KR101220417B1 - Calcone derivatives having apoptosis-inducing activation - Google Patents
Calcone derivatives having apoptosis-inducing activation Download PDFInfo
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- KR101220417B1 KR101220417B1 KR1020100109098A KR20100109098A KR101220417B1 KR 101220417 B1 KR101220417 B1 KR 101220417B1 KR 1020100109098 A KR1020100109098 A KR 1020100109098A KR 20100109098 A KR20100109098 A KR 20100109098A KR 101220417 B1 KR101220417 B1 KR 101220417B1
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Abstract
The present invention relates to a chalcone derivative having apoptosis-inducing activity, and more specifically, represented by the following Chemical Formula 1, which can be used as a composition for preventing or treating cancer by inducing Type-I apoptosis activity in cancer cells. One chalcone derivative 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone and a method for preparing the same, a pharmaceutical composition containing the same and a health functional food.
[Formula 1]
The novel chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, according to the present invention exhibits anticancer effect properties having activity of inducing apoptosis, and thus, anticancer agents or It can be usefully used as a dietary supplement.
Description
The present invention relates to a chalcone derivative having apoptosis-inducing activity, and more specifically, represented by the following Chemical Formula 1, which can be used as a composition for preventing or treating cancer by inducing Type-I apoptosis activity in cancer cells. One chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, and a method for preparing the same, a pharmaceutical composition containing the same and a health functional food.
[Formula 1]
The way in which the cells die is divided into necrosis, which is killed by external physical stimulation, and programmed cell death, in which a planned death process is induced by the activation or inactivation of the cell signal transduction system.
Necrotic death is a reaction in which the cell itself expands and ruptures, causing inflammation around the damaged cells. Cell self-apoptosis is a process for controlling the growth of incomplete cells and is a self-regulating response to quantitative balance with the normal function of cells.
There are two types of apoptosis, type-I (apoptosis) and type-II (autophagic cell death). In general, type-I self-killing involves condensation of chromatin, fragmentation of DNA, and formation of small apoptotic bodies. In particular, the process by apoptosis is characterized by not causing inflammation due to phagocytosis of surrounding cells (Experimental Cell Research 256,12-18,2000).
Type-I apoptosis is induced by the activity of Caspase, a type of Cysteine protease (Cell (1996) 87; 171, Biochem J (1997) 326; 1-16). More than 10 types of caspases have been found to date. Among them, when cytochrome-C is released from the mitochondrial membrane by cell stimulation that induces cell death, caspase-9 is activated, and active caspase-9 activates caspase-3. Active caspase-3 induces apoptosis by breaking down a variety of proteins important for cell activity.
Poly ADP-Ribose Polymerase (PARP) is a 113 kDa DNA repair enzyme that repairs damaged DNA. Since PARP protein is cut into 89-kDa and 24-kDa fragments by caspase enzymes during type-I apoptosis, the production of 89-kDa and 24-kDa fragments of PARP protein is type- It is considered a major biochemical marker to validate the I cell self-killing process (Nature (1994) 371: 346-347).
Therefore, in the present invention, the generation of PARP protein fragments was measured as a means of measuring the effect of inducing apoptosis of cancer cells of the novel chalcone derivatives. In the flow cytometry, we observed that sub-G1 cells with a DNA content of less than 2N DNA content of G1 phase were consistent with the induction of type-I apoptosis, suggesting that 113-kDa PARP protein was 89- Efforts to find an effective compound that induces PAD fragment fragments of kDa and 24-kDa resulted in a novel chalcone derivative, type 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone. It was confirmed that -I apoptosis was induced and completed the present invention.
The present invention has been made to solve the above problems and by the necessity of the above, the technical problem to be achieved by the present invention is a novel compound exhibiting Type-I apoptosis inducing effect and an anticancer pharmaceutical composition containing the same as an active ingredient and It is to provide health functional food.
In order to achieve the above object, the present invention is a chalcone derivative represented by the following formula (1), 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or pharmaceutically thereof Acceptable salts and methods for their preparation are provided.
