KR101966124B1 - Composition comprising extract of Ecklonia cava or phlorotannin compounds isolated from thereof for preventing or treating influenza - Google Patents
Composition comprising extract of Ecklonia cava or phlorotannin compounds isolated from thereof for preventing or treating influenza Download PDFInfo
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- KR101966124B1 KR101966124B1 KR1020160149377A KR20160149377A KR101966124B1 KR 101966124 B1 KR101966124 B1 KR 101966124B1 KR 1020160149377 A KR1020160149377 A KR 1020160149377A KR 20160149377 A KR20160149377 A KR 20160149377A KR 101966124 B1 KR101966124 B1 KR 101966124B1
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- extract
- dibenzo
- influenza
- tetraol
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Abstract
The present invention relates to a composition for preventing or treating influenza comprising Ecklonia cava extract or a fluorotannine compound isolated therefrom as an active ingredient.
Or a phlorotannin compound derived therefrom, such as dibenzo [1,4] dioxine-2,4,7,9-tetraol, tetraol (Compound 1), Dioxinodehydroeckol (Compound 2), and 6,6'-bieckol (Compound 3) were tested for avian influenza virus or swine influenza virus Antiviral activity, and is expected to be useful for the development of compositions for the prevention and treatment of influenza.
Description
The present invention relates to a composition for preventing or treating influenza comprising Ecklonia cava extract or a fluorotannine compound isolated therefrom as an active ingredient, and more particularly to a composition for preventing or treating avian influenza (avian influenza) or swine influenza swine influenza. < / RTI >
Influenza, commonly known as the flu, is an acute respiratory disease caused by influenza virus. Influenza occurs all over the world, including Korea. In regions with seasonal variations, it is prevalent in winter every year. Influenza is highly contagious. It affects the elderly, children and people with other illnesses, leading to increased mortality and increased incidence of complications. It is not limited to some areas, but is caused by a new strain of influenza virus Can be a global problem. Prevention and treatment of influenza is one of the important social issues.
Influenza viruses belong to orthomyxoviridae and are classified as A, B and C as RNA viruses belonging to the orthomyxoviridae family. In particular, the virus A is a virus that has been confirmed to be infected mainly in humans and is confirmed to be infected in pigs, other mammals and various wild birds compared to the B or C viruses. Recently, avian influenza virus influenza virus, swine influenza virus and influenza A virus subtype H1N1.
There are two proteins on the surface of influenza virus, hemagglutinin (HA, H) and neuraminidase (NA, N). By the combination of hemagglutinin and neuraminidase Influenza virus subtypes are determined (Schnitzler SU, et al., 2009; Wright PF, et al., 2007). Namely, there are 16 species of hemagglutinin, and there are nine species of neuraminidase, and a total of 144 types of influenza virus can be generated. In case of avian influenza virus infection, H5 type, H7 type and H9 type are mainly involved, and in humans, only H1 type, H2 type and H3 type and two types of neuraminidase (N1 and N2) are related In theory, humans should not be infected with the avian influenza virus. Recently, however, there has been an instance in which avian influenza virus has been directly transmitted to humans without undergoing genetic recombination.
Avian influenza (AI) spreads quickly through wild birds and migratory birds, as well as by contact with poultry such as chickens, ducks and turkeys. In recent years, avian influenza has occurred periodically and has been characterized for a longer period of time. Since the influenza A (H5N8) virus was confirmed as a highly pathogenic avian influenza virus in Korea, on Jan. 16, 2014, the avian influenza virus in Korea has been confirmed as a H5N8 virus, and the number of poultry such as chickens and ducks has exceeded 12 million. And it is estimated that the opportunity loss cost including direct and indirect loss such as the disposal compensation cost and the purchase amount of income amount to more than 1 trillion won. The avian influenza, which had been lulled for a while in the summer of 2014, has been on the increase in frequency and intensity since its first occurrence in Yeongam, Jeonnam on September 24, 2014, In February 2015, H5N8, a highly pathogenic avian influenza virus, was detected in the feces of wild birds collected in rivers in metropolitan areas. Since avian influenza virus antibodies were also detected in the virus-infected dogs, Treatment is an important national issue.
