JP2014005246A - New quercetin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new quercetin derivative having anticancer activity stronger than quercetin and ferulic acid, a method of preparing the new quercetin derivative efficiently and safely, and an anticancer agent, food, medical supplies and quasi drugs containing the new quercetin derivative.SOLUTION: Provided is a producing method of a new quercetin derivative having anticancer activity superior than quercetin and ferulic acid by a simple and easy method of heat-treating quercetin and ferulic acid in the presence of metal salt.

Description

  The present invention relates to a novel quercetin derivative, a method for producing the novel quercetin derivative, an anticancer agent, a food, a pharmaceutical and a quasi-drug containing the novel quercetin derivative.

  Quercetin is one of the secondary metabolites of plants and is present in many plants and foods. For example, it is known that quercetin and its glycoside are contained in a large amount in onions, buckwheat, green asparagus and citrus fruits.

  Various studies have been conducted on quercetin and quercetin derivatives. For example, it has been reported that quercetin and quercetin derivatives have effects such as cyclooxygenase 2 and NFκB biosynthesis inhibition action, improvement of bone density, osteoclast differentiation inhibitory factor production promotion, calcium absorption promotion, etc. (Patent Document 1) ~ 4). Further, phosphorylated quercetin (Patent Document 5), dihydroquercetin derivative (Patent Document 6) and the like have been reported.

  On the other hand, ferulic acid is a precursor of lignin and lignan, which are the main components of trees, and is a relatively abundant component in nature, and is abundant in the skin layer of rice bran and potato. Physiological functions have also been reported for this ferulic acid. For example, a cell differentiation promoting agent containing ferulic acid as an active ingredient (Patent Document 7), an external preparation for skin whitening containing ferulic acid as an active ingredient (Patent Document 8), an antioxidant containing ferulic acid as an active ingredient (Patent Document 7) 9), a coloring aid for fish eggs composed of ferulic acid and nicotinic acid amide (Patent Document 10), an antibacterial agent containing ferulic acid as an active ingredient (Patent Document 11), and an Alzheimer's disease preventive effect of ferulic acid (Non-Patent Document 1) )It has been known.

  In addition, as prior arts related to ferulic acid derivatives, for example, an ultraviolet absorber containing a ferulic acid ester derivative as an active ingredient (Patent Document 12), an external skin drug containing a ferulic acid ester of phytosterols as an active ingredient (Patent Document) 13) is known. The compound about the ferulic acid resveratrol is also known (patent document 14).

  Since many of ferulic acid, quercetin, and derivatives thereof exhibit excellent utility, technical disclosures for efficiently producing these as raw materials and lead compounds have been made. Examples of ferulic acid production methods include production by condensation reaction of vanillin and malonic acid (Non-patent Document 2), production method from rice bran (Patent Document 15), and production method using eugenol as a raw material (patent) Document 16), a production method using an enzyme from coniferyl aldehyde (Patent Document 17) and the like are known.

According to a survey by the Ministry of Health, Labor and Welfare, about 30% of Japanese deaths in 2008 are malignant neoplasms or cancer. In current research on anticancer agents, flavonoids such as quercetin are known as compounds derived from natural products that can be ingested on a daily basis (Non-patent Document 3).
However, the development of safe therapeutic and preventive drugs for cancer that have stronger anticancer activity and can be taken on a daily basis is desired.

JP 2001-233768 A JP 2002-234844 A JP 2007-137775 A US Pat. No. 5,478,579 Special table 2012-505251 gazette Japanese Patent No. 4790561 JP-A-5-310526 JP-A-6-256137 Japanese Patent No. 3855293 JP 2000-325049 A Japanese Patent No. 4395623 Japanese Patent No. 397398 Japanese Patent No. 3493659 Special table 2010-538079 gazette Japanese Patent Publication No. 7-78032 Japanese Patent Laid-Open No. 9-154591 Japanese Patent Laid-Open No. 10-155596

British Journal of Pharmacology, 133, 89-96 (2001) Journal of the American Chemical Society, 74, 5346-5348 (1952). Medical Research Reviews, 23 (4), 519-534 (2003)

  In light of the above-described situation regarding quercetin, ferulic acid, and derivatives thereof, the present inventors have searched for a new physiological activity or a compound having a strong physiological activity, and have conducted intensive studies to establish a production method thereof. Surprisingly, we succeeded in producing a novel quercetin derivative having anticancer activity superior to quercetin and ferulic acid by a simple and safe method of heat treating quercetin and ferulic acid in the presence of a metal salt. The present invention has been completed.

