KR20140005080A - Composition comprising an hydroxychalcone compounds as an active ingredient for anti-cancer activity - Google Patents

Abstract

The present invention relates to an anticancer composition comprising a hydroxychalcone compound as an active ingredient and a health functional food having an effect in the prevention or improvement of cancers. The compound according to the present invention has an angiogenesis-inhibitory activity in a chorioallantoic model, particularly inhibiting angiogenesis by tumorigenesis, and has excellent anticancer activity through the suppression of tumor growth. Therefore, the hydroxychalcone compound according to the present invention can be used for a pharmaceutical purpose for treating and preventing various cancer diseases and a food purpose for improving and preventing cancer symptoms.

Description

[0001] The present invention relates to an anticancer composition containing a hydroxychalcone compound as an active ingredient,

The present invention relates to an anticancer composition containing a hydroxychalcone compound as an active ingredient and a health functional food having an effect of preventing or ameliorating cancer.

Over the past 30 years, the incidence and mortality rates of cancer have not declined as a whole, despite the enormous investments made in research on the cause and treatment of cancer worldwide. Thus, the importance of prevention is now emphasized as an alternative to cancer convalescence. In particular, the non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, So-called chemoprevention, which is used to inhibit and control the cancerous process, has emerged as a new strategy to substantially reduce cancer incidence and mortality.

Chemoprevention is a new strategy to prevent cancer by inhibiting, delaying or reversing the cancerous growth of normal cells using safe chemical substances or mixtures thereof that are not toxic. It is a new strategy to prevent cancer by treating cancer patients with anticancer drugs Is a different concept from chemotherapy of cancer and is considered to be an important strategy leading to the victory of cancer. Studies on various medicinal plants and food-derived compounds which have been proved to be safe for the prevention of these cancers It is actively underway.

In addition, many epidemiological studies have shown that micronutrients such as carbohydrates and fibrin, as well as vitamins and minerals, reduce the incidence of cancer. It is well known that antioxidant vitamins (Vit. A, Vit. C. and Vit. E) and vitamin precursors such as beta - carotene, which are abundant in green vegetables and fruits, are effective in cancer prevention. A series of clinical trials to systematically validate the anti-cancer effects of antioxidant vitamins and trace elements have been under way, led by the National Cancer Institute.

In a study of 29,584 people aged 40 to 69 residing in the Linxian region of China, the highest incidence of esophageal cancer and gastric cancer in the world, people who daily consumed daily recommended amounts of vitamin E, beta-carotene, and selenium The mortality rate of cancer was much lower than that of the control group. But the vegetables and fruits we eat on a daily basis contain compounds that have a number of cancer-protective actions in addition to antioxidant vitamins. Phytochemicals, which refer to plant-derived chemicals, are often superior to antioxidant vitamins, although their nutritional value may not be as good as their antioxidant vitamins, There are many things that are made to protect oneself from pests, surrounding animals, or ultraviolet rays.

On the other hand, the cells are constructing a defense system to adapt themselves to external stress. Especially, when the antioxidant system is consumed firstly by oxidative stress caused by reactive oxygen species (ROS), a series of antioxidant It is accompanied by the induction of genes. In addition, the expression of genes related to antioxidative and secondary antitoxin enzymes is regulated by the antioxidant response element (ARE), which is a unique nucleotide sequence found in each gene promoter. The major enzyme regulated by ARE (GST), γ-Glutamyl Cysteine Synthetase (γ-GCS), Thioredoxin Reductase-1, Thioredoxin, and the like, have. The activity of transcription through the ARE is regulated mainly by NF-E2-related factor 2 (Nrf2), which shares the basic region leucine zipper (bZIP) structure. Mitogen- Activated Protein Kinase (MAPK), Protein Kinase C, and Phosphatidylinositol 3-Kinase. Indeed, the chemical stresses induced by various drugs or antibiotics that produce reactive oxygen species will result in activation of the MAPK signaling system, followed by the activation of the Nrf2-Maf-defendant ARE genes including the second-order antitoxin enzymes as well as stress enzymes Has been reported to have a biologic defense function or regulate cell growth or apoptosis. NQO1 is known as DT-diaphorase and is an NADH- or NADPH-dependent two-electron reducing agent. It is an important enzyme for metabolism of living organisms. It reduces the two electrons in various quinones to produce corresponding hydroquinone derivatives. Although the function of NQO1 is different from that of NQO1, toxicity is reduced and it is easy to be excreted. However, it also reacts with oxygen molecules to produce active oxygen and participate in the alkylation process of DNA. HO-1 is a type of HSP system and has been known to have a biologic defense function in response to various stress stimuli such as hypoxic state, heavy metal such as UV radiation, cadmium, lead, mercury and reactive oxygen species, It has been reported that tumor growth is suppressed when HO-1 inhibitor is administered, and this mechanism is known to be induced through the activation of transcription by Nrf2, an ARE.

In order to properly evaluate these cancer prevention functions, it is essential to understand precisely the cancerous process. During the initiation, promotion, and progression phases, the initiation can occur in a very short period of time, and DNA or cells that have once mutated in the initiation process can not be restored to their original state Since it is an irreversible step, it is difficult to expect substantial cancer prevention efficacy just by blocking cancer initiation. On the other hand, the promoting step is reversible and usually proceeds over a long period of time, and may not only block or delay the process, but may also restore the original normal cell state in some cases. The progressive stage is an irreversible stage in which some of the benign tumor cells are transformed to penetrate into other tissues and metastasize.

Therefore, it is most desirable to inhibit or reverse the promoting step, which is a reversible process, in order to expect effective cancer prevention efficacy. Since the step of promoting carcinogenesis involves the inhibition of homeostasis of cells due to oxidative stress, it is necessary to establish a technology to identify and control the relationship with the promotion of carcinogenesis through the search of a molecular index reflecting the oxidative tissue damage. .

Korean Patent No. 10-0614222 Korean Patent Publication No. 10-2011-0019262

Accordingly, an object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer containing as an active ingredient a hydroxychronic compound capable of effectively preventing or treating cancer.

Another object of the present invention is to provide a health functional food for preventing or ameliorating a cancer comprising a hydroxychalcone compound and a pharmaceutically acceptable carrier.

In order to accomplish the above object, the present invention provides a process for producing 1- (2-hydroxyphenyl) -3-phenylpropenone, 1- (3-hydroxyphenyl) ) -3-phenylpropenone, (3-hydroxyphenyl) -1-phenylpropenone, 3- (2-hydroxyphenyl) -1-phenylpropenone, 3- (2-hydroxyphenyl) propene, 1- (2-hydroxyphenyl) -3- (3-hydroxyphenyl) propenone, 1- (3-hydroxyphenyl) propenone, 1- (3-hydroxyphenyl) propenone, 3- (3-hydroxyphenyl) propene, 3- (2-hydroxyphenyl) -1- For the prophylaxis or treatment of cancer comprising as an active ingredient a compound selected from 1- (4-hydroxyphenyl) propenone or 1,3-bis (4-hydroxyphenyl) propenone or a pharmaceutically acceptable salt thereof A pharmaceutical composition is provided.