In addition, the bird flu virus caused by the new H7N9 avian influenza virus in China in 2013 is deadly to humans, resulting in 24 out of 118 patients infected with the H7N9 virus until April 28, 2013, resulting in a mortality rate of more than 20% Which was a powerful disease. Concerns about infections continue to rise in 2015 so that Canadian women who have been to China have been reported to have been infected with the H7N9 avian influenza virus. Commonly observed in these avian influenza viruses is the mutation of the gene that causes the amino acid mutation of the virus, showing the possibility that it can be mutated into a possibility of transmission between man and man.
Swine influenza was reported for the first time in 1918, and pigs were found to contain human influenza virus (N-acetylneuraminic acid α2,6 galactose) and influenza viral receptors (N-acetylneuraminic acid α2,3 galactose and are known to act as mixing vessels that can be infected to humans through reassortment or adaptation in the body of the avian influenza virus. The novel influenza virus, the first of its kind in Mexico in 2009, has been infected with swine influenza virus H1N1 and transformed into a virus that can be transmitted to humans (Dawood FS, et al., 2009; Zimmer SM, et al., 2009).
In order to prevent the influenza virus infection, it is necessary to secure a vaccine. However, as a preventive measure against the national vaccine, it is almost impossible to make a vaccine that can prevent all RNA viruses that cause antigen mutation every time. Therefore, in order to prepare for the diseases caused by new pathogens caused by avian influenza, swine influenza and swine influenza, or mutations and mixtures thereof, it is essential to develop a therapeutic agent capable of preventing and treating these diseases.
Currently, tamiflu (oseltamivir phosphate), an oral therapeutic agent developed as a selective inhibitor against virus-derived neuraminidase, and relenza (ingredient name: : zanamivir). In the case of Tamiflu, side effects such as nausea, vomiting, nervous system or psychiatric disorder were reported. In Japan, about 15 cases of pediatric patients were confirmed after Tamiflu was approved. In addition, Tamiflu, an oral therapeutic agent, has a problem that it is difficult to respond promptly to the emergence of resistant viruses, and recently, the emergence of resistant viruses against Tamiflu has been reported (Lee, JH, 2009; Hauge SH, et al., 2009 ) It is necessary to develop a new treatment for influenza.
Recently, studies on the development and application of functional materials in the field of pharmaceuticals, food, and cosmetics have become vigorous. In particular, there have been many reports of biologically active components of marine plant extracts, such as natural on-land plant extracts or biologically compatible and stable marine plant extracts (Moore RE, 1978; Koyanagi S., et al. 2003).
Ecklonia cava is a type of brown algae belonging to the kelp middlestock and is distributed on the temperate coasts of the peninsula and Japan. It is widely used in food additives, livestock feed, fertilizer, and pharmaceuticals (Heo SJ, et al., 2005; Yoo CY, et al., 2015). It has been known that there are components such as carotenoid, fucoidan and phlorotannin in the gut (Yoo CY, et al., 2015). Recently, many studies have shown that the gentian extract has antioxidant, anti-inflammatory , Anti-allergic activity, tryrosinase inhibitory activity and inhibition of collagenase expression (Kim et al., 2009; Heo SJ, et al., 2009; Le QT , et al., 2009; Joe MJ, et al., 2006).
Accordingly, the inventors of the present invention found that the phytotoxic extract or the fluorotannine-based compounds isolated therefrom had excellent antiviral activity against influenza virus in the process of studying antiviral agents against natural products, I could finish it.
As a prior art, Japanese Patent Registration No. 4105535 discloses an antiviral agent comprising florotannin derived from seaweed as a main component. However, since the influenza virus is not described, the structure differs from that of the present invention. Korean Patent No. 1542882 discloses a pharmacological composition comprising a Ganoderma lucidum extract, a fraction thereof, and a flurothanine compound, but is different from the composition of the present invention in that the therapeutic effect of viral hemorrhagic sepsis is described. Korean Patent Publication No. 2011-0086473 discloses a composition for preventing or treating a coronavirus infection comprising a Ganoderma lucidum extract or a fraction thereof as an active ingredient, but the fluro tannin compound and the influenza virus of the present invention are not described, There is a difference in configuration.
It is an object of the present invention to provide a composition for preventing or treating influenza comprising Ecklonia cava extract or a fluorotannine compound isolated therefrom as an active ingredient.
The present invention relates to dibenzo [1,4] dioxine-2,4,7,9-tetraol (compound 1) having the following formula (1) , deoxy Ecole with no formaldehyde (Dioxinodehydroeckol) (compound 2) and 6,6' non Ecole (6,6'-bieckol) Ecklonia cava, including at least one compound selected from the group consisting of (compound 3) (Eckonia The present invention relates to a pharmaceutical composition for preventing or treating avian influenza or swine influenza.
