CN111329857B - Fluorobenzamide derivative injection and anti-breast cancer application thereof - Google Patents

Fluorobenzamide derivative injection and anti-breast cancer application thereof Download PDF

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CN111329857B
CN111329857B CN202010278602.9A CN202010278602A CN111329857B CN 111329857 B CN111329857 B CN 111329857B CN 202010278602 A CN202010278602 A CN 202010278602A CN 111329857 B CN111329857 B CN 111329857B
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breast cancer
fluorobenzamide
fluorobenzamide derivative
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CN111329857A (en
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曹伟红
牛晓燕
王海冀
柳晓义
王宇
马中良
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Affiliated Hospital of University of Qingdao
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Abstract

The invention provides a fluorobenzamide derivative injection and an application thereof in resisting breast cancer, and belongs to the technical field of medicines. The test shows that the fluorobenzamide derivative BOF has strong cytotoxicity on MCF-7 breast cancer cells, but has no toxicity on MCF-10A normal mammary epithelial cells. In addition, the invention greatly improves the water solubility of the fluorobenzamide derivative BOF by adding the glycine as a cosolvent, thereby preparing the high-concentration anti-breast cancer injection.

Description

Fluorobenzamide derivative injection and anti-breast cancer application thereof
Technical Field
The invention belongs to the technical field of medicines, relates to a novel anticancer application of a compound, and more particularly relates to a fluorobenzamide derivative injection and an application of a fluorobenzamide derivative in preparation of an anti-breast cancer medicine.
Background
According to the data of the world health organization statistics, cancer patients are growing at a rate of 35 ten thousand per year since 2012, which is about to become the biggest threat to human health, and especially for women, breast cancer has become one of the common cancers. However, relatively more importance is placed on cancer prevention in economically developed regions such as europe and america, and the early screening popularization enables many breast cancer patients to find and treat the breast cancer patients at an early stage, so that the recovery probability is relatively high. However, the current attitude of China to breast cancer is not as good as that of Europe and America regardless of national policy, public awareness and medical level, so that the discovery of breast cancer is basically in a late stage, and the cure rate of breast cancer in China is low.
Although clinical treatment of breast cancer has made significant breakthroughs, the rate of recurrence and the rate of metastasis are still increasing. Currently, the treatment of breast cancer mainly comprises surgery, radiotherapy and chemotherapy, however, the development of breast cancer is limited, for example, it is difficult to completely eliminate tumor tissue by surgery, and radiotherapy causes great damage to normal tissue. Paclitaxel and other therapeutic drugs have significant anti-tumor efficacy and have become the most common drugs for treating breast cancer. However, long-term use thereof causes toxic side effects and drug resistance, resulting in an increased risk of metastasis. Therefore, the medicinal workers all over the world are constantly working on the development of new chemotherapeutic drugs to remedy the disadvantages of the existing drugs.
Breast Cancer MCF-7cell line was isolated from pleural effusion of a 69 year old white female Breast Cancer patient, which retains many of the characteristics of differentiated mammary epithelium, is a commonly used Breast Cancer cell line, the most studied human Breast Cancer cell line in the world, and has been popularized by various Research groups for over 40 years [ Lee Adrian V., oestereich Stemfi, davidson Nancy E.MCF-7 Cells-Changing the couse of Breast Cancer Research and Care for 45Years.journal of the National Cancer institute.2015.107 (7): 1-4]. Therefore, the research result of the cell line has great influence on the research of the breast cancer and the prognosis of patients.
CN110818672A discloses cyclobutenone compounds with novel structures obtained through efficient competitive [2+2] cycloaddition reaction, and antioxidant detection is carried out through a DPPH method, so that target compounds have good antioxidant effect. However, by searching the prior art at home and abroad, no document discloses that the cyclobutenone compound has anticancer activity, and no document reports that the compound is used for resisting breast cancer.
Disclosure of Invention
The inventor firstly discovers that the fluorobenzamide derivative BOF has the biological activity of inhibiting the proliferation of the breast cancer MCF-7, and can prepare a medicament for resisting the breast cancer by utilizing the discovery. Accordingly, a first object of the present invention is to provide a pharmaceutical use of a fluorobenzamide derivative, namely: the application of fluorobenzamide derivatives in preparing medicaments for inhibiting the proliferation of breast cancer cells; and the application of the fluorobenzamide derivative in preparing the anti-breast cancer medicament.
It is noted that the above-mentioned fluorobenzamide derivative BOF has the formula C 18 H 12 FNO 4 (molecular weight 325) and the chemical name is N- [2- (2H-1,3-benzodioxol-5-yl) -4-oxocyclobut-1-en-1-yl]4-fluorobenzamide with hydrogen spectrum data as follows: 1 H NMR(400MHz,DMSO-d 6 ) δ 10.68 (s, 1H), 7.89 (d, J =4.0hz, 2h), 7.70 (d, J =4.0hz, 2h), 7.52-7.39 (m, 2H), 6.93 (d, J =8.0hz, 1h), 6.11 (s, 2H), 4.35 (s, 2H), the chemical structural formula of which is as follows:
Figure BDA0002445707890000021
in addition, the fluorobenzamide derivative BOF is found to have poor water solubility in experiments, and the solubility of the derivative BOF in water is lower than 1mg/ml, so that the preparation of an injection is not facilitated. Therefore, the inventors estimated that the solubility was not improved to 2mg/ml or more by adding a solubilizer such as propylene glycol, tween, poloxamer, PEG, polyoxyethylene castor oil, or the like. In further experiments, the inventor unexpectedly finds that a certain amount of glycine as a cosolvent can greatly enhance the water solubility of BOF, so that a high-concentration BOF injection can be prepared. Therefore, the second objective of the present invention is to provide a fluorobenzamide derivative injection, and the specific technical scheme is summarized as follows:
the fluorobenzamide derivative injection comprises a fluorobenzamide derivative, a cosolvent and an isoosmotic adjusting agent, wherein the cosolvent is glycine.
Further preferably, the fluorobenzamide derivative injection as described above, wherein the concentration of each component in the injection is:
fluorobenzamide derivatives 2-10mg/ml
0.5-5mg/ml glycine
3-9mg/ml of isoosmotic adjusting agent.
Still further preferably, the fluorobenzamide derivative injection as described above, wherein the concentration of each component in the injection is:
5-10mg/ml fluorobenzamide derivative
Glycine 1-4mg/ml
6-9mg/ml of isoosmotic adjusting agent.
Still further preferably, the fluorobenzamide derivative injection as described above, wherein the isotonicity adjusting agent is selected from any one of the following: sodium chloride, glucose, mannitol, and sorbitol. The isotonic regulator is most commonly used with sodium chloride or glucose effect.
The invention has the beneficial effects that: the fluorobenzamide derivative BOF has strong cytotoxicity on MCF-7 breast cancer cells, but has no toxicity on MCF-10A normal mammary epithelial cells. In addition, the invention greatly improves the water solubility of the fluorobenzamide derivative BOF by adding the glycine as a cosolvent, thereby preparing the high-concentration anti-breast cancer injection.
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FIG. 1: the effect of different drug concentrations on the survival rate of human breast cancer cells.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments. It will be understood by those skilled in the art that the following examples are illustrative of the present invention only and should not be construed as limiting the scope of the present invention. In addition, the specific technical operation steps or conditions not indicated in the examples are performed according to the technical or conditions described in the literature in the field or according to the product specification. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1 screening experiment for flux of fluorobenzamide derivative (BOF)
50ml of distilled water is added into 3 beakers of 100ml, 1g of propylene glycol, 2g of propylene glycol and 4g of propylene glycol are added into the beakers of 3 ml respectively, 0.5g of BOF is added into the beakers of 3 ml respectively after uniform stirring, the mixture is repeatedly stirred for 2min by a glass rod, and the dissolution of the BOF is observed. The results showed that the solutions in 3 beakers were turbid and that the bottom of the beaker appeared to be insoluble particles after 1h of standing.
According to the method, experiments are carried out after the propylene glycol is respectively replaced by tween 80, poloxamer, propylene glycol, PEG400, polyoxyethylene castor oil and glycine, and the results show that only the glycine can promote the dissolution of the BOF, and other cosolvents cannot improve the solubility of the BOF to be more than 2mg/ml, possibly because the glycine and the BOF form a soluble compound.
EXAMPLE 2 screening experiment for Glycine amount
50ml of distilled water was added to 5 beakers of 100ml, followed by 0.05g, 0.1g, 0.2g, 0.4g and 0.8g of glycine, respectively, and after stirring uniformly, 0.5g of BOF was added to each of the 5 beakers, and the mixture was stirred with a glass rod repeatedly for 2 minutes to observe the dissolution of BOF. The results showed that the solution was cloudy in a beaker to which 0.05g glycine was added; the solutions in the other beakers were clear and no insoluble particles appeared after 1h of standing.
EXAMPLE 3 culture of human Breast cancer MCF-7cells
RPMI1640 medium containing 10% FBS was used as a complete medium. First, the MCF-7cells were thawed, the flasks were placed at 37 ℃ and 5% CO 2 After the cells are digested into spherical shapes by microscopic observation after 0.25% of pancreatic enzyme is used for digestion, a culture medium containing serum is added into a culture bottle to stop the digestion process. The cells were then carefully blown off and added to a 15mL centrifuge tube, centrifuged (1000 r/min,5 min), the supernatant decanted after centrifugation, the appropriate amount of the complete culture medium was aspirated into the centrifuge tube using a pipette gun, the cells were carefully blown down, and a small amount of this suspension was added to a fresh flask and placed in a cell incubator for further culture.
EXAMPLE 4 Effect of fluorobenzamide derivatives (BOF) on the survival of breast cancer MCF-7cells
Collecting the logarithmic phase of MCF-7cells, beating into single cell suspension with the culture solution of FBS at a concentration of 10%, counting with a counting plate, and adjusting the cell concentration to a desired concentration at 5X 10 per well 3 A/100Mu L of the suspension is inoculated into a 96-well plate, the plate is placed in an incubator for culture, after the cells are attached to the wall, 100 mu L of a culture medium containing medicines (blank control is arranged) is added into each well, and 3 multiple wells are arranged at each medicine concentration. After further 24h incubation, 10. Mu.L MTT was added to each well, incubated for 4h, the supernatant was spun off, 100. Mu.L DMSO was added to each well, the shaker was placed at room temperature, shaken for 10 min, the absorbance (OD) of the 96-well plate was measured using a microplate reader at 490nm, and the cell viability was calculated from the absorbance.
FIG. 1 shows the survival rate of human breast cancer cells measured by MTT method, and it can be seen from the graph that when the concentration of the drug is not less than 130mg/L, the survival percentage of the human breast cancer cells after the BOF acts on the human breast cancer cells is far lower than that of the control group, and a certain dose-effect relationship exists, which indicates that the BOF can inhibit the growth of the breast cancer cells.