In one embodiment of the present invention, the composition may be contained at a concentration of 0.1 uM to 20 uM.

In one embodiment of the present invention, the cancer may be selected from the group consisting of liver cancer, stomach cancer, colon cancer, lung cancer, breast cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer and myopia ocular tumor.

In one embodiment of the present invention, the compound may be one having an activity of inhibiting angiogenesis and inhibiting tumor growth.

The present invention also relates to a process for the production of 1- (2-hydroxyphenyl) -3-phenylpropenone, 1- (3-hydroxyphenyl) Propenone, (3-hydroxyphenyl) -1-phenylpropenone, 3- (2-hydroxyphenyl) -1-phenylpropenone, 3- (2-hydroxyphenyl) propene, 1- (2-hydroxyphenyl) -3- (3-hydroxyphenyl) propenone, 1- (3-hydroxyphenyl) propenone, 1- (3-hydroxyphenyl) propenone, 3- (3-hydroxyphenyl) propene, 3- (2-hydroxyphenyl) -1- Which comprises a compound selected from 1- (4-hydroxyphenyl) propenone or 1,3-bis (4-hydroxyphenyl) propenone as an active ingredient.

In one embodiment of the present invention, the cancer may be selected from the group consisting of liver cancer, stomach cancer, colon cancer, lung cancer, breast cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer and myopia ocular tumor.

In one embodiment of the invention, the food may be in the form of a powder, granules, tablet, capsule or drink.

 The compounds according to the present invention have an anti-angiogenic activity in a villous somatic cell model, and particularly have an excellent anticancer activity by inhibiting angiogenesis induced by tumor formation and inhibiting tumor growth. Therefore, the hydroxychalcone compound according to the present invention can be used not only for the pharmaceutical use for the treatment and prevention of various cancer diseases, but also for the food application for improving or preventing cancer symptoms.

Figures 1A and 1B show the inhibitory effect of compounds 10-15 according to the invention on VEGF-induced angiogenesis ( ^* P < 0.05 compared to the control group, ^# P < 0.05 compared to the VEGF- ),
Figures 2a and 2b illustrate the inhibitory effect of compounds 16-24 according to the invention on the angiogenesis induced by VEGF (compared with the control group ^{* P <0.05;# P <} 0.05 compared with VEGF- treated group ).
FIG. 3 shows the results of inhibiting angiogenesis and tumor growth of the compounds according to the present invention.

The present invention relates to a process for the production of 1- (2-hydroxyphenyl) -3-phenylpropenone, 1- (3-hydroxyphenyl) , (3-hydroxyphenyl) -1-phenylpropenone, 3- (2-hydroxyphenyl) -1-phenylpropenone, 3- (2-hydroxyphenyl) propene, 1- (2-hydroxyphenyl) -3- (3-hydroxyphenyl) propenone, 1- (3-hydroxyphenyl) propenone, 1- (3-hydroxyphenyl) propenone, 3- (3-hydroxyphenyl) propene, 3- (2-hydroxyphenyl) -1- For the prophylaxis or treatment of cancer comprising as an active ingredient a compound selected from 1- (4-hydroxyphenyl) propenone or 1,3-bis (4-hydroxyphenyl) propenone or a pharmaceutically acceptable salt thereof It is characterized in that it provides a pharmaceutical composition.

Cancer, the leading cause of death in Korea, is a threat to public health and should be treated through surgery, medication, and radiation therapy if it continues to develop. However, since the after-effects of the administration of the drug are serious and the problem due to the after-effects always arises, the present inventors have made efforts to develop a novel drug without side effects, and thus the inventive hydroxychalcone compound has a high activity to inhibit angiogenesis By confirming, it has been found that the hydroxychronic compound can be used as a composition for prevention and treatment of cancer.

In order to verify this fact, the present inventors conducted the following experiment through one embodiment of the present invention. In order to confirm the anti-angiogenic effect in vivo, CAM analysis was performed. As a result, It was found that the angiogenesis was strongly inhibited, and the highest activity was observed especially in the compounds 19, 21 and 22 (see Table 1).

Furthermore, the inventors of the present invention confirmed that the compound of the present invention was treated with the compound of the present invention to inhibit angiogenesis induced by tumor formation and to inhibit the growth of the tumor. In addition, it was found that the tumor suppressing effect is more excellent than that of the positive control group treated with the same concentration of U4312 or chalcone (DPhP) (see FIG. 3).

Thus, it was found that the hydroxychalcone compound can prevent and treat diseases caused by abnormally proliferated angiogenesis.

As used herein, the term &quot; a disease caused by angiogenesis &quot; refers to a tumor, a corneal ulcer, a macular degeneration associated with aging, diabetic retinopathy, proliferative vitreoretinopathy, immature retinopathy, ocular inflammation, keratoconus, Sjogren's syndrome, Osteoarthritis, osteoarthritis, septic arthritis, psoriasis, abnormal wound union, bone disease, proteinuria, abdominal aortic aneurysm disease, degenerative cartilage loss due to traumatic joint injury, nervous system degenerative diseases, cirrhosis, And is preferably at least one selected from the group consisting of inflammatory bowel disease, inflammatory bowel disease, corneal disease, arteriosclerosis, restenosis, central nervous system inflammatory disease, Alzheimer's disease, skin aging and cancer invasion and metastasis, Tumor, corneal ulcer, macular degeneration associated with aging, diabetic retinopathy, proliferative vitreoretinopathy, immature retinopathy, ocular inflammation, It comprises a weight cornea, Sjogren's syndrome, myopia ophthalmic tumor or corneal transplants geobujeung.

The hydroxychronic compound of the present invention can treat diseases caused by angiogenesis, but more specifically, can be used as an anticancer composition.

The composition according to the present invention may include liver cancer, stomach cancer, colon cancer, lung cancer, breast cancer, rectal cancer, brain cancer, skin cancer and pancreatic cancer, It can be colon cancer.

In addition, the compounds of the present invention may be prepared into pharmaceutically acceptable salts and solvates by methods conventional in the art.

As salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, lactic acid, glycollic acid, gluconic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt in particular, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds unless otherwise indicated. For example, pharmaceutically acceptable salts include the sodium, calcium, and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate rate, methane sulfonate (mesylate) and p - toluene sulfonate (tosylate) and a salt, the salt manufacturing method or manufacturing process known in the art &Lt; / RTI &gt;

Another object of the present invention is to provide a process for preparing a compound of the present invention which can be prepared by a synthetic method known in the art and can be chemically synthesized by the method shown in the following reaction formulas, no.

[Reaction Scheme 1]

Scheme 1. Synthesis of hydroxychalcones.

Reagents and conditions: (i) KOH (10 equiv) / NaOH (5 equiv), EtOH, 224 h, 20 ° C, 3694% yield; (ii) BF ₃ Et ₂ O (0.5 equiv), Dioxane, 2h, 20 ° C, 74% yield.