[Chemical Formula 1]
The chewing gum extract may be an extract obtained by extracting the chewing gum with at least one solvent selected from the group consisting of water, C1 to C4 lower alcohols, acetone, ethyl acetate and hexane.
The present invention also provides a dibenzo [l, 4] dioxine-2,4,7,9-tetraol of formula (I) at least one compound selected from the group consisting of tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3) As an active ingredient, to a pharmaceutical composition for preventing or treating avian influenza or swine influenza.
[Chemical Formula 1]
The present invention also relates to a dibenzo [1,4] dioxine-2,4,7,9-tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3). The present invention relates to a health functional food for improving avian influenza or swine influenza, which contains Eckonia cava extract as an active ingredient.
[Chemical Formula 1]
The chewing gum extract may be an extract obtained by extracting the chewing gum with at least one solvent selected from the group consisting of water, C1 to C4 lower alcohols, acetone, ethyl acetate and hexane.
The present invention also provides a dibenzo [l, 4] dioxine-2,4,7,9-tetraol of formula (I) at least one compound selected from the group consisting of tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3) As an active ingredient, a health functional food for alleviating avian influenza or swine influenza.
[Chemical Formula 1]
The present invention also relates to a dibenzo [1,4] dioxine-2,4,7,9-tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3). And an animal drug for preventing or treating avian influenza or swine influenza comprising Eckonia cava extract as an active ingredient.
[Chemical Formula 1]
The chewing gum extract may be an extract obtained by extracting the chewing gum with at least one solvent selected from the group consisting of water, C1 to C4 lower alcohols, acetone, ethyl acetate and hexane.
The present invention also provides a dibenzo [l, 4] dioxine-2,4,7,9-tetraol of formula (I) at least one compound selected from the group consisting of tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3) As an active ingredient, an animal drug for the prevention or treatment of avian influenza or swine influenza.
[Chemical Formula 1]
The present invention also relates to a dibenzo [1,4] dioxine-2,4,7,9-tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3). And an animal feed additive for improving avian influenza or swine influenza containing Eckonia cava extract as an active ingredient.
[Chemical Formula 1]
The chewing gum extract may be an extract obtained by extracting the chewing gum with at least one solvent selected from the group consisting of water, C1 to C4 lower alcohols, acetone, ethyl acetate and hexane.
The present invention also provides a dibenzo [l, 4] dioxine-2,4,7,9-tetraol of formula (I) at least one compound selected from the group consisting of tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3) To an animal feed additive for improving avian influenza or swine influenza.
[Chemical Formula 1]
The present invention also relates to a dibenzo [1,4] dioxine-2,4,7,9-tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3). The present invention relates to a natural disinfectant for preventing avian influenza or swine influenza, which contains Eckonia cava extract as an active ingredient.
[Chemical Formula 1]
The chewing gum extract may be an extract obtained by extracting the chewing gum with at least one solvent selected from the group consisting of water, C1 to C4 lower alcohols, acetone, ethyl acetate and hexane.
The present invention also provides a dibenzo [l, 4] dioxine-2,4,7,9-tetraol of formula (I) at least one compound selected from the group consisting of tetraol (compound 1), dioxinodehydroeckol (compound 2), and 6,6'-bieckol (compound 3) As an active ingredient, to a natural disinfectant for the prevention of avian influenza or swine influenza.
[Chemical Formula 1]
Hereinafter, the present invention will be described in detail.
The chewing gum extract may be an extract derived from at least one solvent selected from the group consisting of water, C1 to C4 lower alcohols, acetone, ethyl acetate and hexane. The C1 to C4 lower alcohols may be methanol, ethanol, Propanol, isofuran, butanol, and the like. Preferably ethanol, butanol and acetone. Most preferably ethanol and butanol.
The solvent may add from 5 to 500 times the weight of the menthol.
In addition, the chewing gum extract is obtained by concentrating an extract obtained by extracting a cheongcheo with at least one solvent selected from the group consisting of water, C1 to C4 lower alcohols, acetone, ethyl acetate and hexane, and diluting the diluted concentrate with an ion exchange resin Or may be a fraction obtained by fractionation by elution with an organic solvent by adding thereto column chromatography.
The diluted solution may be prepared by adding water to the concentrate of Ganoderma lucidum extract, and the weight of the concentrate may be 10 to 50 times the weight of the concentrate.
