CN108299292B - Application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or medicinal salt thereof in treating breast cancer - Google Patents
Application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or medicinal salt thereof in treating breast cancer Download PDFInfo
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- 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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Abstract
The invention discloses an application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or a medicinal salt thereof in a medicament for treating breast cancer, belonging to the technical field of biological medicines. 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline is a quinoline derivative, which is called DBMSQ for short; the pharmaceutically acceptable salts refer to pharmaceutically acceptable salts, and include salts formed with inorganic acids such as phosphoric acid, hydrochloric acid and sulfuric acid, and salts formed with organic acids such as citric acid and tartaric acid. The experiment of the invention shows that: the compound DBMQ not only can obviously inhibit the proliferation and the induction of apoptosis of various human breast cancer cells, but also has the capability of inhibiting the migration and the invasion of the human breast cancer cells and embodies good anti-breast cancer potential; and the compound is easy to prepare, and is expected to provide a new choice for clinical breast cancer treatment through further development.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of a quinoline derivative 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline in treating breast cancer.
Background
Worldwide, breast cancer is the cancer with the highest morbidity and mortality among women (nearly 170 ten thousand cases and more than 50 thousand deaths per year) and is one of the malignant tumors with the highest mortality in China. According to the tumor registration data, the incidence rate of the breast cancer in urban and rural areas in China shows a continuous rising trend in nearly ten years, and the rising range of the breast cancer in rural areas is faster than that in urban areas. Although treatments including surgery, radiation therapy and chemotherapy are effective in increasing cure rates or overall survival, it remains one of the highest mortality diseases in women. Although conventional clinical treatment methods for cancer can successfully treat some local malignant tumors, the death of patients is usually caused by tumor invasion and metastasis, and the toxic and side effects of many antitumor drugs also influence the treatment effect of cancer; similarly, similar problems exist in the treatment of breast cancer. Therefore, the development of more targeted anti-breast cancer drugs with lower toxicity is very slow.
Migration and invasion are typical features of breast cancer, leading to the spread and metastasis of breast cancer. Cancer cells are transferred to tissues and organs such as brain, lung and the like through circulation pathways such as lymphatic vessels, blood vessels and the like to form a metastasis, which is an important cause of high mortality of breast cancer. Therefore, inhibition of cancer invasion and migration is expected to become a potential breast cancer treatment strategy, and search for compounds capable of effectively inhibiting tumor cell migration and invasion is also the direction of efforts of numerous researchers.
Quinoline compounds and derivatives thereof are very important as nitrogen-containing heterocyclic compounds, show wide biological activities such as antibiosis, anti-inflammation, antivirus and anticancer, and the compounds are relatively stable and easy to synthesize, thereby becoming ideal structures for drug design and drawing more and more attention.
Disclosure of Invention
In view of the fact that the current breast cancer treatment is not ideal, the invention aims to screen compounds capable of treating breast cancer from a series of synthetic quinoline derivatives, so that the compounds have high anti-breast cancer activity, including the effects of remarkably inhibiting proliferation, migration and invasion of breast cancer cells and inducing apoptosis of the breast cancer cells.
In order to achieve the above object, the present invention is achieved by the following technical solutions.
The invention provides a quinoline derivative which can be used for treating breast cancer, the compound is 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or medicinal salt thereof, the compound is called DBMQ for short, and the structural formula is as follows:
the invention relates to application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or a medicinal salt thereof in treating breast cancer, in particular to the medicinal salt of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline, which is a pharmaceutically acceptable salt, and comprises a salt formed by inorganic acid such as phosphoric acid, hydrochloric acid and sulfuric acid and a salt formed by organic acid such as citric acid and tartaric acid.
The invention relates to an application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline in treating breast cancer, and particularly relates to 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline capable of remarkably inhibiting breast cancer cell proliferation.
The invention relates to an application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline in treating breast cancer, in particular to 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline capable of remarkably inducing apoptosis of breast cancer cells.