[Formula 1]
In the present invention, the preparation method comprises the steps of (1) dissolving 2-hydroxy-1-acetonaphtone and 2,4,6-trimethoxybenzaldehyde in ethanol; (2) adding 50% KOH aqueous solution to the solution at 3 to 5 ° C; (3) stirring the mixed solution for 15 to 20 hours and then lowering the temperature to 3 to 5 ° C; (4) neutralizing adding HCl solution to the cooled solution; (5) extracting the aqueous solution with chloroform; (6) separating the extracted organic layer with a separatory funnel and dehumidifying with magnesium sulfate; And (7) filtering the mixture from which the water was removed under reduced pressure, removing the solvent from the filtrate, and separating and purifying by using column chromatography.
In another aspect, the present invention is a cancer containing a 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Provided is a prophylactic or therapeutic pharmaceutical composition.
In the present invention, the 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof induces Type-I apoptosis activity in cancer cells It is characterized by preventing or treating cancer.
The present invention also provides a health functional food containing 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof as an active ingredient.
The novel chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, according to the present invention exhibits anticancer effect properties having activity of inducing apoptosis, and thus, anticancer agents or It can be usefully used as a dietary supplement.
1 is a hydrogen nuclear magnetic resonance of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone according to the present invention measured by a Bruker 400 MHz nuclear magnetic resonance spectrometer Spectral spectrum ( 1 H-NMR) is shown.
2 is a carbon nuclear magnetic resonance of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone according to the present invention measured by a Bruker 400 MHz nuclear magnetic resonance spectrometer Spectral spectrum ( 13 C-NMR) is shown.
Figure 3 is a novel chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone (denoted by # 74) PARP of 113-kDa size according to the present invention Shows the result of Western blot analysis in which a piece of PARP fragment of 89-kDa size is induced.
Hereinafter, the present invention will be described in detail.
The present invention provides a chalcone derivative represented by Formula 1 below, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof.
[Formula 1]
The present invention also provides a method for preparing 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone represented by the formula (1).
The preparation method of the present invention comprises the steps of (1) dissolving 2-hydroxy-1-acetonaphtone and 2,4,6-trimethoxybenzaldehyde in ethanol; (2) adding 50% KOH aqueous solution to the solution at 3 to 5 ° C; (3) stirring the mixed solution for 15 to 20 hours and then lowering the temperature to 3 to 5 ° C; (4) neutralizing adding HCl solution to the cooled solution; (5) extracting the aqueous solution with chloroform; (6) separating the extracted organic layer with a separatory funnel and dehumidifying with magnesium sulfate; And (7) filtering the mixture from which the water was removed under reduced pressure, removing the solvent from the filtrate, and separating and purifying by using column chromatography.
4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, a novel chalcone derivative of the present invention, has the effect of preventing or treating cancer by inducing Type-I apoptosis activity. Have
Therefore, the present invention provides a pharmaceutical for the prevention or treatment of cancer containing the 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a composition.
The composition comprising the compound of the present invention is preferably used for the prevention or treatment of colon cancer, stomach cancer, prostate cancer, breast cancer, kidney cancer, liver cancer, brain tumors, lung cancer, uterine cancer, colon cancer, bladder cancer, pancreatic cancer, blood cancer, etc. It is not limited to these.
Compounds of formula (1) included in the compositions of the present invention may also be used in the form of their salts, which include acid addition salts with various organic or inorganic acids that are pharmaceutically or physiologically acceptable. Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid. , Maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfate.
The composition of the present invention may further comprise a pharmacologically or physiologically acceptable carrier, excipient, diluent in addition to the compound of Formula 1 or a compound thereof.
Examples of suitable carriers, excipients and diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like. When formulated, the composition may further include conventional fillers, extenders, binders, disintegrants, surfactants, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like.
The composition of the present invention may be formulated in various forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral formulations, sterile injectable solutions, etc. It may be used orally or may be administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration and the like.