Claims (8)

1. The application of fluorobenzamide derivative in preparing medicine for inhibiting breast cancer cell proliferation is as follows:
Figure 599311DEST_PATH_IMAGE001
。
2. the use of a fluorobenzamide derivative according to claim 1 for the manufacture of a medicament for inhibiting proliferation of breast cancer cells, wherein the breast cancer cells are the human breast cancer MCF-7cell line.
3. The application of the fluorobenzamide derivative in preparing the anti-breast cancer medicament is as follows:
Figure 379049DEST_PATH_IMAGE001
。
4. the use of a fluorobenzamide derivative according to claim 3 for the preparation of a medicament for the treatment of breast cancer, wherein the medicament is an injection, the injection comprises the fluorobenzamide derivative, a cosolvent and an isotonic regulator, and the cosolvent is glycine.
5. The use of a fluorobenzamide derivative according to claim 4 for the preparation of a medicament against breast cancer, wherein the concentration of each component in the injection solution is:
fluorobenzamide derivatives 2-10mg/ml
0.5-5mg/ml glycine
3-9mg/ml of isoosmotic adjusting agent.
6. The use of a fluorobenzamide derivative according to claim 5 for the preparation of a medicament against breast cancer, wherein the concentration of each component in the injection solution is:
5-10mg/ml fluorobenzamide derivative
Glycine 1-4mg/ml
6-9mg/ml of isoosmotic adjusting agent.
7. Use of a fluorobenzamide derivative according to any one of claims 4 to 6 for the manufacture of a medicament against breast cancer, wherein the isotonicity adjusting agent is selected from any one of the following: sodium chloride, glucose, mannitol, and sorbitol.
8. The use of a fluorobenzamide derivative according to claim 7 for the preparation of a medicament against breast cancer, wherein the isotonicity adjusting agent is sodium chloride or glucose.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006034111A1 (en) * 2004-09-17 2006-03-30 Osi Pharmaceuticals, Inc. (arylamidoaryl)squaramide compounds
EP2878677A1 (en) * 2013-11-28 2015-06-03 Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE) Activators of protein phosphatase 5
CN105287370A (en) * 2015-11-24 2016-02-03 福州海王福药制药有限公司 Preparation method of inosine and composition injection thereof
CN110818672A (en) * 2019-03-25 2020-02-21 河南湾流生物科技有限公司 Cyclobutenone compound with antioxidant effect and preparation method thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2657051A1 (en) * 2006-07-07 2008-01-10 Schering Corporation 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006034111A1 (en) * 2004-09-17 2006-03-30 Osi Pharmaceuticals, Inc. (arylamidoaryl)squaramide compounds
EP2878677A1 (en) * 2013-11-28 2015-06-03 Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE) Activators of protein phosphatase 5
CN105287370A (en) * 2015-11-24 2016-02-03 福州海王福药制药有限公司 Preparation method of inosine and composition injection thereof
CN110818672A (en) * 2019-03-25 2020-02-21 河南湾流生物科技有限公司 Cyclobutenone compound with antioxidant effect and preparation method thereof

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