KR101700599B1 - Use of thienopyridine derivatives having anti-cancer effect or combination therapeutic effect with radiation - Google Patents
Use of thienopyridine derivatives having anti-cancer effect or combination therapeutic effect with radiation Download PDFInfo
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- KR101700599B1 KR101700599B1 KR1020150165505A KR20150165505A KR101700599B1 KR 101700599 B1 KR101700599 B1 KR 101700599B1 KR 1020150165505 A KR1020150165505 A KR 1020150165505A KR 20150165505 A KR20150165505 A KR 20150165505A KR 101700599 B1 KR101700599 B1 KR 101700599B1
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
Description
The present invention relates to the use of a novel thienopyridine derivative having an anticancer effect or therapeutic effect of radiation therapy.
Recently, the incidence of cancer is rapidly increasing due to rapid development of industry, change of global ecosystem and dietary life, but it is still known as a refractory disease because the mechanism of cancer development is unclear. The currently used anticancer drugs can be broadly divided into biological agents such as enzymes and vaccines, pure synthetic drugs, and medicines derived from natural products. Anticancer drugs have various pharmacological actions depending on the type of cancer, and toxic side effects vary widely And it is a problem in cancer treatment because it appears. In addition, the anticancer drug effectively inhibits the growth of cancer cells, but it may sometimes show toxicity to normal cells. Therefore, many scholars have made efforts to develop anticancer drugs that are more effective and can maximize toxicity to normal cells.
Lung cancer is the second most common cause of gastric cancer, and the mortality rate from lung cancer among cancer deaths is the highest since 2000 due to poor prognosis. Lung cancer is classified into small cell lung cancer and non - small cell lung cancer histologically. Chemotherapy and radiotherapy are recommended for small cell lung cancer and radical resection is the best method for non - small cell lung cancer. Lung cancer has difficulty in local control of tumor and microscopic metastatic cancer cells that are difficult to detect by imaging. Therefore, the 5-year survival rate of less than 10% in radiotherapy alone is not good because it may cause recurrence in remote organs after radiation-limited radiation therapy. Therefore, in order to prevent recurrence in these remote organs, chemotherapy is combined with radiation therapy in various ways, and it is found that this combination therapy is superior to radiation alone therapy.
On the other hand, peroxisome proliferator activated receptors (PPARs) are nuclear receptors belonging to the steroid / thyroid hormone / retinoid receptor superfamily, which are transcription factors whose activity is regulated by several kinds of ligands. It is also a key regulator of glucose and lipid metabolism, and has been shown to regulate cell division, differentiation, and cell death in various tissues. Activation of PPAR is known to have various anticancer activities. The therapeutic agent for thiazolidinediones diabetes, including troglitazone (TGZ), ciglitazone, rosiglitazone or pioglitazone, is a synthetic PPAR gamma agonist and TGZ is also used for the treatment of human colon cancer, It is known to have a cytotoxic effect on various cancers such as breast cancer, liver cancer, lung cancer, kidney cancer and prostate cancer.
It is known that PPAR [beta] / [delta] activity is able to attenuate lung cancer and L165041, a high-affinity synthetic PPAR [beta] / delta ligand, inhibits cellular proliferation of human lung cancer and eliminates PPAR [ It is known to aggravate lung cancer in transgenic mice. It is known that the expression of PPARγ is decreased in patients with poor prognosis of lung cancer, and the activity of PPAR-γ by endogenous agonists and synthetic agonists inhibits the growth of lung cancer cells. Treatment of non-small cell lung cancer with PPAR-γ activator has been reported to induce apoptosis and differentiation. It has also been reported that ciglitazone inhibits tumors derived from A-549 in nude mice.
