CN112972455B - Application of compound in preparation of antitumor drugs - Google Patents
Application of compound in preparation of antitumor drugs Download PDFInfo
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- CN112972455B CN112972455B CN201911281632.9A CN201911281632A CN112972455B CN 112972455 B CN112972455 B CN 112972455B CN 201911281632 A CN201911281632 A CN 201911281632A CN 112972455 B CN112972455 B CN 112972455B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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Abstract
The invention provides application of 2- (1, 7-nonadiene-3, 5-diyne) furan, or an optical isomer or a solvate thereof in preparation of an anti-tumor medicament. The compounds of the invention have inhibitory effects on LAG3/MHC II binding in vitro; the compound also has certain inhibition effect on the proliferation of various cancer cells; furthermore, the compounds of the invention can reduce the tumor weight in vivo in tumor-bearing mice of various tumors thereof.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of a compound in treating cancers.
Background
Cancer is a generic term for a variety of diseases that can affect any part of the body, and other terms used are malignant tumors and neoplasms. One defining characteristic of cancer is the rapid production of abnormal cells that grow beyond their usual boundaries and can invade adjacent parts of the body and spread to other organs. This process is called metastasis, which is a major cause of cancer mortality. Currently, cancer is one of the leading causes of death worldwide. According to the world health organization, 8400 million people will die of cancer during the period from 2005 to 2015 if no intervention is performed.
Cancer cells have the ability to grow and spread uncontrollably, they can affect almost any part of the human body, and often invade surrounding tissues and can migrate to other sites. Cancer is a major cause of death worldwide: in 2004, cancer died in 740 million (about 13% of all deaths). Lung, gastric, colon, liver and breast cancers are the leading culprit for most cancer deaths each year. The most common types of cancer vary between men and women. Over 30% of cancer deaths can be avoided. Tobacco use is the most important risk factor for cancer variation. Cancer is caused by a single cell variation, which may be caused by external factors and genetic factors. The number of cancer deaths will continue to increase globally, and in 2030, the number of deaths is expected to reach 1200 million. In addition, according to the statistics of the us cancer association in 2013 and the national clinical oncology conference in 2013, the survival rate of the total cancer in the us is 66%, while the survival rate of the total cancer in china is 31%, which is less than half of the survival rate in the us. Therefore, overcoming the cancer is always a major problem to be solved urgently in the medical field, and especially in China, more and more independent innovative new antitumor drugs are urgently needed to be developed to improve the overall cure rate or 5-year survival rate of Chinese cancer patients, so as to bring welfare to cancer-suffering people in China and even in the whole world.
Therefore, the method has extremely important significance for accelerating the research and development of novel anti-tumor novel substances with high efficiency, multiple targets, multiple mechanisms, broad spectrum, safety and low price and capable of reducing the recurrence rate.
Disclosure of Invention
In view of the above, the main purpose of the present invention is to provide a compound for use in preparing a medicament for treating various cancers.
Specifically, the invention provides application of 2- (1, 7-nonadiene-3, 5-diyne) furan or an optical isomer thereof or a solvate thereof in preparing an anti-tumor medicament.
Specifically, the anti-tumor drug is an oral administration dosage form, an injection administration dosage form or an external administration preparation.
Specifically, the antitumor drug includes, but is not limited to, injection, suspension, emulsion, solution, syrup, tablet, capsule, granule, spray, aerosol.
Further, the antitumor drug further comprises a chemotherapeutic agent or an immunotherapeutic agent. Wherein, the chemotherapeutic agent or the immunotherapeutic agent can be active substances which have corresponding antitumor effects except the compound protected by the invention.
Further, the aforementioned optical isomer may be selected from (E, E) -2- (1, 7-nonadiene-3, 5-diyne) furan. The atractylodin has the following structural formula:
when the compound disclosed by the present invention, or an optical isomer, racemate, solvate or pharmaceutically acceptable salt thereof is used as a drug, it can be used as it is, or in the form of a pharmaceutical composition/preparation. The pharmaceutical composition comprises 0.1-99%, preferably 0.5-90% of the compound of the present invention, the remainder may be other active ingredients having similar or synergistic effects, and may also be or further include pharmaceutically acceptable carriers and/or excipients which are non-toxic and inert to humans and animals.