Therefore, an object of the present invention is to provide a novel quercetin derivative having stronger anticancer activity than quercetin and ferulic acid, and to provide a method for efficiently and safely producing the novel quercetin derivative.
Another object of the present invention is to provide an anticancer agent characterized by containing the novel quercetin derivative, and further a food, a pharmaceutical and a quasi drug.

The gist of the present invention is as follows.
[1] Formula (1):

A novel quercetin derivative represented by or a pharmaceutically acceptable salt thereof,
[2] An anticancer agent comprising the novel quercetin derivative or the pharmaceutically acceptable salt thereof according to [1],
[3] A food, pharmaceutical or quasi-drug containing the novel quercetin derivative or the pharmaceutically acceptable salt thereof according to [1],
[4] Production of the novel quercetin derivative or the pharmaceutically acceptable salt thereof according to [1], wherein the target compound is produced by heat-treating quercetin and ferulic acid in the presence of a metal salt. Regarding the method.

The novel quercetin derivative of the present invention or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as a novel quercetin derivative) is useful as a novel anticancer agent because of its superior anticancer activity compared to quercetin and ferulic acid. is there.
Moreover, since the novel quercetin derivative of the present invention is excellent in safety in addition to being excellent in physiological activity as described above, it can be incorporated into foods, pharmaceuticals and quasi drugs.

FIG. 1 shows the chromatogram obtained in Example 1. From the top, a chromatogram before reaction, (1) a chromatogram using mineral water as a metal salt, and (2) a chromatogram using trimagnesium phosphate octahydrate are shown. In the figure, the peak A indicates the novel quercetin derivative of the present invention.

Hereinafter, the present invention will be described in detail.
The novel quercetin derivative of the present invention has the formula (1):

Or a pharmaceutically acceptable salt thereof.

  Examples of the pharmaceutically acceptable salt of the novel quercetin derivative include alkali metal salts such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt, calcium salt and barium salt; aluminum salt; Metal hydroxide salts such as aluminum hydroxide salts; amine salts such as alkylamine salts, dialkylamine salts, trialkylamine salts, alkylenediamine salts, cycloalkylamine salts, arylamine salts, aralkylamine salts, and heterocyclic amine salts Amino acid salts such as α-amino acid salts and ω-amino acid salts; peptide salts or primary, secondary, tertiary or quaternary amine salts derived from them; These pharmaceutically acceptable salts can be used alone or in admixture of two or more.

  The novel quercetin derivative of the present invention having the structure as described above can be chemically synthesized according to a method well known in the art, but the reaction process is complicated and requires harmful reagents and processes. In addition, chemical synthesis involves the complexity of removing impurities, and from the viewpoint of safety, it is necessary to thoroughly purify a novel quercetin derivative. Therefore, in view of these points, when the novel quercetin derivative of the present invention is produced industrially, the chemical synthesis method is unsuitable.

  Therefore, as a result of intensive studies, the present inventors have conducted heat treatment of quercetin and ferulic acid in the presence of a metal salt, so that a novel quercetin can be obtained without the need for harmful reagents and steps as in the chemical synthesis method described above. It has been found that derivatives can be produced efficiently and safely. Below, the manufacturing method (henceforth the manufacturing method of this invention) of the novel quercetin derivative of this invention is demonstrated concretely.

In the production method of the present invention, quercetin is used as a precursor. Quercetin may be naturally derived or may be a chemically synthesized chemical product with high purity. When natural quercetin is used, it does not need to be completely purified, and the desired production reaction proceeds as described later, and finally the novel quercetin derivative of the present invention is obtained. Mixtures containing can also be used.
However, from the viewpoint of the recovery rate of the novel quercetin derivative, a mixture containing 1% by weight or more in terms of quercetin is desirable as a raw material.
As the mixture containing quercetin, an extract from a raw material such as citrus or onion demon skin, a freeze-dried product, or the like may be used.