The ion exchange resin may be selected from Diaion HP-20 (Diaion HP-20), SP825, AXT204, XAD1600T, MN200, SP70, SP710 and the like. Preferably Diaion HP-20, SP825, AXT204, XAD1600T and MN2000, and most preferably Diaion HP-20.
The organic solvent may be C1 to C4 lower alcohol and acetone. The C1 to C4 lower alcohols may be methanol, ethanol, propanol, isofuran, butanol, and the like. Preferably ethanol and acetone, and most preferably 70% ethanol.
Dibenzo [l, 4] dioxine-2,4,7,9-tetraol of Formula 1 (Compound 1 ), Dioxinodehydroeckol (compound 2) and 6,6'-bieckol (compound 3) compounds can be obtained by fractionating the gut extract by chromatography, Chromatography was performed using Diaion HP-20 column chromatography, silica gel column chromatography, RP-18 column chromatography, LH-20 column chromatography LH-20 column chromatography, preparative reversed-phase high performance chromatography, medium pressure liquid chromatography, and high-performance liquid chromatography You can choose to use it.
Meanwhile, the compound of the present invention can be synthesized according to a conventional method in the art, and can also be prepared as a pharmaceutically acceptable salt.
The phytotoxic extract or the phlorotanin compound isolated therefrom may be administered orally or parenterally in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups or aerosols, external preparations, Suppositories, and sterile injectable solutions. Examples of carriers, excipients and diluents that can be contained in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, 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. The solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like. These solid preparations can be prepared by adding to the phytotoxic extract of the present invention or the phlorotannin-based compound separated therefrom at least one excipient, Starch, calcium carbonate, sucrose or lactose, and gelatin. 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 paper, laurin, glycerogelatin and the like.
The dosage of the pharmaceutical composition will depend on the age, sex, body weight of the subject to be treated, the particular disease or condition to be treated, the severity of the disease or condition, the route of administration and the judgment of the prescriber. Dosage determinations based on these factors are within the level of ordinary skill in the art and generally the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferable dosage is 0.1 mg / kg / day to 500 mg / kg / day. The administration may be carried out once a day or several times. The dose is not intended to limit the scope of the invention in any way.
The pharmaceutical composition may be administered to mammals such as rats, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine mucosal or intracerebral injection. The phytotoxic extract of the present invention or the fluorotannine-based compound isolated therefrom has little toxicity and side effects, and therefore can be safely used for long-term use for preventive purposes.
The present invention also provides a health functional food comprising a phytotoxic extract or a pharmacologically acceptable food supplement containing a phlorotannin compound separated therefrom. The health functional food of the present invention includes forms such as tablets, capsules, pills, and liquids, and the phytotoxic extract of the present invention or the food to which the phlorotannin compound isolated therefrom can be added includes, for example, Various foods, beverages, gums, tea, vitamin complex, and health functional foods. Specifically, the present invention provides a health functional food for influenza improvement comprising a phytotoxic extract or a pharmacologically acceptable food-aid additive containing a fluorotannine compound separated therefrom.
The animal feed additive may be used as an additive for animal feed, and the menthol extract of the present invention or a fluorotannine compound isolated therefrom may be added to the animal feed in an amount of 0.001 to 30 wt%, preferably 0.001 wt% By weight to 10% by weight, and most preferably 0.001% by weight to 5% by weight.
The natural disinfectant is a composition for disinfection of influenza virus and can be prepared into various forms such as a liquid, a tablet, a granule, and a powder.
The present invention relates to a composition for the prevention or treatment of influenza comprising Ecklonia cava extract or a fluorotannine compound isolated therefrom as an active ingredient. The present invention relates to a composition for preventing or treating influenza, comprising a gangrene extract or a phlorotannin compound Benzo [1,4] dioxine-2,4,7,9-tetraol (Compound 1), dioxinodihydroco ( Dioxinodehydroeckol (Compound 2) and 6,6'-bieckol (Compound 3) were found to have antiviral activity against avian influenza virus or swine influenza virus.
Thus, the phytotoxic extract of the present invention or the dibenzo [1,4] dioxine-2,4,7,9-tetraol separated therefrom, tetraol (Compound 1), Dioxinodehydroeckol (Compound 2), and 6,6'-bieckol (Compound 3) compounds for the prevention or treatment of influenza, It is expected to be useful for the development of health functional food, animal feed additive or natural disinfectant.