For example, EtOH aryl methyl ketone of the same molar amount of (aryl methyl ketone; acetophenone, 2 '/ 3' / 4'-hydroxyacetophenone, 6 (R 1 = a -d)) and aryl-methyl aldehyde (methyl aryl aldehyde; benzaldehyde , 2/3/4-hydroxy benzaldehyde, 7 (R2 = ad)) was added a 50% aqueous solution of KOH or NaOH and catalytic condensation ( Claisen - Schmidt condensation reaction.

The compounds of the present invention obtained by the above method strongly inhibited angiogenesis induced by the treatment of neovascularization inducers such as vascular endothelial growth factor in the chicken villi model, It can be used as a composition for treating and preventing cancer.

The composition of the present invention contains 0.01 to 99% by weight of the compound, based on the total weight of the composition.

However, the composition is not limited thereto, and may vary depending on the condition of the patient, the type of disease, and the progress of the disease.

The compositions comprising the compounds of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions.

The composition containing the compound according to the present invention may be formulated in the form of powders, granules, tablets, capsules, oral preparations such as suspensions, emulsions, syrups and aerosols, external preparations, suppositories and sterilized injection solutions, Examples of carriers, excipients and diluents that can be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate and mineral oil. 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, Or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate 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 suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.

The preferred dosage of the compound of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound is preferably administered at 0.01 mg / kg to 10 g / kg per day, preferably 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses. Therefore, the dose is not intended to limit the scope of the present invention in any aspect.

The composition of the present invention may be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration may be expected, including, for example, oral and rectal, or intravenous.

The present invention also relates to a process for the preparation of 1- (2-hydroxyphenyl) -3-phenylpropanone, 1- (3-hydroxyphenyl) Phenon, (3-hydroxyphenyl) -1-phenylpropenone, 3- (2-hydroxyphenyl) -1-phenylpropenone, 3- (2-hydroxyphenyl) propene, 1- (2-hydroxyphenyl) -3- (3-hydroxyphenyl) propenone, 1- (3-hydroxyphenyl) propenone, 1- (3-hydroxyphenyl) propenone, 3- (3-hydroxyphenyl) propene, 3- (2-hydroxyphenyl) -1- Which comprises a compound selected from 1- (4-hydroxyphenyl) propenone or 1,3-bis (4-hydroxyphenyl) propenone as an active ingredient.

The health functional food containing the compound of the present invention can be used variously for medicines, foods and beverages for prevention and improvement of cancer diseases. Examples of foods to which the compound of the present invention can be added include various foods, beverages, gums, tea, vitamin complexes, health supplements and the like, and they can be used in powder, granule, tablet, have.

Food forms to which the compounds of the present invention can be added include various foods of candy, beverages, gums, tea, vitamin complexes, or foods that are health supplement foods.

The compound of the present invention can be added to food or beverage for the purpose of prevention and improvement of cancer. At this time, the amount of the compound in the food or beverage may generally be from 0.01 to 15% by weight of the total food weight of the health food composition of the present invention, and the health beverage composition is preferably 0.02 to 10 g based on 100 ml, Can be added in a proportion of 0.3 to 1 g.

The health beverage composition of the present invention may contain various flavoring agents or natural carbohydrates as an additional ingredient, such as ordinary beverages, in addition to containing a mixture of the above-mentioned compounds as essential ingredients in the indicated ratios, have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose such as maltose, sucrose and the like and polysaccharides such as dextrin, cyclodextrin and the like Sugar, and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavors (tau martin, stevia compounds (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.

In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited to these embodiments.

< Reference Example  1> Preparation for experiment

Starting materials and reagents were purchased from Aldrich Chemical Co., Junsei or others and used without further purification. HPLC grade acetonitrile (ACN) and methanol were purchased from Burdick and Jackson, USA. Thin-layer chromatography (TLC) and column chromatography (CC) were performed on Kieselgel 60 F ₂₅₄ (Merck) and silica gel (Kieselgel 60,230-400mesh, Merck) were used, respectively, and all compounds with aromatic rings were visualized on TLC plates with UV light (both short wavelength and long wavelength). NMR spectrum was used for ¹ H-NMR and 62.5 MHz for Bruker AMX 250 (250 MHz, FT) and ¹³ C-NMR. Chemical shifts measured migration from TMS. (Chemical shifts ( ? ) In ppm and coupling constants ( J ) in Hz). Melting points were calibrated using an open capillary tube with an electrothermal 1A9100 digital melting point apparatus.

HPLC analysis was performed using two instruments (Shimadzu LC-10 AT pumps gradient-controlled HPLC system, Shimadzu system controller (SCL-10A VP) and photo diode array detector (SPD-M10A VP) The volume (10 μL) of the sample was measured under the constant condition (gradient dilution: 10% A in B for 50% to 100% in A, 100% to 50% in B for 150 min, flow rate: 1.0 mL / min, t 254 nm UV detection , mobile phase a was 20 mM ammonium formate (AF) treated double distilled water and B was fed to the column _{(X- Terra5μMreverse-phaseC 18 column (} 4.6ⅹ250 mm) in 20 mM AF process in water 90% ACN solvent Im) compound purity Is expressed as a percentage (%).

< Example  1> General synthesis process

The following example compounds were synthesized according to the following methods A to C by the KOH / NaOH / BF ₃ -Et ₂ O catalytic condensation reaction ( Claisen- Schmidt condensation reaction).

1-1. Method A

To the solution of aryl methyl ketone (acetophenone, 2 '/ 3' / 4'-hydroxyacetophenone) and aryl methyl aldehyde (benzaldehyde, 2/3/4-hydroxy benzaldehyde) 10 eq.) Of 50% aqueous solution was added and stirred at 20 [deg.] C for 2-24 hours. The reaction mixture was neutralized with 6 M aqueous HCl solution (pH adjusted to 2), extracted with ethyl acetate, and washed with water and brine. And further purified by recrystallization or column chromatography to obtain pure solid compounds.

1-2. Method B

Was synthesized analogously to Method A, except that 6 M aqueous NaOH solution (5 eq) was used.

1-3. Method C

BF ₃ -Et ₂ O (0.5 equiv) was added to the same molar amount of aryl methyl ketone (4'-hydroxyacetophenone) and aryl methyl aldehyde (4-hydroxybenzaldehyde) in a high amount of dioxane And the mixture was stirred at 20 ° C for 2 hours. The reaction mixture was extracted with ethyl acetate, and washed with water and brine. Further purification by column chromatography gave pure solid compounds.