In the production method of the present invention, ferulic acid is also required as a precursor. Ferulic acid may be of natural origin or may be a chemically synthesized chemical product with high purity. When naturally occurring ferulic acid is used, it does not need to be completely purified. As long as the desired formation reaction proceeds and finally the novel quercetin derivative of the present invention is obtained, ferulic acid is used. Mixtures containing other ingredients can also be used.
However, from the viewpoint of the recovered amount of the new quercetin derivative, a mixture containing 1% by weight or more of ferulic acid is desirable as a raw material. Examples of such raw materials include ferulic acid as a rice bran extract or food additive, a ferulic acid-containing culture solution by microbial fermentation as shown in the prior art, and a ferulic acid-containing solution after an enzymatic reaction.

In the production method of the present invention, quercetin, ferulic acid, or a mixture of quercetin and ferulic acid is dissolved in a suitable solvent. At this time, if the solvent is only water, the solubility of quercetin and ferulic acid in water is extremely low, and therefore, the solvent may be dissolved only in a mixed solution of water and an organic solvent or in an organic solvent. There is no restriction | limiting in particular about the compounding ratio of water and an organic solvent, and the kind of organic solvent, Quercetin and ferulic acid should just fully melt | dissolve. Among them, it is preferable from the viewpoint of safety and cost to use a solvent containing only methanol or ethanol, or a mixed solution of water and methanol, water and ethanol, or the like. Use ethanol or water-containing ethanol as a solvent for safety and legal purposes when the final purification of the post-reaction composition containing the new quercetin derivative is not fully applied to food. It is desirable.
There is no particular limitation on the concentration of quercetin and ferulic acid in the solution containing the resulting quercetin, ferulic acid, or a mixture of quercetin and ferulic acid, but there are also merits such that the higher the respective concentration, the less the amount of solvent used Therefore, it is preferable to adjust the concentrations of quercetin and ferulic acid close to the concentrations at which quercetin and ferulic acid are saturated with respect to the respective solvents.
Further, quercetin and ferulic acid may not be completely dissolved in the solution before the formation reaction. For example, when a quercetin-containing solution and a ferulic acid-containing solution are mixed, even if the quercetin concentration and ferulic acid concentration in each solution are both equal to or higher than the saturated concentration, when the mixed solution is used, it becomes close to the saturated concentration. You should adjust as follows.

  Next, it is preferable to adjust the pH of the solution containing quercetin and ferulic acid (hereinafter, quercetin and ferulic acid-containing solution) to less than 8. As an adjustment method, for example, after preparing a solution containing quercetin and ferulic acid, a pH adjuster may be added to adjust the pH, or the pH of the solvent may be adjusted in advance when preparing the solution. If the pH at the start of the reaction of the quercetin-ferulic acid-containing solution is 8.0 or more, other reactions and decomposition of the target compound also occur on the other hand, so that the final recovered amount of the new quercetin derivative decreases. Therefore, the pH at the start of the reaction is desirably 3 or more and less than 8.

In the production method of the present invention, a metal salt is added to the quercetin and ferulic acid-containing solution. The metal salt may be any of an acid salt, a basic salt, and a normal salt, and may be any of a single salt, a double salt, and a complex salt. Furthermore, the metal salt may be one kind or a mixture of plural kinds. As an example of the metal salt, those approved as food additives are preferable in terms of safety. For example, magnesium salt, calcium salt, sodium salt, potassium salt, zinc salt, copper salt and the like that are permitted to be added to foods can be mentioned.
Moreover, as a mixture of the metal salts, for example, a mineral premix (Tanabe Seiyaku Co., Ltd., a mineral mixture mainly composed of zinc gluconate, ammonium iron citrate, calcium lactate, copper gluconate, and magnesium phosphate) In addition, substances containing several kinds of metal salts are listed. Moreover, mineral water can also be mentioned as a mixture containing a some metal salt.
In addition, as content of the said metal salt, what is necessary is just the quantity which can produce | generate a novel quercetin derivative, and there is no limitation in particular.