Fig. 1 shows the antiviral activity depending on the kind of Ganoderma lucidum extract, and swine influenza virus (H1N1) was used.
Fig. 2 shows the results of confirming the cytotoxicity of the phlorotannin compounds (Compounds 1 to 3) isolated from the chewing gum extract.
Figure 3 shows the results of confirming antiviral activity against (A) avian influenza virus (H9N2) and (B) swine influenza virus (H1N1) of the fluorotannine compounds (compounds 1 to 3) of the present invention .
Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the intention is to provide an exhaustive, complete, and complete disclosure of the principles of the invention to those skilled in the art.
≪ Example 1: Preparation of gut extract and measurement of antiviral activity >
Example 1-1. Moth Preparation of extract
Gam-tae has been sold at the Koseo-bukhangbang Resources Bank of Chosun University in Gwangju Metropolitan City.
300 ml of each of the solvents listed in Table 1 below was added to 30 g of Tetrahedron, and ultrasonic extraction was performed for 3 hours to remove the solid content to obtain an extract. The obtained extract was concentrated under reduced pressure to prepare an extract, and the extraction amount was confirmed. The results are shown in Table 1.
Example 1-2. Moth Identification of the antiviral activity of the extract
(A / chicken / Korea / 01310/2001) and swine influenza virus H1N1 (A / Sw / Kor) obtained from the Central Vaccine Institute to confirm the antiviral activity of the menthol extract extracted in Example 1-1. / CAN1 / 04, KCTC11165BP), and the antiviral activity was confirmed by analyzing the cell viability by the virus infection.
1 × 10 4 Maddin-Darby canine kidney (MDCK) cells were seeded into 96-well plates in a 96-well plate, and then cultured in 5% FBS (fetal bovine serum), 1% penicillin / streptomycin And Dulbecco's Modified Eagle's Medium (DMEM) containing 0.4% L-glutamine. The culture medium was discarded, and the culture medium was discarded and washed with PBS (phosphate buffer saline). Then, the cells were infected with infection medium (DMEM + 0.5% BSA (bovine serum albumin) + 1 μg / ml trypsin), and swine influenza virus or avian influenza virus was inoculated at a concentration of 50
MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) assay was performed using cells cultured for 5 days. MTT solution was added to the cultured cells, and the cells were reacted at 37 ° C. Then, the culture solution was removed and 200 μl of DMSO (dimethyl sulfoxide) was added. After mixing well with pipetting, the cells were allowed to stand for 10 minutes, and the absorbance at 550 nm was measured to confirm cell viability. At this time, the cell survival rate by the extract of each solvent was calculated based on the cell survival rate of 100% of the normal control group, and the results are shown in FIG. 1 and Table 2. In Table 2, the cell survival rate by the extract was used as the same concept as the antiviral activity because the cell death by the influenza virus was inhibited by the antiviral activity of the extract according to each solvent.
Antiviral activity (%)
As shown in Fig. 1 and Table 2, in the case of the negative control treated with swine influenza virus, the cell death was caused by the virus, whereas in the positive control treated with the antiviral ribavirin, the cell death by the virus was suppressed . In addition, in the case of the phlegm extract of the present invention, acetone, butanol and 70% ethanol extract showed the best cell death suppression activity, that is, antiviral activity.
Therefore, the optimum extraction conditions were determined by extracting with 70% ethanol solvent which is soluble in food.
≪ Example 2: Preparation of gut fractions >
The extracts obtained in Example 1-1 were applied to Diaion HP-20 column chromatography (diaion HP-20 column chromatography) to prepare fractions.
Of the extracts obtained in Example 1-1, 70% ethanol was used as a solvent, and the extracts were suspended in water, adsorbed on HP-20 resin, and distilled water was poured to remove unnecessary polar substances and salts. Then 70% ethanol and acetone fractions were obtained by eluting the adsorbed material on HP-20 resin using 70% ethanol and acetone. The MTT assays performed in Example 1-2 were performed to confirm the antiviral activity of the obtained fractions. The results are shown in Table 3. At this time, the final concentration of the fraction was 5 占 퐂 / ml.
Antiviral activity (%)
As shown in Table 3, the anti-viral activity of the 70% ethanol fraction obtained by fractionation of Ganoderma lucidum using Diaion HP-20 column chromatography was confirmed to show high antiviral activity.
The other fractions, acetone fraction, showed lower antiviral activity than the 70% ethanol fraction.