< Example  2>

1- (2- Hydroxyphenyl ) -3-phenylpropenone (1- (2- Hydroxyphenyl ) -3- 메틸 프로렌one , 10)

Hydroxyacetophenone (2.40 mL, 20.00 mmol) and benzaldehyde (2.02 mL, 20.00 mmol) were used in accordance with Method A of Example 1 to give 1- (2-Hydroxy- 3-phenylpropenone (2.72 g, 60.7%, 12.1 mmol).

mp 97.197.8 [deg.] C .;

R _f (ethylacetate / n- hexane 1: 2 v / v): 0.46

HPLC purity: 100%

^{1 H- NMR (250 MHz, CDCl} 3) δ 12.84 (s, 1H, 1-phenyl 2'-OH), 7.96 (d, J = 15.5Hz, 1H, CO-C = C H), 7.95 (dd, J = 8.1, 1.6Hz, 1H, 1-phenyl 6'-H), 7.70 (d, J = 15.5Hz, 1H, CO-C H = C), 7.70-7.66 (m, 2H, 3-phenyl H- 3, H-3, H-4, H-6), 7.51 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H, H-5), 7.05 (dd, J = 8.4, 0.9 Hz, 1H, 1-phenyl 3'-H), 6.99 (ddd, J = 8.1, 7.2, 1.2 Hz 1H,

^{13 C- NMR (62.5 MHz, CDCl} 3) δ 193.72, 163.57, 145.48, 136.43, 134.54, 130.94, 129.64, 129.04, 128.66, 120.04, 119.97, 188.86, 118.63.

< Example  3>

1- (3- Hydroxyphenyl ) -3- Phenylpropenone  (1- (3- Hydroxyphenyl ) -3- 메틸 프로렌one , 11)

(3-hydroxyacetophenone, 4.08 g, 30.00 mmol) and benzaldehyde (3.03 mL, 30.00 mmol) were used in accordance with the method A of Example 1 to obtain 1- -Hydroxyphenyl) -3-phenylpropenone (5.90 g, 87.7%, 26.3 mmol).

mp 120.2120.6 DEG C .;

R _f (ethylacetate / n- hexane 1: 2 v / v): 0.35

HPLC purity: 100%

¹ H-NMR (250 MHz, CDCl ₃ ) ? 7.86 (d, J = 15.7 Hz, 1H, CO-C = C H ), 7.66-7.62 1-phenyl H-2), 7.60 (d, J = 7.8 Hz, 1H, 1-phenyl H-6), 7.55 (d, J = 15.7 Hz, 1H, CO-C H = C), 7.44-7.41 (dd, J = 8.0, 2.4 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1H, 1-phenyl H-4), 6.59 (br, 1H, 1-phenyl 3-OH).

^{13 C- NMR (62.5 MHz, CDCl} 3) δ 190.87, 156.43, 145.52, 139.44, 134.69, 130.73, 129.91, 128.97, 128.56, 121.87, 120.99, 120.50, 115.19.

< Example  4>

1- (4- Hydroxyphenyl ) -3- Phenylpropenone  (1- (4- Hydroxyphenyl ) -3- 메틸 프로렌one , 12)

Hydroxyacetophenone (2.72 g, 20.00 mmol) and benzaldehyde (2.02 mL, 20.00 mmol) were used according to the method A of Example 1 to obtain the title compound as a light yellow solid 3-hydroxyphenyl) -3-phenylpropenone (3.85 g, 86.1%, 17.2 mmol).

mp 180.0180.7 [deg.] C;

R _f (ethylacetate / n- hexane 1: 2 v / v): 0.40

HPLC purity: 100%

^{1 H-NMR (250 MHz,} DMSO- d 6) δ 10.46 (br, 1H, 1-phenyl 4-OH), 8.08 (d, J = 8.5Hz, 2H, 1-phenyl H-2, H-6) , 7.93 (d, J = 15.7Hz , 1H, CO-C = C H), 7.857.84 (m, 2H, 3-phenyl H-2, H-6), 7.70 (d, J = 15.6Hz, 1H , CO-C H = C) , 7.457.42 (m, 3H, 3-phenyl H-3, H-4, H-5), 6.90 (d, J = 8.5Hz, 2H, 1-phenyl H-3 , H-5).

¹³ C-NMR (62.5 MHz, DMSO- d ₆ ) δ 187.32, 162.48, 142.95, 135.10, 131.45, 130.56, 129.27, 129.12, 128.95, 122.29, 115.61.

< Example  5>

3- (2- Hydroxyphenyl )-One- Phenylpropenone  (3- (2- Hydroxyphenyl )-One- 메틸 프로렌one , 13)

(2- (2-hydroxybenzaldehyde, 2.09 mL, 20.00 mL) according to Method A of Example 1, acetophenone (2.33 mL, 20.00 mmol) Hydroxyphenyl) -1-phenylpropenone (3.95 g, 88.2%, 17.6 mmol).

mp 149.9150.6 [deg.] C .;

R _f (ethylacetate / n- hexane 1: 2 v / v): 0.37

HPLC purity: 98%

¹ H-NMR (250 MHz, DMSO- d ₆ ) ? 10.31 (br, IH, 3-phenyl 2 -OH), 8.108.06 d, J = 15.8Hz, 1H, CO-C = C H), 7.87 (d, J = 15.8Hz, 1H, CO-C H = C), 7.85 (dd, J = 7.3, 1.4Hz, 1H, 3 phenyl H-6), 7.687.52 (m, 3H, 1-phenyl H-3, H-4, H-5), 7.26 (dt, J = 8.2, 1.5 Hz, ), 6.94 (dd, J = 8.2, 0.8 Hz, 1H, 3-phenyl H-3), 6.89 (t, J = 7.2 Hz, 1H, 3-phenyl H-5).

^{13 C- NMR (62.5 MHz, DMSO-} d 6) δ 189.75, 157.51, 139.80, 138.13, 133.19, 132.37, 129.05, 128.96, 128.60, 121.57, 121.12, 119.68, 116.46.

< Example  6>

3- (3- Hydroxyphenyl )-One- Phenylpropenone  (3- (3- Hydroxyphenyl )-One- 메틸 프로렌one , 14)

Using acetophenone (1.16 mL, 10.00 mmol) and 3-hydroxybenzaldehyde (1.22 g, 10.00 mmol) according to Method A of Example 1 above, a light yellow solid 3- (3-hydroxyphenyl) -1-phenylpropenone (2.11 g, 94.1%, 9.4 mmol) was obtained.

mp 170.1170.9 [deg.] C;

R _f (ethylacetate / n- hexane 1: 2 v / v): 0.35

HPLC purity: 98%

¹ H-NMR (250 MHz, DMSO- d ₆ ) ? 9.67 (br, IH, 3-phenyl 3 -OH), 8.15-8.11 d, J = 15.6Hz, 1H, CO-C = C H), 7.697.53 (m, 3H, 1-phenyl H-3, H-4, H-5), 7.67 (d, J = 15.6Hz, 1H, CO-C H = C ), 7.337.24 (m, 2H, 3-phenyl H-5, H-6), 7.22 (br, 1H, 3-phenyl H-2), 6.87 (ddd, J = 7.7, 2.1, 1.0 Hz, 1H, 3-phenyl H-4).

^{13 C NMR (62.5 MHz, DMSO-} d 6) δ 189.45, 158.00, 144.53, 137.79, 136.13, 133.35, 130.12, 129.02, 128.72, 122.09, 120.07, 118.08, 115.50.