  Next, the quercetin and ferulic acid containing solution is heat-treated in the presence of a metal salt. By this heat treatment, a new quercetin derivative is formed. In order to efficiently promote the production reaction, it is preferable to adjust the heating temperature of the quercetin-ferulic acid-containing solution to 110 ° C. or higher. Also, considering the boiling point of the solvent used, pressure heating is desirable. For example, put a solution containing quercetin and ferulic acid in an open container and heat the container at a high temperature exceeding the boiling point of the solvent. Put a solution containing quercetin and ferulic acid in a sealed container and heat the container. It is preferable to heat the solution so that the solution temperature reaches 110 ° C. or higher at least partially, such as by using it under pressure. From the viewpoint of recovery efficiency, it is more preferable that the solution temperature be 110 ° C. to 150 ° C. uniformly. The heating time is not limited as in the case of the heating temperature, and may be a time condition in which the target reaction efficiently proceeds. In particular, the heating time depends on the heating temperature, and it is desirable to set the heating time according to the heating temperature. For example, when heating near 130 ° C., a heating time of 5 minutes to 360 minutes is desirable. Further, the heating may be performed once or may be repeated repeatedly in a plurality of times. In the case of heating in a plurality of times, it is preferable to add a new solvent to supplement the evaporated solvent.

  The completion of the production reaction of the novel quercetin derivative by the heat treatment may be judged by confirming the production amount of the novel quercetin derivative by component analysis by HPLC, for example.

The resulting reaction solution contains the produced novel quercetin derivative of the present invention.
In addition, when a novel quercetin derivative is produced by a process using only safe raw materials, it can be used in foods, pharmaceuticals or quasi drugs in the state of a mixture containing the novel quercetin derivative. For example, when natural quercetin and ferulic acid are dissolved in a water-containing ethanol solvent and heated with mineral water or mineral premix, the resulting reaction solution can be used as one of the food ingredients. It is.

  In addition, when it is desired to improve the flavor and further enhance the functionality, the reaction solution can be concentrated to increase the concentration of the new quercetin derivative, or the reaction solution can be purified to obtain a pure product of the new quercetin derivative. . The concentration and purification can be performed by a known method. For example, the novel quercetin derivative can be concentrated by extraction from the reaction solution by a solvent extraction method using chloroform, ethyl acetate, ethanol, methanol or the like, a supercritical extraction method using carbon dioxide gas, or the like. It is also possible to perform concentration and purification using column chromatography. A membrane treatment method such as a recrystallization method or an ultrafiltration membrane can also be applied.

  In addition, when the novel quercetin derivative represented by the formula (1) is separated and recovered from the reaction solution, column chromatography, HPLC or the like may be used.

  If necessary, the concentrated or purified product obtained as described above can be dried under reduced pressure or lyophilized to remove the solvent, whereby the powdered novel quercetin derivative of the present invention can be obtained.

  The novel quercetin derivative of the present invention obtained as described above has an excellent anticancer activity as compared with quercetin and ferulic acid. Therefore, the anticancer agent which contains a novel quercetin derivative as an active ingredient can be provided.

  In particular, considering the field of physiological activity of the novel quercetin derivative of the present invention, it is preferably used in the field of health promotion such as prevention / treatment for cancer, and further in the field of disease healing.

  In addition, the further effect efficacy which the novel quercetin derivative obtained by this invention has can be used in the range which can be estimated from the obtained physiological activity data.

  Since the safety of quercetin and ferulic acid as raw materials has been confirmed, it is considered that the safety of the novel quercetin derivative of the present invention is also excellent.

  In addition, since the novel quercetin derivative of the present invention exhibits the physiological activity as described above, it can be used in foods, pharmaceuticals, quasi drugs and the like.

  The food may be in any form such as beverage, alcoholic beverage, jelly, confectionery, etc., and among confectionery, hard candy, soft candy, gummy candy, tablet that is excellent in storage and carrying due to its capacity etc. There are no particular limitations. Moreover, since the novel quercetin derivative has an excellent anticancer activity, it can be made into a candy, gummy candy, tablet or the like that can be easily taken for the purpose of preventing cancer. The food includes functional food, health food, health-oriented food, and the like.

  Examples of the pharmaceutical include solid preparations such as powders, tablets, pills, capsules, fine granules and granules, liquids such as liquids, suspensions and emulsions, gels and the like. If necessary, the granules of capsules containing tablets, pills, granules, granules can be sugar-coated with sugars such as sucrose, sugar alcohols such as maltitol, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. A coating may be applied, or a film of gastric or enteric material may be coated. Moreover, in order to improve the solubility of a formulation, the said formulation can also be given a known solubilization process. Based on a conventional method, the solution may be used in an injection or a drip.

  Examples of the quasi-drug include toothpaste, mouthwash, mouth rinse, and drink.