Solid preparations 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, lactose, gelatin, and the like. Mix and formulate. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to commonly used simple diluents such as water and liquid paraffin.
Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, 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. Bases for injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
By "administration" in the present invention is meant to provide the patient with the desired material in any suitable way, the route of administration of the composition of the present invention being oral or parenteral via all common routes as long as the target tissue can be reached. May be administered. In addition, the composition may be administered by any device in which the active agent may migrate to the target cell.
In the present invention, "patient" means a human and an animal such as a monkey, dog, goat, pig, or rat having a disease that can improve symptoms by administering the composition of the present invention. The composition according to the invention can be applied not only for humans (treatment, inhibition or prevention) but also to other commercially useful animals.
In another aspect, the present invention provides a method for inhibiting, preventing and treating cancer and cancer metastasis by administering to a patient a composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The composition of the present invention can be administered in parallel with the conventional disease treatment.
The composition of the present invention is administered in a pharmaceutically effective amount.
In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level means the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent drug use, and other factors well known in the medical arts. The compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
Further, the dosage of the compound according to the present invention may be varied depending on the degree of absorption, body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, severity of disease, However, for the desired effect, the compound of the present invention is preferably administered at 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight per day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
The compound of formula 1 of the present invention can be synthesized using the synthesis method of Scheme 1 or various methods well known in the art.
The present invention also provides a dietary supplement containing 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof as an active ingredient.
Hereinafter, the present invention will be described in more detail with reference to Examples.
However, the following examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not interpreted to be limited by these examples.
Example 1: Preparation of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone
In the present invention, to synthesize a novel chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, was synthesized as follows using the method of Scheme 1 below.
[Reaction Scheme 1]
2-hydroxy-1-acetonaphthone (1864 mg, 10 mmol) and 2,4,6-trimethoxybenzaldehyde (2,4,6-trimethoxybenzaldehyde, 1964 mg, 10 mmol) is dissolved in 70 ml of ethanol, and then 15 ml of 50% aqueous KOH solution is added slowly at about 4 minutes at 4 ° C. After stirring the mixed solution at room temperature for 18 hours, the temperature is lowered to about 4 ° C. After neutralizing by adding 40 ml of 6 N HCl solution to the cooled solution, the aqueous solution was extracted twice with 100 ml of chloroform. Each of the extracted organic solvents is combined, magnesium sulfate is added to remove water, and the remaining mixture is filtered under reduced pressure. Next, after removing the solvent of the filtrate by using a rotary evaporator, the remaining mixture was purified by column chromatography to obtain 2.9 g of the target mixture in a solid state (72% yield).
The melting point of the synthesized material was 96 ~ 99 ℃, to confirm the formation of the target compound hydrogen nuclear magnetic resonance spectra spectrum shown in Figure 1 (Bruker 400MHz) and carbon nuclear magnetic resonance spectrum shown in Figure 2 (
Example 2. Western Blot Analysis
In order to confirm the cancer-inhibitory activity of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone in the present invention, human uterine cancer cell line (HeLa) in the ATCC (American Type Culture) Collection, USA), treated with 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone obtained in Example 1, and then the cells were 89-kDa sized PARP. The type-I self-apoptotic induction effect of the cells was analyzed by measuring fragment generation.
Specifically, 1 × 10 6 HeLa cells were dispensed into a 60 mm cell culture dish, followed by incubation for 24 hours in a 37 ° C. cell culture cell supplied with 5% CO 2 , and 4,5-benzo-1-hydroxy-2. Fragment of PARP induced by 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone after treatment with ', 4', 6'-trimethoxychalcone at 20 μM concentration The fragments were analyzed by Western blot to investigate.
