
Table 1 results of elemental analysis of the complexes in the examples
Thus, the complex of the resulting reddish brown bulk crystal can be determined, and its structural formula is as follows:
in order to fully illustrate the application of the 5-bromo-8-hydroxyquinoline cobalt complex with high anti-cancer activity in pharmacy, the applicant carries out an anti-tumor activity experiment.
1. Proliferation inhibition activity test of target object on 2 human cell lines
1. Cell strain and cell culture
The experiment selects 2 human cell lines such as human ovarian cancer drug-resistant strain cell SK-OV-3/DDP and normal HL-7702 cells.
All the human cell lines are cultured in RPMI-1640 culture solution containing 100U/mL penicillin, 10wt% calf blood and 100U/mL streptomycin, and the culture solution is placed at 37 ℃ and contains CO with the volume concentration of 5% 2 Culturing in incubator.
2. Preparation of test Compounds
All compounds used were > 95% pure and their DMSO stock was diluted with physiological buffer to 20 μmol/L final solution (DMSO final concentration 1%) at which the extent of inhibition of growth of normal or selected tumor cells by each compound was tested.
3. Cell growth inhibition experiment (MTT method)
(1) Taking normal cells or tumor cells in logarithmic growth phase, preparing a cell suspension with the concentration of 5000 cells/mL by using a culture solution containing 10% calf serum after trypsin digestion, and inoculating 190 mu L of the cell suspension into a 96-well culture plate for each well to enable the density of cells to be detected to 1000-10000 wells (the edge wells are filled with sterile PBS);
(2)5％ CO 2 incubating at 37 ℃ for 24 hours until cell monolayers are fully paved at the bottom of the wells, adding 10 mu L of a drug with a certain concentration gradient into each well, and setting 4 compound wells for each concentration gradient;
(3)5％ CO 2 incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) mu.L of MTT solution (5 mg/mL PBS, i.e., 0.5% MTT) was added to each well and incubation was continued for 4h;
(5) Stopping culturing, carefully sucking out the culture solution in the holes, adding 150 mu L of DMSO into each hole to fully dissolve formazan precipitate, uniformly mixing by using a shaker, measuring the optical density value of each hole at the wavelength of 570nm for an enzyme-labeling instrument and the reference wavelength of 450 nm;
(6) Setting zeroing holes (culture medium, MTT, DMSO) and control holes (cells, culture solution, MTT, drug dissolution medium with the same concentration and DMSO) at the same time;
(7) The number of living cells is judged based on the measured optical density value (OD value), and the greater the OD value, the stronger the cell activity. Using the formula:
calculating the inhibition rate of each compound on the growth of the selected cells, and calculating the IC of each tested compound on each selected cell strain by using a Bliss method 50 Values. The results are shown in Table 2 below.
TABLE 2 IC of compounds against various cell lines 50 Value (mu M)
IC from Table 2 50 As a result of the activity, the complex [ Co (BrQ) 3 ]·CH 3 The OH has obvious effect of inhibiting SK-OV-3/DDP of ovarian cancer drug-resistant strain cells, and IC 50 The activity on SK-OV-3/DDP is far greater than that of ligand H-BrQ, metal salt CoCl, with a value as low as 0.27+ -0.09 mu M 2 ·6H 2 O, clinical cisplatin and cobalt complexes reported in the literature (IC) against the anticancer activity of this cell line 50 Value of>0.3. Mu.M; ling, f. -p; ACS Med. Chem. Lett.,2019,10:1603-1608; zou, h. -h; et al, dalton trans.,2022,51,8840-8847). And complex [ Co (BrQ) 3 ]·CH 3 OH has low toxicity to normal HL-7702 cells, and IC thereof 50 Value of>50.0. Mu.M; description [ Co (BrQ) 3 ]·CH 3 OH has good tumor selectivity to tumor cells. In a word, the 5-bromo-8-hydroxyquinoline cobalt complex 1 shows excellent antitumor activity, has potential medicinal value, and is expected to be used for preparing various antitumor drugs.
Claims (4)
1. The 5-bromo-8-hydroxyquinoline cobalt complex with high anticancer activity is characterized in that the chemical structural formula is shown as the following formula:
2. the method for synthesizing a 5-bromo-8-quinolinolato cobalt complex as in claim 1, wherein 0.300mmol of 5-bromo-8-quinolinolato and 0.100mmol of CoCl are weighed respectively in a thick-walled drug-resistant tube 15.0cm long 2 ·6H 2 O, add 2.5mL MeOH, 0.5mL CH 2 Cl 2 And 0.5mL triethylamine, vacuumizing, sealing the pipe orifice, and carrying out coordination reaction at 80 ℃ for 3 days to obtain a target product [ Co (BrQ) of reddish brown bulk crystals 3 ]·CH 3 OH。
3. Use of the 5-bromo-8-hydroxyquinoline cobalt complex according to claim 1 in the preparation of a medicament for targeted treatment of ovarian cancer.
4. The use of the 5-bromo-8-hydroxyquinoline cobalt complex according to claim 1 in the preparation of a medicament for targeted treatment of ovarian cancer of a drug-resistant strain.
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