When preparing foods, pharmaceuticals or quasi drugs using the novel quercetin derivative of the present invention, the components usually used in foods, pharmaceuticals or quasi drugs are arbitrarily selected as long as the effects of the present invention are not impaired. Can be blended.
For example, in the case of food, food such as water, alcohol, starch, protein, fiber, carbohydrate, lipid, vitamin, mineral, flavoring, coloring, sweetener, seasoning, stabilizer, preservative Can be combined with raw materials or materials usually blended in
In the case of pharmaceuticals and quasi-drugs, the main ingredients, base materials, surfactants, foaming agents, wetting agents, thickeners, clearing agents, flavoring agents, coloring agents, stabilizers, preservatives, bactericides, etc. Based on a combination and a conventional method, it can be made into a liquid, ointment-like or sprayable final form.

  When the novel quercetin derivative of the present invention is added to food, it is usually preferable to add 0.001 to 20% by weight based on the food.

  When the novel quercetin derivative of the present invention is used for pharmaceutical purposes, for example, the amount of intake thereof is not particularly limited as long as the desired improvement, treatment or prevention effect is obtained. , Sex, constitution and other conditions, the type and degree of disease, and the like. The intake is preferably about 0.1 mg to 1,000 mg per day, which can be divided into 1 to 4 times a day.

  When adding the novel quercetin derivative of the present invention to a quasi-drug, it is usually preferable to add 0.001 to 30% by weight in the quasi-drug.

  Further, since the novel quercetin derivative of the present invention is excellent in safety, not only for humans, for example, non-human animals such as rats, mice, guinea pigs, rabbits, sheep, pigs, cows, You may mix | blend with therapeutic agents or feed, such as horses, cats, dogs, monkeys, chimpanzees, etc. mammals, birds, amphibians, reptiles. As feed, for example, livestock feed used for sheep, pigs, cattle, horses, chickens, etc., feed for small animals used for rabbits, rats, mice, etc. The pet food used for a cat, a small bird, a squirrel, etc. is mentioned.

  EXAMPLES Next, although this invention is demonstrated in detail based on an Example, this invention is not limited only to this Example.

(Example 1: Examination of production method of novel quercetin derivative)
100 mg of quercetin dihydrate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 100 mg of ferulic acid (manufactured by Wako Pure Chemical Industries, Ltd.) are dissolved in 2 mL of ethanol, and (1) mineral water (trade name “Gerol Steiner” Sapporo Beverage ( 2 mL), (2) Trimagnesium phosphate octahydrate (manufactured by Wako Pure Chemical Industries, Ltd., main component of mineral premix), 100 mL of water and 2 mL of water were added respectively, and quercetin and ferulic acid-containing solution ( Two kinds of pH: (1) 4.7, (2) 5.0) were prepared. This quercetin-ferulic acid-containing solution was heated at 130 ° C. for 60 minutes in an autoclave (“SANYO LABO AUTOCLAVE” manufactured by Sanyo Electric Co., Ltd.). 1 mL was taken out from each of the obtained reaction solutions, made up to 50 mL with methanol, and 10 μL of this was analyzed by HPLC.

The HPLC analysis was performed under the following conditions.
Column: Column for reverse phase “Develosil (registered trademark) C-30-UG-5” (4.6 mm.d. × 250 mm)
Mobile phase: A: H ₂ O (0.1% trifluoroacetic acid (TFA)), B: Acetonitrile (0.1% TFA)
Flow rate: 1 mL / min
Injection: 10 μL
Detection: 254 nm
Gradient (volume%): 100% A / 0% B to 0% A / 100% B for 33 minutes, 100% B for 7 minutes (all linear)

The obtained chromatogram is shown in FIG. From the top, before the reaction, the chromatograms of the reaction solutions (1) and (2) are shown. Peaks other than quercetin and ferulic acid observed before the reaction were detected from the reaction solutions (1) and (2) after the reaction, and it was confirmed that a plurality of compounds were produced.
It was the peak of A, which is a novel quercetin derivative described later, that had a significant difference in the amount produced before and after the reaction. In addition, there was almost no difference in the production amount of the peak component of A between the reaction solutions of (1) and (2), that is, the difference in the production amount of the novel quercetin derivative depending on the type of metal salt used this time was small. .