≪ Example 3: Isolation of fluorotannine compound >
To 100 g of dried ginger powder was added 2 L of 70% ethanol, and the mixture was sonicated three times a day. The mixture was concentrated under reduced pressure to obtain 25 g of 70% ethanol extract. The obtained extract was suspended in 500 ml of distilled water to prepare a suspension. The suspension was passed through HP-20 column chromatography, and about four times as much distilled water as the suspension was subjected to chromatography to elute unadsorbed substances in the HP-20 resin. Then, 70% ethanol and 100% acetone were added sequentially to 1 L each to elute, thereby obtaining a 70% ethanol fraction (8 g) and an acetone fraction (1 g).
Among them, the 70% ethanol fraction was subjected to reverse phase column chromatography (column type: RP-18, column size: 1: 3 to 5: 1 [v: v]) under a methanol / distilled water concentration gradient 2.0 x 3.0 cm, particle size: 40 to 63 μm) to obtain four small fractions (F1 to F4).
1.8 g of the fraction F2 was dissolved in methanol: water (76: 24 [v: v]) for 0 to 10 minutes using acetonitrile: water (20: (Column type: YMC J-sphere ODS-H80, column size: 10 x 250 mm, particle size: 10 탆, flow rate: 2) for 10 to 50 minutes using the isocratic mobile phase as a mobile phase Ml / min, UV detection: 254 nm) to obtain Compound 1 (3 mg) and Compound 3 (3 mg).
Further, 5.3 g of the above-mentioned fraction F3 was subjected to high performance liquid chromatography (column type: YMC (trade name)) for 0 to 65 minutes using acetonitrile: water (20:80 [v: v] J-sphere ODS-H80, column size: 10 x 250 mm, particle size: 10 탆, flow rate: 2 ml / min, UV detection: 254 nm) to obtain Compound 2 (3 mg).
≪ Example 4: Identification of the physicochemical structure of the compound isolated from menthol &
Example 4-1. Dibenzo [1,4] dione -2,4,7,9- Tetraol (Compound 1)
Dibenzo [1,4] dioxine-2,4,7,9-tetraol;
Brown powder;
UV (methanol)? Max nm (log?) 196 (2.24), 230 (2.81)
HRESIMS m / z 247.0284 [MH] - (calcd for C 12 H 8
1 H-NMR (DMSO- d 6 , 300 MHz) δ 5.96 (2H, d, J = 2.7Hz, H-β3, H-8), 5.78 (2H, d, J = 2.7Hz, H-1, H -6).
13 C-NMR (DMSO- d 6 , 75 MHz) δ 152.83 (C-2, C-7), 145.81 (C-4, C-9), 142.78 (C-5a, C-10), 122.86 (C -4a C-9a), 98.26 (C-3, C-8), 93.87 (C-1, C-6).
Example 4-2. Dioxino dehydrocole (Compound 2)
Dioxinodehydroeckol;
Brown powder;
UV (methanol)? Max nm (log?) 195 (2.26), 235 (2.85);
ESIMS m / z 369 [MH] - ;
1 H-NMR (DMSO- d 6 , 300 MHz) δ 6.10 (1H, s, H-7), 6.05 (1H, d, J = 2.7Hz, H-2), 6.01 (1H, d, J = 2.7 Hz, H-10), 5.84 (1H, d, J = 2.7 Hz, H-4), 5.82 (1H, d, J = 2.7 Hz, H-12).
13 C-NMR (DMSO- d 6 , 75 MHz) δ 153.25 (C-3), 152.98 (C-11), 146.06 (C-1), 145.91 (C-9), 142.02 (C-4a), 141.66 (C-12a), 140.1 (C-6), 137.13 (C-7a), 131.53 (C-13b), 122.60 C-2, C-10), 97.9 (C-7), 93.89 (C-4, C-12).
Example 4-3. 6,6'-biecol (Compound 3)
6,6'-bieckol;
Brown powder;
UV (methanol)? Max nm (log?) 198 (2.31), 210 (2.34), 230 (2.27);
ESIMS m / z 743 [M + H] < + > 741 [MH] -
1 H-NMR (DMSO- d 6 , 300 MHz) δ 6.09 (s, H-3), 6.04 (1H, s, H-8), 5.80 (1H, d, J = 1.8Hz, H-4 ') , 5.74 (1H, d, J = 2.1 Hz, H2 ', H-6').