Patients who received a thiazolidinedione, a PPAR-γ agonist to treat diabetes, were significantly less likely to develop lung cancer, and PPAR-γ ligands were also shown to protect the body from lung cancer. In addition to PPAR-γ-dependent pathways, PPAR-γ ligands have been reported to have anti-cancer activity through pathways independent of PPAR-γ. Indeed, PPAR-γ ligands are known to have independent pathways and association with lung cancer.
It is an object of the present invention to provide a pharmaceutical composition for preventing or treating cancer which can act as a PPAR-γ ligand and which contains a thienopyridine derivative having an anticancer effect and radiotherapeutic effect as an active ingredient.
Another object of the present invention is to provide a pharmaceutical composition for enhancing radiation sensitivity comprising the thienopyridine derivative as an active ingredient.
In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises, as an active ingredient, a thienopyridine derivative represented by the following general formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof.
[Chemical Formula 1]
The present invention also provides a pharmaceutical composition for enhancing radiation sensitivity comprising a thienopyridine derivative represented by the general formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
The novel thienopyridine derivatives according to the present invention are PPAR-gamma ligands and have anticancer activity against various cancers as well as selective cytotoxicity against cancer cells, so they can act as anticancer agents that can minimize side effects. In addition, it can be usefully used as a radiotherapy sensitizer in radiation therapy for cancer.
Figure 1 shows the ability to differentiate into CB06 in 3T3L1 cells.
Fig. 2 shows the results of confirming the inhibitory effect of CB06 on cancer cell growth.
FIG. 3 is a result of confirming the death of arsenic lung cancer cells by treatment with CB06.
FIG. 4 shows the result of measuring the cell survival rate by the WST-1 method in order to measure the radiation sensitivity of CB06.
FIG. 5 shows the result of analysis of whether or not colony formation after radiation treatment was performed to confirm the effect of CB06 as a therapeutic agent for radiation therapy.
The present invention provides a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient, a thienopyridine derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof.
[Chemical Formula 1]
Specifically, the thienopyridine derivative is a 2 - [(4-methyl-1-piperidinyl) carbonyl] thieno [2,3- b] pyridin- 1-piperidinyl) carbonyl] thieno [2,3-b] pyridin-3-amine).
The cancer may specifically be selected from the group consisting of bladder cancer, stomach cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, colon cancer, bone cancer, skin cancer, skin or intraocular melanoma, uterine cancer, rectum cancer, Renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brain stem, lung cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, liver cancer, liver cancer, Glioma, pituitary adenoma, and the like. More specifically, the cancer is lung cancer, breast cancer, colorectal cancer, or white blood cell cancer. More specifically, the cancer is non-small cell lung cancer.
The present invention also provides a pharmaceutical composition for enhancing radiation sensitivity comprising a thienopyridine derivative represented by the following general formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
[Chemical Formula 1]
The thienopyridine derivative may be a 2 - [(4-methyl-1-piperidinyl) carbonyl] thieno [2,3- b] pyridin- carbonyl] thieno [2,3-b] pyridin-3-amine).
The pharmaceutical compositions may further comprise suitable carriers, excipients or diluents conventionally used in the manufacture of pharmaceutical compositions.
Examples of the carrier, excipient or diluent which can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .
In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.
In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .
Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
The amount of the thienopyridine derivative which is an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the age, sex, body weight and disease of the patient, but it is preferably 0.001 to 1000 mg / kg, preferably 0.01 to 100 mg / It may be administered once or several times.
The dose of the thienopyridine derivative according to the present invention may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.
The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intratracheal, intrauterine or intracerebroventricular injections.
The pharmaceutical composition may contain the thienopyridine derivative in an amount of about 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total pharmaceutical composition.
In addition, the thienopyridine derivative according to the present invention may be used as a health food in addition to a pharmaceutical composition. The health food may be provided in the form of powder, granules, tablets, capsules, syrups or beverages. The health food may be used together with food or food additives other than the thienopyridine derivative according to the present invention as an active ingredient, May be appropriately used depending on the method. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
The effective dose of the compound contained in the health food may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range for the purpose of health and hygiene or long-term intake for the purpose of health control, Since the active ingredient has no problem in terms of safety, it can be used in an amount exceeding the above range.