(Example 2: Mass production of novel quercetin derivative)
1 g of quercetin dihydrate and 1 g of ferulic acid were dissolved in 20 mL of ethanol, and 20 mL of mineral water was added to obtain a solution containing quercetin and ferulic acid (pH = 4.7). This quercetin-ferulic acid-containing solution was heated in an autoclave at 130 ° C. for 180 minutes. When 1 mL of the obtained reaction solution was made up to 50 mL with methanol and analyzed by HPLC in the same manner as in Example 1, the same chromatogram as in Example 1 was confirmed.

(Example 3: Isolation and structure determination of a novel quercetin derivative)
Among the reactants obtained in Example 2, the compound contained in the peak indicated by A in FIG. 1 was isolated by preparative HPLC and dried by a conventional method, whereby 212.70 mg of a new compound (hereinafter referred to as UHA3039) was obtained. It was. The isolated and purified UHA3039 was a yellow powdery substance.

Subsequently, when the molecular weight of the UHA3039 was measured by high resolution negative-FAB-MS (Fast Atom Bombardment-Mass Spectrometry), the measured value was 451.4029. From the comparison with the theoretical value, the following molecular formula was obtained. .
Theoretical value C24H19O9 (M−H ⁻ ): 451.4023
Molecular formula C ₂₄ H ₂₀ O ₉

  Next, the UHA3039 is subjected to nuclear magnetic resonance (NMR) measurement, and from analysis of 1H-NMR, 13C-NMR and various two-dimensional NMR data, the UHA3039 has a structure represented by the formula (1). confirmed. Therefore, it was shown that the novel quercetin derivative represented by the formula (1) can be efficiently produced by the method of the present invention.

  For the NMR measurement value, UHA3039 is used.

Table 1 shows the results of ¹ H nuclear magnetic resonance spectrum and ¹³ C nuclear magnetic resonance spectrum. The values were δ and ppm, and the solvent was measured with dimethyl sulfoxide (DMSO-d ₆ ).

The physicochemical properties of UHA3039 are as follows.
(Properties)
Yellow powder (soluble)
Water: Slightly soluble methanol: Dissolved ethanol: Dissolved DMSO: Dissolved chloroform: Dissolved ethyl acetate: Dissolved

(Example 4: Anticancer effect of UHA3039 on human myeloid leukemia cells)
Next, in order to see the effect of each compound on cancer cells, the cancer cell proliferation inhibitory action using HL-60 cells (Human proneolytic leukemia cells: human myeloid leukemia cells) was tested.

For the culture of HL-60 cells, a high nutrient medium “RPMI-1640” (Sigma) containing 4 mM glutamine (manufactured by L-Glutamine Sigma-Aldrich Japan), 10% fetal bovine serum (FBS Biological industries). Aldrich Japan) was used. For the test, a 96-well plate for cell culture (manufactured by Corning Japan Co., Ltd.) was used and seeded with 100 μL per well of HL-60 cells adjusted to a cell number of 5 × 10 ⁵ cells / mL. Used for.

Three types of samples were used: quercetin, ferulic acid, and UHA3039 which is the product of the present invention. In the sample preparation, each compound was dissolved in dimethyl sulfoxide (DMSO, manufactured by Wako Pure Chemical Industries, Ltd.), and the final concentrations in the HL-60 cell culture solution were 6.3 μM, 12.5 μM, The test was started under the culture conditions of 37 ° C. and 5% CO ₂ by adding 25 μM, 50 μM and 100 μM. A negative control was prepared by adding the same amount of DMSO as a solvent.

The number of viable cells was quantified by the MTT method using “Cell counting kit-8” (manufactured by Dojin Chemical Laboratory). That is, 24 hours after the start of the test, 10 μL of the Cell counting kit-8 solution was added to each well and stirred well. The light-shielding reaction was performed for 1 hour at 37 ° C. and 5% CO ₂ . Thereafter, absorbance was measured at a measurement wavelength of 450 nm using a plate reader (“MULTISKAN FC”, manufactured by Thermo Fisher Scientific Co., Ltd.), and the cell viability was calculated based on the obtained data. The cell viability is a value calculated by setting the number of viable cells in a culture solution to which only DMSO as a solvent is added as 100% and the number of viable cells in each compound concentration as a relative value. From the relationship between the concentration of each compound and the cell viability, a concentration IC ₅₀ (50% inhibitory concentration) that suppresses cell proliferation by 50% was calculated (Table 2). From the results shown in Table 2, it was confirmed that UHA3039 had excellent cancer cell growth inhibitory ability. This anticancer activity was not observed in ferulic acid and quercetin, and only UHA3039 showed high anticancer activity. Therefore, the high significance of converting quercetin and ferulic acid into novel quercetin derivatives was shown.