Specifically, the antitumor drug includes, but is not limited to, drugs against lung cancer, breast cancer, colorectal cancer, liver cancer, hematological tumor, sarcoma, prostate cancer, bile duct cancer, esophageal cancer, small cell lung cancer, triple negative breast cancer, nasopharyngeal cancer, oral cancer, tongue cancer, laryngeal cancer, kidney cancer, cardiac cancer, pyloric cancer, pancreatic cancer, intestinal cancer, bladder cancer, cervical cancer, uterine cancer, ovarian cancer, lip cancer, skin cancer, bone cancer, sarcoma, malignant brain glioma, ewing's tumor, hodgkin's disease, or non-hodgkin's disease.
The invention also provides application of 2- (1, 7-nonadiene-3, 5-diyne) furan or optical isomers thereof or solvates thereof in preparing LAG3/MHC II inhibitors. Wherein the optical isomer can be selected from (E, E) -2- (1, 7-nonadiene-3, 5-diyne) furan.
The invention researches the influence of 2- (1, 7-nonadiene-3, 5-diyne) furan on LAG3/MHC II in vitro, cancer cells and the inhibition effect of transplanted tumors in nude mice. The experimental results show that the compound of the invention has the inhibition effect on in vitro LAG3/MHC II binding; the composition also has certain inhibition effect on proliferation of NCI-H23 human non-small cell lung cancer adenocarcinoma cells, HT-29 human colon cancer cells, T47D human breast cancer cells, SK-OV-3 human ovarian cancer cells, H22 liver cancer cell strains, ZR-75-30 human mammary duct cancer cells, A431 human skin cancer cells, U87MG human brain astrocytoma cells, NCI-H2170 human lung squamous cancer cells and NCI-H1975 human lung adenocarcinoma cells; furthermore, the compounds of the invention can reduce the tumor weight in vivo in tumor-bearing mice of a variety of tumors. The above results indicate that the compound disclosed by the invention has certain antagonistic effect on lung cancer, breast cancer, colorectal cancer, liver cancer, hematological tumor, sarcoma, prostate cancer, bile duct cancer, esophageal cancer, small cell lung cancer, triple-negative breast cancer, nasopharyngeal cancer, oral cancer, tongue cancer, laryngeal cancer, renal cancer, cardia cancer, pyloric cancer, pancreatic cancer, intestinal cancer, bladder cancer, cervical cancer, uterine cancer, ovarian cancer, lip cancer, skin cancer, bone cancer, sarcoma, malignant brain glioma, ewing's tumor, hodgkin's disease and non-Hodgkin's disease.
Drawings
FIG. 1 is a graph of the effect of various concentrations of atractylodin on LAG3/MHC II binding in vitro.
Detailed Description
The following detailed description of the embodiments of the present invention will be given in conjunction with examples to better understand the aspects of the present invention and the advantages of its various aspects. However, the specific embodiments and examples described below are for illustrative purposes only and are not limiting of the invention.
Secondly, it should be noted that the concentrations not indicated in the present invention are all in volume percent (v/v). All percentages, ratios, proportions, or parts are by weight unless otherwise specified. In addition, if the specific conditions are not indicated, the invention is carried out according to the conventional conditions or the conditions suggested by the manufacturer, and the used raw material drugs or auxiliary materials and the used reagents or instruments are the conventional products which can be obtained commercially.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention.
Experimental example 1: effect of atractylodin on LAG3/MHC II binding in vitro
1. Experimental Material
1.1 drugs and reagents: atractylodin; LAG3/MHC II BINDING AssAY KITS (cisbio).
1.2 instruments and devices: electronic balances (sidoris); microplate reader (PE).
2. Experimental methods
Dissolving a drug in DMSO (dimethyl sulfoxide) to 50mM as a storage solution, diluting the drug with a diluent in a kit to a required drug concentration before an experiment, respectively adding 2uL of compound/antibody/diluent, 4uL of Tag1-LAG3 protein and 4uL of Tag2-MACH II protein according to the instruction sequence of the kit operation, standing for 15min in a dark place at room temperature, adding 10uL of anti-Tag1-Tb and anti-Tag2-XL665 which are uniformly mixed in advance into each hole, standing for 1h in a dark place at room temperature, and detecting the fluorescence value of each hole under a fluorescence microplate reader.
3. Results of the experiment
As shown in figure 1, the inhibition rate of atractylodin on in vitro LAG3/MHC II binding is continuously increased along with the increase of the administration concentration, and the IC50 of the inhibition rate is 8.59uM according to calculation.
Experimental example 2: effect of atractylodin on cancer cells
1. Experimental Material
1.1 drugs and reagents: atractylodin (MCE); RPMI1640 (GIBCO), fetal bovine serum (GIBCO); MTT (sigma).