The invention relates to an application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline in treating breast cancer, and particularly relates to 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline capable of remarkably inhibiting migration of breast cancer cells.
The invention relates to an application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline in treating breast cancer, and particularly relates to 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline capable of remarkably inhibiting breast cancer cell invasion.
The invention also provides a preparation method of the 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline, which comprises the following specific steps:
(1) weighing 0.02 mol of 2-methyl-8-hydroxyquinoline, dissolving in 30 mL of methanol in a 100 mL two-neck round-bottom flask, adding 0.04 mol of sodium bicarbonate, and stirring; will contain 0.06 mol Br2Is slowly added to the flask, the mixture is stirred for 30 min, then 0.17 mol Na are added2SO3Quenching the solid, filtering the mixture, pouring the filtrate into water, stirring for 30 min, filtering and vacuum drying to obtain the white product 5, 7-dibromo-2-methyl-8-hydroxyA quinolinyl group.
(2) Controlling the temperature to be 0 ℃, slowly dripping 0.01 mol of the 5, 7-dibromo-2-methyl-8-hydroxyquinoline tetrahydrofuran solution prepared in the step (1) into a tetrahydrofuran suspension of 0.0417 mol of NaH, keeping the temperature at 0 ℃ after dripping is finished, continuing stirring for 0.5 h, slowly adding 0.035 mol of chloromethyl methyl ether into the tetrahydrofuran suspension, and then returning to the room temperature and stirring for 12 h; after the reaction was complete, filtration was carried out, the filtrate was poured into water, extracted three times with DCM and then with anhydrous Na2SO4Drying for 2 h, filtering, and evaporating the solvent under reduced pressure to obtain a crude product; and finally, separating the target product by using DCM/petroleum ether with the volume ratio of 1:1 as an eluent column: 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline.
Compared with the prior art, the invention has the beneficial effects that:
1. the compound 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline is a compound with the highest activity screened from a series of synthesized quinoline derivatives, and the activity of the compound in breast cancer is not reported.
2. The compound 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline can obviously inhibit the proliferation of breast cancer cells and can induce the breast cancer cells to generate obvious apoptosis; scratch experiments and Transwell experiments show that the compound can inhibit the migration and invasion of breast cancer cells with high migration capacity. The results show that the compound DBMQ has good anti-breast cancer activity and has potential application value in the aspect of future breast cancer treatment.
3. The synthesis method of the compound 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline is simple and efficient, and has potential drug development prospect.
4. The compound 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline can be used as a lead compound for developing breast cancer drugs, and can be used for developing breast cancer resistant drugs with higher activity through further structural modification.
Drawings
FIG. 1 is a schematic diagram of a DBMQ preparation method.
FIG. 2 growth inhibitory effect of DBMSQ on breast cancer cells MCF-7.
FIG. 3 growth inhibition of breast cancer cells MDA-MB231 by DBMQ.
Figure 4 DBMMQ induced significant apoptosis in breast cancer cells;
in the figure, P value <0.05, which is statistically significant.
FIG. 5 DBMQ inhibits the migration of highly metastatic breast cancer cells MDA-MB 231;
in the figure, P value <0.01, which is statistically significant.
FIG. 6 DBMQ inhibits invasion of highly metastatic breast cancer cells MDA-MB 231;
in the figure, P values <0.001, which are statistically significant.
Detailed Description
The present invention will be described in further detail by way of examples with reference to the accompanying drawings, which are provided to illustrate the present invention and not to limit the scope of the present invention. In the following examples, unless otherwise specified, all the methods used were conventional methods, and all the reagents and materials used were available from companies.