(Example 5: Difference in production amount of UHA3039 depending on heating temperature)
A mixed solution (pH = 4.7) of quercetin 100 mg, ferulic acid 100 mg, ethanol 2 mL, and mineral water 2 mL was heated at 70 ° C., 90 ° C., 110 ° C., and 130 ° C. for 20 minutes in an autoclave. 1 mL of the post-reaction composition obtained under each temperature condition was diluted to 50 mL with methanol and analyzed by HPLC in the same manner as in Example 1.

  As a result, the formation of UHA3039 was confirmed at 110 ° C. or higher. The production ratio (% by weight) from the total amount of quercetin and ferulic acid is 70 ° C., 90 ° C. is not produced, 110 ° C. is extremely small, and 130 ° C. is 7.1%. Was generated.

(Example 6: Preparation of UHA3039-containing extract)
Onion hull extract powder (quercetin-containing material) 10 g, ferulic acid (food additive, manufactured by Tsukino Rice Fine Chemical Co., Ltd.) 1 g, ethanol 10 mL, mineral water 10 mL mixed solution (pH = 5.0) Was heated in an autoclave at 130 ° C. for 180 minutes. The obtained reaction solution was heated under reduced pressure to dryness to obtain 11 g of UHA3039-containing extract. In the obtained 11 g of UHA3039-containing extract, 0.053 g of UHA3039 was contained when confirmed by the same method as in Example 3. This work was repeated as necessary.

(Example 7: Food containing UHA3039)
1 g of UHA3039-containing extract obtained in Example 6 was dissolved in 100 mL of ethanol in advance, 500 g of sugar and 400 g of starch syrup were mixed and dissolved in this, and after mixing 100 g of fresh cream, 20 g of butter, 70 g of condensed milk, and 1.0 g of emulsifier, The pressure was reduced by −550 mmHg in a vacuum kettle and concentrated under a condition of 115 ° C. to obtain a milk hard candy having a moisture value of 3.0% by weight. This milk hard candy is easy to eat as a confectionery, as well as reducing the risk of cancer spread in cancer patients, reducing the risk of developing cancer, and as a functional food that is expected to prevent cancer. Can also be used.

(Example 8: Drug containing UHA3039)
UHA3039 obtained by the same method as in Examples 2 and 3 was dissolved in ethanol, added to microcrystalline cellulose and adsorbed, and then dried under reduced pressure. Using this adsorbent, a tableted product was obtained according to a conventional method. The formulation is 10 parts by weight of UHA3039, 23 parts by weight of corn starch, 12 parts by weight of lactose, 8 parts by weight of carboxymethyl cellulose, 32 parts by weight of microcrystalline cellulose, 4 parts by weight of polyvinylpyrrolidone, 3 parts by weight of magnesium stearate, 8 parts by weight of talc. Street. This tableted product can be effectively used as a pharmaceutical for the purpose of healing cancer.

(Example 9: Quasi-drug containing UHA3039)
1.2 g of UHA3039 obtained by the methods of Examples 2 and 3 was dissolved in 10 mL of ethanol, to which 20 g of taurine, 0.12 g of vitamin B1 nitrate, 0.6 g of sodium benzoate, 4 g of citric acid, 60 g of sugar, polyvinylpyrrolidone Purified water in which 10 g was dissolved was mixed, and further made up to 1000 mL with purified water. The pH was adjusted to 3.2 using dilute hydrochloric acid. 50 ml of 1000 ml of the obtained solution was filled in a glass bottle and sterilized at 80 ° C. for 30 minutes to complete a quasi-drug drink. In addition to the purpose of nutritional supplementation, this drink is effective as a quasi-drug for the purpose of reducing the risk of cancer spread in cancer patients, reducing the risk of developing cancer, and preventing cancer. Available.

Claims (4)

Formula (1):

Or a pharmaceutically acceptable salt thereof.   An anticancer agent comprising the novel quercetin derivative according to claim 1 or a pharmaceutically acceptable salt thereof.   A food, medicine or quasi-drug containing the novel quercetin derivative according to claim 1 or a pharmaceutically acceptable salt thereof.   The method for producing a novel quercetin derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the target compound is produced by heat-treating quercetin and ferulic acid in the presence of a metal salt.

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