< Example  7>

3- (4- Hydroxyphenyl )-One- Phenylpropenone  (3- (4- Hydroxyphenyl )-One- 메틸 프로렌one , Manufacturing of 15)

3- (4-tert-butoxycarbonylamino) -thiazol-4-ylamine was obtained according to Method A of Example 1 using acetophenone (2.33 mL, 20.00 mmol) and hydroxybenzaldehyde (2.44 g, 20.00 mmol) Hydroxyphenyl) -1-phenylpropenone (3.78 g, 84.5%, 16.9 mmol).

mp 174.2175.0 DEG C .;

R _f (ethylacetate / n- hexane 1: 2, v / v): 0.34

HPLC purity: 95%

¹ H-NMR (250 MHz, DMSO- d ₆ ) ? 10.14 (br, IH, 3-phenyl 4-OH), 8.128.08 d, J = 8.6Hz, 2H, 3-phenyl H-2, H-6), 7.70 (d, J = 15.4Hz, 1H, CO-C = C H), 7.697.51 (m, 4H, 1- phenyl H-3, H-4, H-5, CO-C H = C), 6.84 (d, J = 8.6 Hz, 2H, 3-phenyl H-3, H-5).

¹³ C-NMR (62.5 MHz, DMSO- d ₆ ) δ 189.20, 160.41, 144.77, 138.16, 133.06, 131.29, 128.95, 128.56, 125.97, 118.66, 116.05.

< Example  8>

1,3- Bis (2-hydroxyphenyl) propene  (1,3- Bis (2- hydroxyphenyl ) propenone, 16)

Hydroxyacetophenone (1.80 mL, 15.00 mmol) and 2-hydroxybenzaldehyde (1.57 mL, 15.00 mmol) were used according to Method A of Example 1 to obtain a yellow solid 1 , 3-bis (2-hydroxyphenyl) propenone (2.98 g, 82.8%, 12.4 mmol).

mp 173174 [deg.] C;

R _f (ethylacetate / n- hexane 1: 2 v / v): 0.46

HPLC purity: 100%

^{1 H-NMR (250 MHz,} CDCl 3) δ 12.93 (s, 1H, 1-phenyl 2'-OH), 8.24 (d, J = 15.6Hz, 1H, CO-CH = C H), 7.96 (dd, J = 8.1, 1.3Hz, 1H, 1-phenyl H-6), 7.89 (d, J = 15.6Hz, 1H, CO-C H = CH), 7.64 (dd, J = 7.7, 1.3Hz, 1H, 3 phenyl H-6), 7.50 (td, J = 8.8,1.4 Hz, 1H, 1-phenyl H-4), 7.30 (td, J = 8.8, 1.5 Hz, , J = 8.4, 0.8Hz, 1H , 1-phenyl H-3), 7.00 (t, J = 7.3Hz, 1H, 1-phenyl H-5), 6.95 (td, J = 8.1, 1.0Hz, 3- phenyl H-5), 6.87 (d, J = 8.0 Hz, 1H, 3-phenyl H-3), 5.73 (s, 1H, 3-phenyl 2-OH).

¹³ C-NMR (62.5 MHz, CDCl ₃ ) δ 194.47, 163.52, 155.51, 141.00, 136.31, 132.05, 130.14, 129.82, 122.03, 121.26, 121.14, 120.14, 118.85, 118.55, 116.51.

< Example  9>

1- (2- Hydroxyphenyl ) -3- (3- Hydroxyphenyl ) Propenone (1- (2- Hydroxyphenyl ) -3- (3-hydroxyphenyl) propenone, 17)

(3.61 g, 30.00 mmol) and 3-hydroxybenzaldehyde (3.66 g, 30.00 mmol) were used in accordance with the method B of Example 1 to obtain the title compound as a yellow solid - (2-hydroxyphenyl) -3- (3-hydroxyphenyl) propenone (6.49 g, 90.2%, 27.0 mmol).

mp 180181 [deg.] C .;

R _f (ethylacetate / n- hexane 1: 2 v / v): 0.38

HPLC purity: 100%

^{1 H- NMR (250 MHz, DMSO-} d 6) δ 12.44 (s, 1H, 1-phenyl 2'-OH), 9.65 (s, 1H, 3-phenyl 3-OH), 8.23 (dd, J = 8.4 , 1.5Hz, 1H, 1-phenyl H-6), 7.96 (d, J = 15.5Hz, 1H, CO-CH = C H), 7.76 (d, J = 15.5Hz, 1H, CO-C H = CH 2H), 7.55 (td, J = 8.4, 1.3 Hz, 1H, 1-phenyl H-4), 7.34-7.26 phenyl H-2), 7.01-6.95 (m, 2H, 1-phenyl H-3, H-5), 6.90 (dt, J = 7.6,1.1 Hz, 1H, 3-phenyl H-4).

¹³ C NMR (62.5 MHz, DMSO- d ₆ ) δ 193.76, 161.94, 157.96, 145.21, 136.49, 135.93, 131.10, 130.16, 121.92, 121.07, 120.39, 119.41, 118.38, 117.91, 115.69.

< Example  10>

1- (2- Hydroxyphenyl ) -3- (4- Hydroxyphenyl ) Propenone (1- (2- Hydroxyphenyl ) -3- (4-hydroxyphenyl) propenone, 18)

2-hydroxyacetophenone (2.40 mL, 20.00 mmol) and 4-hydroxybenzaldehyde (2.44 g, 20.00 mmol) were used according to Method A of Example 1 to obtain a yellow solid - (2-hydroxyphenyl) -3- (4-hydroxyphenyl) propenone (1.91 g, 39.8%, 7.9 mmol).

mp 163 164 ° C;

R _f (ethylacetate / n- hexane 1: 1 v / v): 0.43

HPLC purity: 95%

^{1 H- NMR (250 MHz, DMSO-} d 6) δ 12.81 (br, 1H, 1-phenyl 2'-OH), 10.27 (br, 1H, 3-phenyl 4-OH), 8.26 (d, J = 7.2 Hz, 1H, 1-phenyl H -6), 7.89 (d, J = 15.7Hz, 1H, CO-CH = C H), 7.83 (d, J = 16.4Hz, 1H, CO-C H = CH), (D, J = 8.6 Hz, 2H, 3-phenyl H-2, H-6), 7.54 (td, J = 8.1, 1.0 Hz, 1H, 2H, 1-phenyl H-3, H-5), 6.86 (d, J = 8.4 Hz, 2H, 3-phenyl H-3, H-5).

¹³ C-NMR (62.5 MHz, DMSO- d ₆ ) ? 193.81, 162.35, 160.89, 145.95, 136.40, 131.82, 130.91, 125.80, 120.75, 119.31, 117.98, 117.86, 116.16.