Example 1: preparation method of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline
2-methyl-8-hydroxyquinoline (3.18 g, 0.02 mol) was weighed out and dissolved in 30 mL of methanol in a 100 mL two-necked round-bottomed flask, and sodium bicarbonate (3.18 g, 0.04 mol) was added thereto and stirred. Adding Br2A solution of (3.2 mL, 0.06 mol) in methanol (10 mL) was slowly added to the flask, the mixture was stirred for 30 min, then Na was added2SO3(22 g, 0.17 mol) solid quenching reaction, filtering the mixture, pouring the filtrate into water, stirring for 30 min, filtering, and drying in vacuum to obtain a white product, namely 5, 7-dibromo-2-methyl-8-hydroxyquinoline.
Taking a tetrahydrofuran solution containing 5, 7-dibromo-2-methyl-8-hydroxyquinoline (3.15 g, 0.01 mol), controlling the temperature to be 0 ℃, slowly dropwise adding the tetrahydrofuran solution into a tetrahydrofuran suspension of NaH (1.0 g, 0.0417 mol), keeping the temperature at 0 ℃ after dropwise adding, continuously stirring for 0.5 h, slowly adding chloromethyl methyl ether (2.7 mL, 0.035 mol), and then returning to the room temperatureStirring for 12 h. After the reaction was complete, filtration was carried out, the filtrate was poured into water, extracted three times with DCM and then with anhydrous Na2SO4Drying for 2 h, filtering, and evaporating the solvent under reduced pressure to obtain a crude product. The target product (5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline) was isolated using DCM/petroleum ether (1:1) as eluent column, see FIG. 1.
Example 2: culture and passaging of breast cancer cells
MCF-7 and MDA-MB231 breast cancer cells used in the experiment were cultured in Dulbecco's Modified Eagle Medium (DMEM) Medium containing 10% fetal bovine serum, 100U/ml penicillin and 100. mu.g/ml streptomycin under the following conditions: 37 ℃ and 5% CO2. The cell growth state is observed at any time, and cell passage can be carried out when the cell growth state generally grows to 80% or more, and the passage method is as follows:
(1) cells were washed once with phosphate buffered saline PBS and then digested with an appropriate amount of trypsin until cells became round and could be sloughed off.
(2) Pancreatin was neutralized with 2 volumes of fresh medium and the cell suspension was collected into centrifuge tubes.
(3) The cell pellet was obtained by centrifugation at 800-.
(4) The cells were resuspended in fresh medium and transferred to a new dish at 1:3 to 1: 4.
Example 3: screening quinoline derivatives with potential anti-breast cancer activity by using MTT (methyl thiazolyl tetrazolium) method
The specific operation steps are as follows:
(1) digesting and collecting the cells in the logarithmic growth phase by using trypsin, resuspending the cells by using a DMEM medium containing 10% fetal calf serum, repeatedly sucking and uniformly mixing the cells to prepare a single cell suspension.
(2) Cell counting: cell counting was carried out using a blood cell counting plate, and the density was set at 8X 104Cell suspension of about one/mL.
(3) Cell inoculation: cells were seeded into 96-well plates with 100 μ L cell suspension per well.
(4) Cell culture: placing 96-well plates in CO2Incubator at 37 ℃ and 5% CO2And culturing the cells under saturated humidity overnight to allow the cells to adhere to the wall.
(5) Compound treatment of cells: compounds with different concentration gradients (0 μ M, 2.5 μ M, 5 μ M, 10 μ M, 25 μ M, 50 μ M, respectively) were prepared, the medium in the 96-well plate was aspirated, 100 μ L of drug solutions with different concentrations was added to each well, a DMEM medium without cells was set as a blank, 3 replicates per concentration were set, and the culture was continued in the cell culture chamber.
(6) After 44 hours of incubation, 10. mu.L of MTT solution (5 mg/mL) was added to each well and incubation continued in the incubator for 4 hours.
(7) After the medium was aspirated, 150. mu.L of dimethyl sulfoxide (DMSO) was added to each well, and blue-violet crystalline formazan formed in the reaction was sufficiently dissolved. The set wavelength was 490 nm on the microplate reader, and the sample was shaken for 5 minutes to read the OD value and the data was saved.