13 C-NMR (DMSO- d 6 , 75 MHz)? 160.45 (C-1 '), 158.93 (C-3', C-5), 151.32 C-9), 141.87 (C-4), 141.35 (C-5a), 137.2 (C-10), 123.61 -6), 97.81 (C-8), 97.78 (C-3), 96.18 (C-4 '), 93.74 (C-2', C-6 ').
<Example 5: Cytotoxicity of fluorotannine-based compound isolated from menthol extract>
MTT assays were carried out to confirm the cytotoxicity of the compounds 1 to 3 isolated in Example 3 above.
1 × 10 4 Madin-Darby canine kindney cells (MDCK) per well were dispensed into a 96-well plate, and then 5% FBS (fetal bovine serum), 1% penicillin / streptomycin And Dulbecco's Modified Eagle's Medium (DMEM) containing 0.4% L-glutamine. The culture medium was discarded, and the culture medium was discarded and washed with PBS (phosphate buffer saline) solution. Then, fresh medium was added to the cells, and each of the compounds 1 to 3 isolated in Example 3 was treated to 100 uM and then cultured for 5 days. At this time, as a normal control group, the cells were treated with nothing, and phloroglucinol and fucofuroeckol A, which were the compounds separated together with the compounds of the present invention 1 to 3, Was also treated as a control for cytotoxicity.
MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) assay was performed using cells cultured for 5 days. MTT solution was added to the cultured cells, and the cells were reacted at 37 ° C. Then, the culture solution was removed and 200 μl of DMSO (dimethyl sulfoxide) was added. After mixing well with pipetting, the cells were allowed to stand for 10 minutes, and the absorbance at 550 nm was measured to confirm cell viability. At this time, the cell survival rate of each compound was calculated as a percentage (%) of the cell survival ratio of the normal control group. The results are shown in FIG.
As shown in FIG. 2, the fucofuoreo-A compounds separated together with the compounds 1 to 3 of the present invention showed cytotoxicity, while the compounds 1 to 3 of the present invention were found not to be cytotoxic.
Example 6. Confirmation of antiviral activity of phlorotannin-based compounds isolated from menthol extracts [
The antiviral activities of the compounds 1 to 3 isolated in Example 3 were confirmed. The experiment was carried out in the same manner as in Example 1-2. At this time, the concentration of each compound was adjusted to 2 uM to 80 uM, and the virus-treated group was treated as the normal control group, the virus-treated group was treated as the negative control group, and the anti-viral agent ribavirin (10 uM) Were used as positive control.
The results of confirming the antiviral activity of each compound are shown in FIG. 3 and Table 4. 3 shows the antiviral activity of the group treated with 20 uM of each compound, and Table 4 shows the EC 50 (half maximal effective concentration) of the compound against swine influenza virus.
Antiviral activity (EC 50 , uM)
As shown in Fig. 3, it can be seen that the compounds 1 to 3 of the present invention inhibit cell death by avian influenza virus (A) and swine influenza virus (B).
In addition, as shown in Table 4, it was confirmed that Compounds 1 to 3 of the present invention had antiviral activity against swine influenza virus.
Thus, it can be seen that the compounds 1 to 3 of the present invention are effective for the prevention and treatment of influenza caused by infection with avian influenza virus or swine influenza virus.
≪ Example 7: Toxicity test &
Example 7-1. Acute toxicity
The present study was conducted to investigate the toxicity of a 70% ethanol extract of the present invention to an animal body in an acute manner (within 24 hours) when an excessive amount of ethanol extract of the present invention was consumed in a short period of time and determine the mortality rate. Twenty mice of the general mouse ICR mouse line were assigned to each of the control and experimental groups. In the control group, only 30% PEG-400 was administered, and the experimental group was orally administered with 70% ethanol extract at a concentration of 1.0 g / kg / day.
As a result of the mortality rate after 24 hours of administration, it was found that the mice survived in the control group to which 30% PEG-400 was administered and in the experimental group to which the 70% ethanol extract of menthol at 1.0 g / kg / day was administered.
Example 7-2. Organ organs toxicity test in experimental group and control group
The long-term toxicity test was carried out on C57BL / 6J mice to examine the effects of the 70% ethanol extract of the present invention at 1.0 g / kg / day and the 30% PEG Blood was collected 8 weeks after the animals were administered a control group of -400, and the concentrations of GPT (glutamic-pyruvic transaminase) and BUN (blood urea nitrogen) in the blood were measured using Select E (Vital Scientific NV, Netherland) .