< Example  11>

1- (2- Hydroxyphenyl ) -1- (3- Hydroxyphenyl ) Propenone (1- (2- Hydroxyphenyl ) -1- (3-hydroxyphenyl) propenone, 19)

(3-hydroxyacetophenone, 4.08 g, 30.00 mmol) and 2-hydroxybenzaldehyde (3.13 mL, 30.00 mmol) were used in accordance with the method B of Example 1 to obtain a green solid - (2-hydroxyphenyl) -1- (3-hydroxyphenyl) propenone (6.35 g, 88.2%, 26.4 mmol).

mp 173174 [deg.] C;

R _f (ethylacetate / n- Hexane 1: 1 v / v): 0.47

HPLC purity: 100%

^{1 H- NMR (250 MHz, DMSO-} d 6) δ 10.00 (br, 2H, 1-phenyl 3'-OH, 3-phenyl 2-OH), 8.02 (d, J = 15.8Hz, 1H, CO-CH = C H), 7.83 (dd , J = 8.1, 1.3Hz, 1H, 3-phenyl H-6), 7.79 (d, J = 15.8Hz, 1H, CO-C H = CH), 7.55 (d, J Phenyl H-6), 7.40 (t, J = 2.2 Hz, 1H, 1-phenyl H-2), 7.35 (t, J = 7.9 Hz, 1H, ), 7.26 (td, J = 8.5, 1.5 Hz, 1H, 3-phenyl H-4), 7.05 (ddd, J = 8.0, 2.4, 0.7 Hz, J = 8.2, 0.8 Hz, 1H, 3-phenyl H-3), 6.85 (t, J = 7.7 Hz, 1H, 3-phenyl H-5).

¹³ C-NMR (62.5 MHz, DMSO- d ₆ ) δ 189.66, 157.91, 157.46, 139.68, 139.58, 132.23, 130.08, 129.10, 121.58, 121.38, 120.26, 119.66, 119.56, 116.44, 114.73.

< Example  12>

1,3- Bis (3-hydroxyphenyl) propene  (1,3- Bis (3- hydroxyphenyl ) &lt; / RTI &gt; propenone, 20)

(3-hydroxyacetophenone, 4.08 g, 30.00 mmol) and 3-hydroxybenzaldehyde (3.66 g, 30.00 mmol) were used in accordance with the method B of Example 1 to obtain the yellow solid , 3-bis (3-hydroxyphenyl) propenone (5.90 g, 82.0%, 24.5 mmol) was obtained.

mp 226227 DEG C .;

R _f (ethylacetate / n- hexane 1: 1 v / v): 0.43

HPLC purity: 100%

^{1 H- NMR (250 MHz, DMSO-} d 6) δ 9.74 (br, 2H, 1-phenyl 3'-OH, 3-phenyl 3-OH), 7.77 (d, J = 15.6Hz, 1H, CO-CH = C H), 7.63 (d , J = 15.4Hz, 1H, CO-C H = CH), 7.62 (d, J = 7.6Hz, 1H, 1-phenyl H-6), 7.43 (s, 1H, 1 phenyl H-2), 7.35 (t, J = 7.9 Hz, 1H, 1-phenyl H-5), 7.30-7.23 (m, 2H, 1H, 3-phenyl H-2), 7.06 (dd, J = 8.0, 2.3 Hz, 1H, 1-phenyl H-4), 6.87 (d, J = 7.4 Hz, 1H,

^{13 C- NMR (62.5 MHz, DMSO-} d 6) δ 189.35, 157.97, 144.34, 139.24, 136.18, 130.15, 122.24, 120.55, 120.09, 119.83, 118.04, 115.46, 114.81.

< Example  13>

1- (3- Hydroxyphenyl ) -3- (4- Hydroxyphenyl ) Propenone (1- (3- Hydroxyphenyl ) -3- (4-hydroxyphenyl) propenone, 21)

Hydroxybenzaldehyde (2.44 g, 20.00 mmol) and 3-hydroxyacetophenone (2.72 g, 20.00 mmol) were used in accordance with the method B of Example 1 to obtain a yellow solid - (3-hydroxyphenyl) -3- (4-hydroxyphenyl) propenone (2.10 g, 43.8%, 8.7 mmol).

mp 245246 DEG C .;

R _f (ethylacetate / n- Hexane 1: 1 v / v): 0.42

HPLC purity: 99%

^{1 H- NMR (250 MHz, DMSO-} d 6) δ 9.94 (br, 2H, 1-phenyl 3'-OH, 3-phenyl 4-OH), 7.73 (d, J = 8.5Hz, 2H, 3-phenyl H-6), 7.63 (d, J = 17.5 Hz, 2H, CO-C H = C H ), 7.59 (d, J = 7.7 Hz, 1H, 1-phenyl H-2), 7.34 (t, J = 7.9 Hz, 1-phenyl H-5), 7.04 (dd, J = 8.0, 2.3 Hz, 6.83 (d, J = 8.4 Hz, 2H, 3-phenyl H-3, H-5).

¹³ C-NMR (62.5 MHz, DMSO- d ₆ ) δ 189.14, 160.36, 157.90, 144.57, 139.63, 131.23, 130.01, 125.99, 120.18, 119.61, 118.82, 116.05, 114.72.

< Example  14>

3- (2- Hydroxyphenyl ) -1- (4- Hydroxyphenyl ) Propenone (3- (2- Hydroxyphenyl ) -1- (4-hydroxyphenyl) propenone, 22)

Hydroxybenzophenone (2.72 g, 20.00 mmol) and 2-hydroxybenzaldehyde (2.09 mL, 20.00 mmol) were used according to the method A of Example 1 to obtain the title compound as a red solid - (2-hydroxyphenyl) -1- (4-hydroxyphenyl) propenone (1.74 g, 36.4%, 7.3 mmol).

mp 197198 ° C;

R _f (ethylacetate / n- hexane 1: 1 v / v): 0.33

HPLC purity: 97%

^{1 H- NMR (250 MHz, DMSO-} d 6) δ 10.32 (br, 2H, 1-phenyl 4'-OH, 3-phenyl 2-OH), 8.02 (d, J = 8.7Hz, 2H, 1-phenyl H-2, H-6) , 8.01 (d, J = 15.9Hz, 1H, CO-CH = C H), 7.84 (d, J = 15.8Hz, 1H, CO-C H = CH), 7.83 (d , J = 8.8Hz, 1H, 3 -phenyl H-6), 7.24 (td, J = 8.4, 1.4Hz, 1H, 3-phenyl H-4), 6.92 (d, J = 7.5Hz, 1H, 3- phenyl H-3), 6.89-6.81 (m, 3H, 3-phenyl H-5, 1-phenyl H-3, H-5).

^{13 C- NMR (62.5 MHz, DMSO-} d 6) δ 187.62, 162.16, 157.20, 138.37, 131.85, 131.14, 129.58, 128.70, 121.79, 121.12, 119.57, 116.36, 115.54.