HeLa cervical cancer cells were treated with 20 μM concentration of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone and harvested cells 24 hours later, followed by 20 mM HEPES ( pH 7.2), 200 μg of cell lysis buffer containing 1% Triton X-100, 10% glycerol, 150 mM NaCl, 10 μg / ml leupeptin and 1 mM PMSF were lysed, The top cell lysate was harvested by centrifugation at 15,000 xg for 30 minutes. Samples prepared to contain 20 μg of protein were subjected to SDS-polyacrylamide gel electrophoresis (SDS-PAGE) to separate proteins present in cells. Electrophoresis of the separated proteins into a polystyrene membrane followed by standardization of a rabbit anti-PARP antibody and an anti-rabbit secondary antibody with horse radish peroxidase (HRP) After the reaction, the degree of PARP protein truncation to 89-kDa size was measured using a chemiluminescence kit purchased from Amersham Pharmacia Biotech (Piscataway, NJ).
As a result, as shown in FIG. 3, PARP protein was observed to be 113-kDa in control cells which had not been treated with HeLa cancer cells, but it was a novel compound 4,5-benzo-1-hydroxy-2 ', 4'. Treatment with, 6'-trimethoxychalcone produced PARP fragment fragments of 89-kDa size. At this time, GAPDH (glyceraldehyde 3-phosphate dehydrogenase), which does not show a change in expression by the drug response, was not observed between the two cell groups. Through these results, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, a novel chalcone derivative compound, has the effect of inducing Type-I apoptosis in HeLa cancer cells. It was confirmed.
Claims (6)
[Formula 1]
The pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition for preventing or treating cancer, characterized in that it comprises a pharmaceutically acceptable carrier, excipient or diluent.
The cancer is composed of breast cancer, colon cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, brain tumor, lung cancer, uterine cancer, colon cancer, bladder cancer, pancreatic cancer, blood cancer, non-small cell lung cancer, thyroid cancer, acute lymphocytic leukemia, and tumors caused by viruses. Cancer prevention or treatment pharmaceutical composition, characterized in that at least one selected from the group.
[Formula 1]
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| KR101306958B1 (en) * | 2010-11-08 | 2013-09-10 | 건국대학교 산학협력단 | Trimethoxyphenyl-4,5-dihydro-1h-pirazol-3-yl-naphthalen-2-ol derivatives having apoptosis-inducing activation |
| US9606730B2 (en) | 2012-05-04 | 2017-03-28 | Samsung Electronics Co., Ltd. | System and method including three dimensional nonvolatile memory device and random access memory |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005533760A (en) * | 2002-04-18 | 2005-11-10 | エスアールアイ インターナショナル | Novel flavanoids and chalcones as chemotherapeutic, chemopreventive, and anti-angiogenic agents |
| KR100567125B1 (en) | 2001-11-01 | 2006-03-31 | 주식회사 안지오랩 | Pharmaceutical composition for inhibiting matrix metalloproteinase activity comprising chalcone or its derivatives |
| US7432303B2 (en) | 1999-12-23 | 2008-10-07 | J. Phillip Bowen | Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7432303B2 (en) | 1999-12-23 | 2008-10-07 | J. Phillip Bowen | Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states |
| KR100567125B1 (en) | 2001-11-01 | 2006-03-31 | 주식회사 안지오랩 | Pharmaceutical composition for inhibiting matrix metalloproteinase activity comprising chalcone or its derivatives |
| JP2005533760A (en) * | 2002-04-18 | 2005-11-10 | エスアールアイ インターナショナル | Novel flavanoids and chalcones as chemotherapeutic, chemopreventive, and anti-angiogenic agents |
Non-Patent Citations (2)
| Title |
|---|
| Prasad et al. Synthesis and Antimicrobial Activity of Some Novel Chalcones of 2-hydroxy-1-Acetonapthone and 3-Acetyl Coumarin. E-Journal of Chemistry, 2006.10., Vol.3, No.13, pp.236-241. * |
| Prasad et al. Synthesis and Antimicrobial Activity of Some Novel Chalcones of 2-hydroxy-1-Acetonapthone and 3-Acetyl Coumarin. E-Journal of Chemistry, 2006.10., Vol.3, No.13, pp.236-241.* |
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