There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
< Experimental Example > Cell culture and chemicals
The following experimental examples are intended to provide experimental examples that are commonly applied to the respective embodiments according to the present invention.
GW9662, a selective PPAR-gamma antagonist, was purchased from Cayman (Ann Arbor, Mich.), And the PPAR-alpha antagonist GW6471 and GSK3787, a PPAR-? / -Dagonist antagonist, were purchased from Sigma-Aldrich (4-methyl-1-piperidinyl) carbonyl] thieno [2,3-b] pyridine-3-amine (CB06 ) Was purchased from ChemBridge Corporation and used.
Human non-small cell lung cancer cell lines H460 and A549 and mouse 3T3-L1 cells purchased from American type culture collection (ATCC, Manassas, Va.) Were inoculated into 10% fetal bovine serum (FBS), 100 U / mL penicillin and 100 μg / The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) medium containing 5% CO 2 at 37 ° C in a medium containing MICIN (Gibco BRL Life Technologies, Gaithersburg, MD, USA).
100 mM of CB06 was dissolved in dimethylsulfoxide (DMSO), respectively, and the stock prepared was stored at -20 ° C until used.
Various concentrations of CB06 (0-100 μM) were added to the culture medium containing 0.2% fetal bovine serum (FBS) to treat the cells.
< Example 1> PPAR -γ Ligand Verification analysis
The PPAR-alpha, beta and gamma antagonists GW6471, GSK3787 and GW9662 and the novel PPAR-gamma agonist CB06 were tested for their ability to induce adipocyte differentiation and whether or not CB06 has PPAR-gamma ligand activity. Cells were treated to induce differentiation into adipocytes.
3T3-L1 cells were plated in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS), 100 U / mL penicillin and 100 μg / mL streptomycin per well in a 6-well plate 4 cells and cultured for 48 hours until the cells were grown to 80%. (Sigma-Aldrich), 5 μg / mL insulin (Sigma-Aldrich), 1 mM dexamethasone (Dex, Sigma-Aldrich), 0.5 mM 3-isobutyl- -Aldrich) and cultured for 48 hours.
Subsequently, 3T3-L1 cells cultured in the presence or absence of 10 μM of each of the PPAR antagonists GW6471, GSK3787 and GW9662 were treated with 10 μM of CB06 and induced differentiation into adipocytes.
After induction of differentiation, cells were replaced with DMEM medium supplemented with 10% fetal bovine serum (FBS) and 5 μg / mL insulin every 48 hours.
After 6 days of differentiation of 3T3-L1 cells, each cell was stained with Oil-Red-O staining method (Lin et al., 2007; Ramirez-Zacarias et al., 1992) The absorbance was measured at 450 nm using a microscope (Olympus, Tokyo, Japan) and dissolving the oil-red-O stained cells with isopropyl alcohol.
As a result, it was confirmed that CB06 is a ligand of PPARy (Fig. 1) because the differentiation ability increased by CB06 is reduced by GW9662.
< Example 2> Cancer cell growth inhibition efficacy analysis
In order to confirm the inhibitory effect of the compound CB06, which was proved by the PPAR-γ ligand, on the cancer cell growth inhibition effect of the human arsenic lung cancer cell line, H460, CB06 treatment followed by WST-1 analysis was performed to measure the cell survival rate.
Cultured H460 cells were treated with CB06 at 1, 10, 50, 100 or 300 μM for 48 hours. (Sigma, St. Louis, Mo.) was added and the mixture was incubated at 37 ° C under 5% CO 2 condition For 4 h, then DMSO was added and the absorbance at 450 nm was measured.
As a result of confirming the proliferation of CB06 using WST-1 reagent, it was confirmed that the proliferation of cells was decreased as the concentration of CB06 was increased (FIG. 2).