< Example  15>

3- (3- Hydroxyphenyl ) -1- (4- Hydroxyphenyl ) Propenone (3- (3- Hydroxyphenyl ) -1- (4-hydroxyphenyl) propenone, 23)

Hydroxybenzaldehyde (2.44 g, 20.00 mmol) and 4-hydroxyacetophenone (2.72 g, 20.00 mmol) were used according to Method B of Example 1 to obtain the title compound as a pale yellow solid 3- (3-hydroxyphenyl) -1- (4-hydroxyphenyl) propenone (3.95 g, 82.3%, 16.4 mmol) was obtained.

mp 261262 [deg.] C;

R _f (ethylacetate / n- hexane 1: 1 v / v): 0.47

HPLC purity: 95%

^{1 H- NMR (250 MHz, DMSO-} d 6) δ 10.49 (br, 1H, 1-phenyl 4'-OH) 9.64 (br, 1H, 3-phenyl 3-OH), 8.06 (d, J = 8.7Hz , 2H, 1-phenyl H- 2, H-6), 7.83 (d, J = 15.6Hz, 1H, CO-CH = C H), 7.59 (d, J = 15.5Hz, 1H, CO-C H = 1H, 3-phenyl H-2), 6.89 (d, J = 8.7 Hz, 2H, 1 H), 7.29-7.23 (m, 2H, phenyl H-3, H-5), 6.85-6.82 (m, 1H, 3-phenyl H-4).

¹³ C-NMR (62.5 MHz, DMSO- d ₆ ) δ 187.36, 162.43, 157.94, 143.22, 136.40, 131.43, 130.10, 129.33, 122.13, 119.91, 117.74, 115.62, 115.37.

< Example  16>

1,3- Bis (4-hydroxyphenyl) propene  (1,3- Bis (4- hydroxyphenyl ) propenone , 24)

According to Method C of Example 1, 4-hydroxyacetophenone (2.72 g, 20.00 mmol) and 4-hydroxybenzaldehyde (3.66 g, 30.00 mmol) were used to obtain a yellow solid , And 3-bis (4-hydroxyphenyl) propenone (4.41 g, 74.4%, 18.3 mmol).

mp 226227 DEG C .; R _f (ethylacetate: n- hexane 1: 1 v / v): 0.35

HPLC purity: 99%

^{1 H- NMR (250 MHz, DMSO-} d 6) δ 10.21 (br, 2H, 1-phenyl 4'-OH, 3-phenyl 4-OH), 8.04 (d, J = 8.7Hz, 2H, 1-phenyl H-2, H-6) , 7.71 (d, J = 8.6Hz, 2H, 3-phenyl H-2, H-6), 7.68 (d, J = 14.3Hz, 1H, CO-CH = C H) , 7.62 (d, J = 15.5Hz , 1H, CO-C H = CH), 6.88 (d, J = 8.7Hz, 2H, 1-phenyl H-3, H-5), 6.83 (d, J = 8.5 Hz, 2H, 3-phenyl H-3, H-5).

¹³ C-NMR (62.5 MHz, DMSO- d ₆ ) δ 187.25, 162.13, 160.04, 143.39, 131.16, 130.96, 129.64, 126.20, 118.73, 115.99, 115.51.

< Reference Example  2> Materials and reagents, instrument analysis

Cortisone acetate was purchased from Aldrich Chemical Co. (St. Louis, Mo., USA), and vascular endothelial growth factor (VEGF) was purchased from Cheju, Korea vascular endothelial growth factor was purchased from R & D systems (Minneapolis, Minn., USA), and whatman filter disc was purchased from Whatman, UK.

< Experimental Example  1> CAM  Analysis of the inhibitory effect of compounds on angiogenesis

Vivo test phase (in (Nguyen M et al., Microvascular (CAM)) analysis was performed to confirm the antiangiogenic effect in vivo Res . , 47, pp31-40, 1994).

On the 10th day, the first small hole was drilled through a hypodermic needle (Green Cross Medical Industry, Korea) at the air sac region, and the chicken pellet was incubated at 37 ° C and 55% A second hole was drilled in the flat part of the porridge that would open the window.

(CAM) was separated from the husk of the periantha by cutting air through the hole in the air sac, the first hole, and the region was cut with a grinding wheel (Multipro 395JA, Dremel, Mexico) cm ² I made a window of size.

Next, vascular endothelial growth factor (VEGF) was treated with cortisone acetate (3 mg / ml) in a Whatman filter disk # 1 (whatman, USA) , Or interleukin-8 (IL-8) at a concentration of 10 ng / CAM.

Individual disks were suspended in 10 μl of PBS containing VEGF or a control solvent and the disks were placed on growing CAMs. The filter discs were placed on the blood vessels through the window made and the compounds of Example 1 of the present invention were added locally to the CAMs after 30 minutes and the drug-treated CAMs were incubated for 3 days.

Three days after the drug treatment, the CAM part on which the filter disk was placed was removed and washed with a phosphate buffer solution. Then, a stereomicroscope (Stemi SV6 stereomicroscope, Carl Zeiss, Germany) and Image-Pro Plus software (Media Cybernetics, MD, USA) were used to measure the number of vascular branches and analyze the data.

As a result of this experiment, it was confirmed that the compounds according to the present invention strongly inhibited VEGF-induced angiogenesis in vivo (see Table 1), and blood vessel branch points were observed in the PBS-treated group And VEGF, respectively. Treatment of the compounds of the present invention against CAM significantly inhibited VEGF-induced angiogenesis in number and small blood vessel length after incubation (see Figures 1a, 1b, and 2a, 2b). In particular, compound 15 exhibited the most potent anti-angiogenic activity in vivo (66%) at 1 / CAM.

Compound 19 also exhibited the strongest inhibitory activity (89%) among the compounds, and compounds 21 and 22 similarly showed strong inhibitory activity (80% and 87%, respectively)

< Experimental Example  2> An inhibitory activity of angiogenesis inhibitory activity and tumor growth inhibition of the compound of the present invention

The present inventors confirmed that 15 compounds of the present invention have a high inhibitory effect on angiogenesis in vivo through Experimental Example 1, and further conducted the following experiment to confirm whether these compounds actually have anticancer activity.

First, a window was made on the ninth day after incubation of chicken fermented eggs, and HT-29 human colorectal cancer cells were mixed with matrigel in a ratio of 1: 1 instead of discs. Then, , Hydroxysticon compound NO. 19, 21 and 22 were treated with colon cancer cells, respectively, wherein the cells were inoculated at a density of 1.5 × 10 ⁶ cells / CAM. After 5 days of inoculation, the tumor-forming CAM was removed and rinsed with phosphate buffer solution. Then, a stereomicroscope (Stemi SV6 stereomicroscope, Carl Zeiss, Germany) and Image-Pro Plus software (Media Cybernetics; ) Was used to measure the number of vascular branches, and the tumor was separated and weighed to analyze the effect of the compound according to the present invention on the growth of new blood vessels and cancer.

As a result, it was shown that the treatment of the compounds of the present invention, NO.19, 21 and 22, inhibited the angiogenesis which plays a role in tumor formation, and the growth of the tumor was also inhibited.