1.2 cells: NCI-H23 human non-small cell lung carcinoma adenocarcinoma cells, HT-29 human colon carcinoma cells, T47D human breast carcinoma cells, SK-OV-3 human ovarian carcinoma cells, H22 liver cancer cell line, ZR-75-30 human ductal carcinoma cells, A431 human skin carcinoma cells, U87MG human brain astrocytoma cells, NCI-H2170 human squamous cell carcinoma cells, NCI-H1975 human lung adenocarcinoma cells (Nanjing Korea Biotech Co., ltd.).
1.3 instruments and devices: electronic balance (sidoris); centrifuge (good in Anhui); flex station calcium streaming workstation (MD); inverted microscope (OLYPUS).
2. Experimental method
2.1 cell culture
Cell subculture in culture flask at 37 ℃ with 5% CO 2 Culturing in an incubator with saturated humidity, discarding culture solution after the cells in the culture bottle grow up basically (the cells are kept in logarithmic growth phase), adding a proper amount of PBS solution for gentle washing, discarding, then adding 1ml of 0.25% trypsin solution for digestion for 2-3 minutes, adding 2ml of complete culture medium to stop the action of pancreatin, transferring the cells into a centrifuge tube, centrifuging for 5min at 1000r, discarding supernatant, adding the complete culture medium, and carefully blowing and beating into single cells. The cells were counted by an automatic cell counter at 1X 10 5 Per mL, 100. Mu.L per well in 96-well cell culture plates, 100. Mu.L of sterile water in marginal wells, and continuing the assay at 37 ℃ with 5% CO 2 After culturing for 18-20 hours in an incubator, molding and administration tests are carried out.
2.2 grouping and administration
Centrifuging after trypsinizing cells, removing supernatant, inoculating the cells into a 96-well plate according to 10000 cells/hole after resuspension counting, adding atractylon solution with final concentration of 1.5, 3, 6, 12, 24 and 48uM after 24h, setting an experiment control group, setting 5 multiple holes for each concentration, and incubating for 72h.
2.3 cell viability assay
Each set of experiments was completed 4h before the end of the timeframe, 10ul MTT was added to each well. Continuing to culture for 4h, carefully sucking up the supernatant, adding 150uL DMSO into each well to dissolve crystals, after the crystals are completely dissolved, measuring the absorbance value at the wavelength of 570nm under an enzyme-linked immunosorbent assay (ELISA) instrument, and calculating the inhibition rate and IC 50 。
3. Results of the experiment
The experimental results of the inhibition effect of atractylodin on the proliferation of each tumor cell are shown in tables 1 and 2, and it can be seen from the tables that atractylodin has a certain inhibition effect on the proliferation of the following 10 tumor cells, and the activity of the tumor cells is gradually reduced along with the gradual increase of the concentration. The IC50 values of NCI-H23 human non-small cell lung cancer adenocarcinoma cells, HT-29 human colon cancer cells, T47D human breast cancer cells, SK-OV-3 human ovarian cancer cells, H22 liver cancer cell lines, ZR-75-30 human ductal carcinoma cells, A431 human skin cancer cells, U87MG human brain astrocytoma cells, NCI-H2170 human lung squamous carcinoma cells and NCI-H1975 human lung adenocarcinoma cells are respectively 7.92, 12.56, 14.80, 26.37, 3.68, 13.53, 9.39, 8.64, 8.20 and 4.88uM according to the formula.
TABLE 1 Effect of atractylodin on NCI-H23, HT-29, T47D, SK-OV-3, H22 cell viability
P <0.01, p <0.05 compared to control
TABLE 2 Effect of atractylodin on ZR-75-30, A431, U87MG, NCI-H2170, NCI-H1975 cell viability
P <0.01, p <0.05 compared to control
Experimental example 3: inhibiting effect of atractylodin on transplanted tumor of nude mouse
1. Experimental Material
1.1 drugs and reagents
Atractylodin; RPMI1640 (GIBCO), fetal bovine serum (GIBCO).
1.2 animals and cells
NCI-H23 human non-small cell lung cancer adenocarcinoma cells, HT-29 human colon cancer cells, T47D human breast cancer cells, SK-OV-3 human ovarian cancer cells, H22 liver cancer cell line (Nanjing Ke Bai Biotech Co., ltd.); nude mice (Yangzhou university center of comparative medicine, SCXK (su) 2017-0007).