(8) Statistical treatment:
cell survival (%) < 100% (administration well OD value-blank control well OD value)/(control well OD value-blank control well OD value).)
Half maximal Inhibitory Concentration (IC) was calculated using Graphpad Prism 6.050）。
The results of screening the synthesized quinoline derivatives by using the MTT method are shown in Table 1, the derivatives HQ-9 have better anti-breast cancer activity, namely the compound 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline, DBMQ for short, is shown in a further verification experiment, the DBMQ can inhibit the growth of MCF7 breast cancer cells in a dose-dependent manner (see figure 2), and the compound also has a remarkable growth inhibition effect on other breast cancer cells such as MDA-MB231, and the results are shown in figure 3.
TABLE 1 IC of quinoline derivatives on breast cancer cells MCF750Value of
| Compound (I) | HQ | HQ-3 | HQ-4 | HQ-5 | HQ-6 | HQ-8 | HQ-9 | HQ-10 | HQ-12 | HQ-13 | HQ-14 | HQ-15 | HQ-16 |
| IC50 (µM) | 82.66 | 177.99 | >200 | 148.05 | >200 | >200 | 24.75 | >200 | >200 | 127.12 | 30.17 | >200 | >200 |
Example 4: DBMQ induces breast cancer cells to generate obvious apoptosis
After examining the effect of DBMMQ on the growth of breast cancer cells, we further investigated whether the compound could induce apoptosis of breast cancer cells. First, we analyzed the expression change of apoptosis-related proteins in cells after compound treatment using immunoblotting.
The immunoblotting was carried out as follows:
MCF and MDA-MB231 cells were treated with the compound for 48 hours, and total protein was extracted from the cells using RIPA lysate. After protein quantification, carrying out lauryl sodium sulfate polyacrylamide gel electrophoresis separation on an equivalent protein sample, then transferring the protein sample on the gel onto a nitrocellulose membrane by a wet transfer method, then sealing the membrane for 1 hour at room temperature by using 5% skimmed milk powder, then incubating a primary antibody (CST company in Germany) resisting PARP and Caspase 9 for overnight at 4 ℃, washing the membrane for 4 times by using TBS (TBS-T) solution containing 1 per mill of Tween-20, then incubating a corresponding secondary antibody, incubating for 2 hours at room temperature, and finally developing by using a high-sensitivity chemiluminescence detection Kit (eECL Western Blot Kit, Beijing kang is century Biotechnology Limited) to obtain a protein band.
The results are shown in FIG. 4, after the breast cancer cells MCF7 and MDA-MB231 are treated by the compound DBMSM for 48 hours, the key proteins Caspase 9 and PARP are obviously cut in the process of apoptosis, and the cells are prompted to move to an apoptotic pathway and are possibly related to the activation of Caspase. Furthermore, we treated cells with the compound in combination with Z-VAD inhibitor of Caspase, and the results showed that Z-VAD significantly inhibited DBMQ-induced apoptosis, suggesting that DBMQ indeed caused apoptosis of breast cancer cells MCF7 and MDA-MB 231.
Example 5: effect of Compound DBMSM on migration and invasion of highly metastatic breast cancer cells MDA-MB231
The inhibition of breast cancer metastasis is very important for improving the treatment effect of breast cancer, so that the influence of the DBMQ of the compound on the migration and invasion capacity of MDA-MB231 is detected by taking a highly metastatic breast cancer cell MDA-MB231 as a model.
Firstly, the influence of DBMQ on the migration capability of MDA-MB231 cells is detected by using a scratch test.
The method comprises the following specific steps:
(1) MDA-MB231 cells were plated at 4X 105The density per well was transferred to six well plates and incubated overnight until the cells reached a density of 90%.
(2) The cells in each well were scratched with a 200. mu.L pipette tip, and the exfoliated cells were washed off with PBS
(3) Serum-free medium solution containing 25 μ M compound was prepared and then added to the cells and solvent control wells without compound were set.