These results also showed that the tumor suppressing effect was superior to that of the group treated with SU 4312, which is an inhibitor of the VEGF receptor used as a positive control, and the chalcone (DPhP) compound at the same concentration (see FIG. 3) .

Therefore, the inventors of the present invention have found that the above 15 compounds according to the present invention can effectively inhibit tumor-induced angiogenesis and inhibit tumor growth as well, and thus can be used as a novel anticancer agent Could know.

Hereinafter, formulation examples of the composition containing the compound of the present invention will be described, but the present invention is not intended to be limited thereto but is specifically described.

Formulation example  One. Sanje  Produce

Compound 19 ............................................. 200 mg

Lactose ................................................. 100 mg

Talc ................................................. .. 10 mg

The above components are mixed and filled in airtight bags to prepare powders.

Formulation example  2. Preparation of tablets

Compound 21 ............................................ 200 mg

Corn starch ........................................... 100 mg

Lactose ................................................. 100 mg

Magnesium stearate .................................... 2 mg

After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

Formulation example  3. Preparation of capsules

Compound 22 ............................................ 200 mg

Crystalline cellulose ...................................... 3 mg

Lactose ............................................ 14.8 mg

Magnesium stearate ................................ 0.2 mg

The above components are mixed in accordance with a conventional method for producing a capsule, and filled in a gelatin capsule to prepare a capsule.

Formulation example  4. Preparation of injections

Compound 15 ............................................ 200 mg

Mannitol ............................................... 180 mg

Sterile sterilized distilled water for injection ................................. 2974 mg

Na ₂ HPO _{4 ,} 12H ₂ O .......................................... .26 mg

(2 ml) per ampoule in accordance with the usual injection method.

Formulation example  5. Liquid  Produce

Compound 19 ............................................ 200 mg

Isolation Party ............................................... 10 g

Mannitol ................................................. .5 g

Purified water................................................. Suitable amount

Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water to adjust the total volume to 100 ml, And sterilized to prepare a liquid preparation.

Formulation example  6. Manufacture of health food

Compound 21 ............................................ 1000 mg

Vitamin mixture ............................................

Vitamin A Acetate .................................... 70 ㎍

Vitamin E .............................................. 1.0 mg

Vitamin B1 ............................................ 0.13 mg

Vitamin B2 ............................................ 0.15 mg

Vitamin B6 .............................................. 0.5 mg

Vitamin B12 ............................................ 0.2 ㎍

Vitamin C ............................................... 10 Mg

Biotin ................................................. 10 [mu] g

Nicotinic acid amide ....................................... 1.7 mg

Folic acid ................................................. ..50 [mu] g

Calcium pantothenate .......................................... 0.5 mg

Mineral mixture ............................................

Ferrous sulfate ............................................ 1.75 mg

Zinc oxide .............................................. 0.82 mg

Magnesium carbonate ......................................... 25.3 mg

Potassium Phosphate ............................................... 15 mg

Secondary Calcium Phosphate ............................................ 55 mg

Potassium citrate ............................................. 90 mg

Calcium carbonate .............................................. 100 mg

Magnesium chloride ............................................. 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

Formulation example  7. Manufacture of health drinks

Compound 22 ............................................ 1000 mg

Citric acid ............................................... 1000 mg

Oligosaccharides ............................................... 100 g

Plum concentrate ............................................... g

Taurine ................................................. ..1 g

Add purified water .................................. Total 900 ml

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour with stirring, and the solution thus prepared was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, &Lt; / RTI &gt;

Although the composition ratio is a mixture of the components suitable for the preferred beverage as a preferred embodiment, the blending ratio may be arbitrarily varied according to the regional and national preferences such as the demand level, the demanding country, and the intended use.

So far I looked at the center of the preferred embodiment for the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (7)

1- (2-hydroxyphenyl) -3-phenylpropenone, 1- (3-hydroxyphenyl) -3-phenylpropenone, 1- (4-hydroxyphenyl) -3-phenylpropenone, 3- (2-hydroxyphenyl) -1-phenylpropenone, 3- (3-hydroxyphenyl) -1-phenylpropenone, 3- (4-hydroxyphenyl) -1-phenylpropenone, 1, 3-bis (2-hydroxyphenyll) propenone, 1- (2-hydroxyphenyl) -3- (3-hydroxyphenyl) propenone, 1- (2-hydroxyphenyl) -3- (4 -Hydroxyphenyl) propenone, 1- (2-hydroxyphenyl) -1- (3-hydroxyphenyl) propenone, 1,3-bis (3-hydroxyphenyll) propenone, 1- (3 -Hydroxyphenyl) -3- (4-hydroxyphenyl) propenone, 3- (2-hydroxyphenyl) -1- (4-hydroxyphenyl) propenone, 3- (3-hydroxyphenyl)- For the prevention or treatment of cancer comprising a compound selected from 1- (4-hydroxyphenyl) propenone or 1,3-bis (4-hydroxyphenyll) propenone or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical compositions. The method of claim 1,
The compound is a pharmaceutical composition for the prevention or treatment of cancer, characterized in that it is contained in a concentration of 0.1uM to 20uM. The method of claim 1,
The cancer is liver cancer, stomach cancer, colon cancer, lung cancer, breast cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer and myopia ophthalmic tumors, characterized in that the pharmaceutical composition for the prevention or treatment of cancer. The method of claim 3,
The compound is a pharmaceutical composition for preventing or treating cancer, characterized in that it has an activity of inhibiting angiogenesis and inhibiting tumor growth. 1- (2-hydroxyphenyl) -3-phenylpropenone, 1- (3-hydroxyphenyl) -3-phenylpropenone, 1- (4-hydroxyphenyl) -3-phenylpropenone, 3- (2-hydroxyphenyl) -1-phenylpropenone, 3- (3-hydroxyphenyl) -1-phenylpropenone, 3- (4-hydroxyphenyl) -1-phenylpropenone, 1, 3-bis (2-hydroxyphenyll) propenone, 1- (2-hydroxyphenyl) -3- (3-hydroxyphenyl) propenone, 1- (2-hydroxyphenyl) -3- (4 -Hydroxyphenyl) propenone, 1- (2-hydroxyphenyl) -1- (3-hydroxyphenyl) propenone, 1,3-bis (3-hydroxyphenyll) propenone, 1- (3 -Hydroxyphenyl) -3- (4-hydroxyphenyl) propenone, 3- (2-hydroxyphenyl) -1- (4-hydroxyphenyl) propenone, 3- (3-hydroxyphenyl)- A health functional food for preventing or improving cancer, comprising a compound selected from 1- (4-hydroxyphenyl) propenone or 1,3-bis (4-hydroxyphenyll) propenone as an active ingredient. The method of claim 5,
The cancer is liver cancer, stomach cancer, colorectal cancer, lung cancer, breast cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer and myopia ophthalmic tumors, characterized in that the health functional food for preventing or improving cancer. The method of claim 5,
The food is a health functional food for the prevention or improvement of cancer, characterized in that the powder, granules, tablets, capsules or beverage form.

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