1.3 instruments
Syringe (1 mL, needle size 27); sterile surgical instruments (including scalpels, scissors, forceps, needle holders, etc.).
2. Experimental methods
2.1 cell culture
Subculturing tumor cells in culture flasks at 37 ℃ with 5% CO 2 Culturing in an incubator with saturated humidity, discarding culture solution after the cells in the culture bottle grow up basically (the cells are kept in logarithmic growth phase), adding a proper amount of PBS solution for gentle washing, discarding, then adding 1ml of 0.25% trypsin solution for digestion for 2-3 minutes, adding 2ml of complete culture medium to stop the action of pancreatin, transferring the cells into a centrifuge tube, centrifuging for 5min at 1000r, discarding supernatant, adding the complete culture medium, and carefully blowing and beating into single cells. Counting by an automatic cell counter, adjusting the cell concentration to be suspension of the required cell concentration, and storing on ice for later use.
2.2 preparation of tumor model
The nude mouse disinfected the skin on the back, lifted the disinfected skin with the left thumb and forefinger, separated the skin from the underlying muscles, and injected 20ul of fully vortexed cell suspension into the lifted skin folds. If resistance is met during injection, the injection angle is not correct, and the needle insertion direction is required to be changed timely.
2.3 Observation and Experimental groups
Tumor growth was observed daily after inoculation, after several weeks, tumor growth was visible, the longest longitudinal and widest transverse diameters of the tumors were measured with a vernier caliper, and tumor volume was calculated using the following formula: 0.5 x length x width 2 until the tumor volume reaches about 100mm 3 When the mice are randomly divided into a tumor model group, a low dose group (10 mg/kg), a medium dose group (20 mg/kg) and a high dose group (40 mg/kg), at least 10 mice in each group are administrated according to the volume of 10mL/kg, the administration is carried out once a day for 15 days continuously, the model group is replaced by the same amount of normal saline, 1h after the last administration, the mice are dislocated and killed, the tumor tissues are carefully stripped, and the mice are weighed and compared.
3. Results
The results of the experiment showed that the tumors were improved in weight average to some extent in comparison with the model control group after various tumors were administered with different concentrations of atractylodin, wherein the medium and high dose groups had statistical differences in comparison with the model group (. P < 0.05;. P < 0.01). The specific data are shown in Table 3.
TABLE 3 Effect of atractylodin on tumor cell tumor weight
P <0.05, P <0.01 compared to model control.
According to experiments, the atractylodin can obviously reduce the activities of NCI-H23 human non-small cell lung cancer adenocarcinoma cells, HT-29 human colon cancer cells, T47D human breast cancer cells, SK-OV-3 human ovarian cancer cells and H22 liver cancer cell line cells in vitro, can reduce the tumor weight of tumor-bearing mice in vivo, and shows that the atractylodin has an inhibiting effect on the 5 tumors.
According to the contents of the above experimental examples, it is preliminarily presumed that atractylodin has a certain antagonistic effect on lung cancer, breast cancer, colorectal cancer, liver cancer, hematological tumor, sarcoma, prostate cancer, bile duct cancer, esophageal cancer, small cell lung cancer, triple negative breast cancer, nasopharyngeal cancer, oral cancer, tongue cancer, laryngeal cancer, renal cancer, cardiac cancer, pyloric cancer, pancreatic cancer, intestinal cancer, bladder cancer, cervical cancer, uterine cancer, ovarian cancer, lip cancer, skin cancer, bone cancer, sarcoma, malignant brain glioma, ewing's tumor, hodgkin's disease, non-hodgkin's disease, and the like.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (1)
1. Use of (E, E) -2- (1, 7-nonadiene-3, 5-diyne) furan as an inhibitor of LAG3/MHC II binding in vitro.
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Non-Patent Citations (3)
| Title |
|---|
| Cytotoxic activities and effects of atractylodin and b-eudesmol on the cell cycle arrest and apoptosis on cholangiocarcinoma cell line;Kanawut Kotawong等;《Journal of Pharmacological Sciences》;20180112;第51-56页，尤其是第51页摘要 * |
| 苍术抗炎、抗肿瘤和免疫调节作用的研究进展;张明发等;《药物评价研究》;20161031;第39卷(第5期);第885-890页，尤其是第887页左栏第2段 * |
| 苍术素现代研究概况;高丽等;《医学信息》;20180930;第31卷(第17期);第37-40、44页，尤其是第39页右栏第2段 * |
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