As a result, GPT, which is known to be related to hepatotoxicity, and BUN, which is known to be related to renal toxicity, showed no significant difference compared to the control group. In addition, liver and kidney were cut from each animal, followed by a general tissue section preparation, histological observation with an optical microscope, and no abnormalities were observed in all tissues.
≪ Formulation Example 1 >
Formulation Example 1-1. Manufacture of tablets
20 g of the gut extract of the present invention or 200 mg of dioxinodehydroeckol (Compound 2) were mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. To this mixture was added a 10% gelatin solution, which was pulverized and passed through a 14-mesh sieve. This was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into tablets.
Formulation Example 1-2. Injection preparation
100 mg of Dioxinodehydroeckol (Compound 2) of the present invention, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20 DEG C for 30 minutes.
<Formulation Example 2: Food Preparation>
Formulation Example 2-1. Manufacture of cooking seasonings
The ginger extract or dioxinodehydroeckol (Compound 2) of the present invention was added to the cooking sauce in an amount of 1 wt%, respectively, to prepare health-enhancing cooking sauce.
Formulation Example 2-2. Manufacture of flour food products
Dioxinodehydroeckol (Compound 2) of the present invention extract or a dioxinodehydroeckol (Compound 2) was added to flour at 0.1 wt%, and bread, cake, cookies, crackers and noodles were prepared using the mixture, Food was prepared.
Preparation Example 2-3. Manufacture of soups and gravies
Health enhancing soup and juice were prepared by adding the mentha extract or dioxinodehydroeckol (Compound 2) of the present invention to the juice at 0.1 wt%, respectively.
Formulation Example 2-4. Manufacture of dairy products
Dioxinodehydroeckol (Compound 2) of the present invention extract or the dioxinodehydroeckol (Compound 2) was added to milk in an amount of 0.1 wt%, and various dairy products such as butter and ice cream were prepared using the milk.
Formulation Example 2-5. Vegetable juice manufacturing
Healthy vegetable juices were prepared by adding the menthol extract of the present invention or dioxinodehydroeckol (Compound 2) to 1,000 ml of tomato juice or carrot juice, respectively.
Formulation Example 2-6. Manufacture of fruit juice
Healthy fruit juice was prepared by adding 0.1 g of each of the menthol extract of the present invention or dioxinodehydroeckol (Compound 2) to 1,000 ml of apple juice or grape juice.
Claims (15)
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Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| KR1020160149377A KR101966124B1 (en) | 2016-11-10 | 2016-11-10 | Composition comprising extract of Ecklonia cava or phlorotannin compounds isolated from thereof for preventing or treating influenza |
| PCT/KR2017/012550 WO2018088777A1 (en) | 2016-11-10 | 2017-11-07 | Composition for preventing or treating influenza, containing, as active ingredient, ecklonia cava extract or phlorotannin-based compound isolated therefrom |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020160149377A KR101966124B1 (en) | 2016-11-10 | 2016-11-10 | Composition comprising extract of Ecklonia cava or phlorotannin compounds isolated from thereof for preventing or treating influenza |
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| KR20180052258A KR20180052258A (en) | 2018-05-18 |
| KR101966124B1 true KR101966124B1 (en) | 2019-04-05 |
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| KR102192712B1 (en) * | 2018-01-25 | 2020-12-18 | 주식회사 헤마스 | An animal feed composition comprising phlorotannin and product for animal |
| GB2579600B (en) * | 2018-12-05 | 2023-07-05 | Byotrol Plc | Anti-viral composition |
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| JP4105535B2 (en) | 2002-12-10 | 2008-06-25 | 熊本県 | Antiviral substance |
| KR20110086473A (en) | 2010-01-22 | 2011-07-28 | 한국생명공학연구원 | Composition for preventing or treatment of coronavirus infection and composition for inhibiting the activy of 3c-like protease comprising ecklonia cava |
| KR101542882B1 (en) | 2013-10-30 | 2015-08-10 | 한국생명공학연구원 | A composition for prevention and treatment of fish viral hemorrhagic septicemia containing extracts of Ecklonia cava |
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Non-Patent Citations (2)
| Title |
|---|
| Bioorganic & Medicinal Chemistry, 2013, 제21권, 페이지 3730-3737* |
| Journal of Agricultural and Food Chemistry, 2011, 제59권, 페이지 6467-6473* |
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| WO2018088777A1 (en) | 2018-05-17 |
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