(4) Photographs were taken under an inverted microscope for 0 hour and position markers were made.
(5) After 48 hours of cell culture, the scratch condition of the corresponding position was photographed.
The result is shown in figure 5, the compound DBMQ obviously inhibits the migration of the highly metastatic breast cancer cell MDA-MB231, P is less than 0.01, and the difference is obvious.
Next, we further investigated the effect of DBMQ on the invasion capacity of MDA-MB231 cells by trans-well experiments.
The method comprises the following specific steps:
coating and hydrating basement membrane: the upper face of the bottom membrane of the Trans well chamber (pore size, 8 μm; Costar, Cambridge, NY, USA) was first coated with matrigel (50 mg/LMatrigel 1:8 dilution), air dried at 4 ℃ and the residual liquid aspirated from the well plate, 50ul of serum-free medium containing 10g/LBSA was added to each well and hydrated in an incubator at 37 ℃ for 30 minutes.
Preparing a cell suspension: the MDA-MB231 cells were digested with pancreatin and formulated to a density of 2X 105Milli hairThe compound DBMMQ was then added to a final concentration of 25 μ M and incubated for 30 minutes at room temperature.
Inoculating cells: 100 μ L of the cell suspension was added to a Transwell chamber and 650 μ L of a medium solution containing no or 25 μ M of the compound was added to the lower chamber of the 24-well plate, taking care that no air bubbles were present between the upper and lower chambers. The plates were placed in a cell incubator for an additional 48 hours.
And (4) counting results: the cells in the upper layer of the chamber were wiped off with a cotton ball, the medium in the well was discarded, the chamber was washed rapidly 3 times with PBS, then 500. mu.L of methanol was added to the lower well, and 200. mu.L of methanol was added to the chamber to fix the cells for 10 minutes. The wells were discarded, the chamber was washed 3 times with PBS, and the residual PBS in the chamber was aspirated clean. The cells in the lower layer of the chamber were stained with 0.2% crystal violet stain for 10-15 minutes, followed by elution of the crystal violet with 33% acetic acid solution and measurement of the absorbance of the eluate (wavelength 570 nm) on a microplate reader.
As shown in FIG. 6, the invasion of cells into the lower layer of the chamber was significantly reduced by the compound DBMQ treatment, and the OD value of the corresponding eluate was significantly reduced, with P <0.001, which was statistically different. The result shows that the DBMQ can remarkably inhibit the invasion capacity of the highly metastatic breast cancer cell MDA-MB 231.
Claims (5)
- Application of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or medicinal salt thereof in preparing anti-breast cancer medicaments.
- 2. The use of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an anti-breast cancer medicament, wherein the use is for inhibiting proliferation of breast cancer cells.
- 3. The use of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an anti-breast cancer medicament, wherein the use is the induction of apoptosis in breast cancer cells.
- 4. The use of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an anti-breast cancer medicament, wherein the use is for inhibiting migration of breast cancer cells.
- 5. The use of 5, 7-dibromo-8- (methoxymethoxy) -2-methylquinoline or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an anti-breast cancer medicament, wherein the use is for inhibiting breast cancer cell invasion.
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| CN101528702A (en) * | 2006-06-08 | 2009-09-09 | 阿雷生物药品公司 | Quinoline compounds and methods of use |
| CN102239149A (en) * | 2008-10-06 | 2011-11-09 | 约翰·霍普金斯大学 | Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101528702A (en) * | 2006-06-08 | 2009-09-09 | 阿雷生物药品公司 | Quinoline compounds and methods of use |
| CN102239149A (en) * | 2008-10-06 | 2011-11-09 | 约翰·霍普金斯大学 | Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders |
Non-Patent Citations (1)
| Title |
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| Three Mn(II) coordination polymers with a bispyridyl-based quinolinate ligand: the anion-;Guozan Yuan et al.;《Dalton Trans.》;20140404;第43卷;第9778页Scheme1; 第9782页右栏第1-3段 * |
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