< Example 3> Thienopyridine Derivative Apoptosis ( Apoptosis ) Relevance analysis
1. Treatment by CB06 treatment Arsenic Cell death confirmation
The annexin V assay was performed to confirm whether cell death by CB06 was induced by apoptosis as in the above experiment.
First, H460 was inoculated at 3.0 × 10 5 cells per 60 mm plate, cultured for 24 hours, treated with 100 μM of CB06 for 12 hours, and the cells were recovered using Annexin V-FITC Apoptosis Detection kit (BioVision, CA, USA) And the number of apoptotic cells was determined by FACSCalibur system after staining for 5 minutes with cancer using annexin V / PI according to the manufacturer's instructions.
As a result of the phophatidylserine staining method exposed to the cell surface at the time of apoptosis, it was confirmed that CB06 (100 μM - 24 hr) induces apoptosis in H460 lung cancer cell line (FIG. 3).
< Example 4> Measurement of radiation sensitivity
A549, and H460 cells were suspended in a 60-mm cell culture plate at a density of 500 cells / well and cultured for 24 hours. After confirming that the cells stably adhered to the floor, they were treated with 50 μM CB06 and γ-irradiated (3.2 Gy / min, Gammacell 3000, Atomic Energy of Canada, Mississauga, ON, Canada) at 2 and 4 Gy intensity Respectively. After 48 hours of incubation, the cell viability was confirmed by the WST-1 method.
As a result, it was confirmed that CB06 showed the therapeutic effect of radiation combination treatment at 50 μM + 4 Gy (FIG. 4).
< Example 5> CB06 as therapeutic agent for radiation combination
H460 lung cancer cell lines were cultured in 3 wells (triplecate) in a 6-well plate, treated with 50 μM CB06, and treated with 0, 2 Gy, 4 Gy or 6 Gy of radiation 30 minutes later. Colonies were observed for 10 days while the culture medium was changed every two days. After 10 days, the colonies were stained with 1% methylene blue staining reagent, and the number of colonies was counted and analyzed by the survival fraction curve.
Dye enhancement ratio was calculated to be 1.625 for 4 Gy + 50μM (Fig. 5).
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (5)
[Chemical Formula 1]
[Chemical Formula 1]
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019231221A1 (en) * | 2018-05-30 | 2019-12-05 | (주)파로스아이비티 | Use of 2,3,5-substituted thiophene compound for enhancement of radiotherapy |
| WO2020085642A1 (en) * | 2018-10-23 | 2020-04-30 | 한국원자력의학원 | Pharmaceutical composition for preventing or treating cancer, containing n-1h-benzimidazol-2-yl-3-(1h-pyrrole-1-yl) benzamide as active ingredient |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05140487A (en) * | 1991-11-15 | 1993-06-08 | Kansai Paint Co Ltd | Electrodeposition coating composition |
| KR20120103220A (en) | 2011-03-10 | 2012-09-19 | 한국화학연구원 | Novel benzofuran-2-carboxamide derivatives and therapeutic uses for mch receptor-1 related diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05140487A (en) * | 1991-11-15 | 1993-06-08 | Kansai Paint Co Ltd | Electrodeposition coating composition |
| KR20120103220A (en) | 2011-03-10 | 2012-09-19 | 한국화학연구원 | Novel benzofuran-2-carboxamide derivatives and therapeutic uses for mch receptor-1 related diseases |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019231221A1 (en) * | 2018-05-30 | 2019-12-05 | (주)파로스아이비티 | Use of 2,3,5-substituted thiophene compound for enhancement of radiotherapy |
| WO2020085642A1 (en) * | 2018-10-23 | 2020-04-30 | 한국원자력의학원 | Pharmaceutical composition for preventing or treating cancer, containing n-1h-benzimidazol-2-yl-3-(1h-pyrrole-1-yl) benzamide as active ingredient |
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