Novel compound derived from myristica fragrans, and anticancer composition comprising same

Abstract

The present invention relates to a novel compound derived from Myristica fragrans and to an anticancer composition comprising same. In the present invention, various novel compounds derived from Myristica fragrans extracts were isolated, and it was confirmed that most of the novel compounds exhibit cytotoxic effects against various cancer cell lines. It was confirmed that five compounds (3, 4, 6, 9, 11) exhibit high cytotoxic effects in gastric cancer and colorectal cancer. In particular, it was confirmed that the compound represented by chemical formula 3 effectively induces apoptosis by regulating the cell cycle of cancer cells, as well as effectively suppresses tumor growth in a xenograft mouse model, and thus can be effectively utilized as an anticancer composition.

Description

Novel compound derived from nutmeg and anticancer composition containing the same

[0001] The present invention relates to a novel compound derived from nutmeg and an anticancer composition comprising the same.

[0002]

[0003] While normal cells can grow and regenerate in a regular and elastic manner as needed, cancer cells proliferate without restraint. These cells form a mass of undifferentiated cells, also known as a tumor. These cancer cells invade surrounding tissues and metastasize to other organs, causing severe pain and ultimately death. Despite medical advancements, the number of cancer patients in Korea has steadily increased, rising by approximately 44% over the past decade. The international anticancer drug market has also grown, reaching an annual market size of approximately $100 billion.

[0004] However, loss of appetite, nausea, and vomiting may occur during or for several days after chemotherapy administration, and hypersensitivity reactions (skin rash, angioedema, dyspnea) may occur immediately after chemotherapy administration and within hours. Furthermore, stomatitis, diarrhea, and neutropenic fever may occur after chemotherapy administration. Therefore, ongoing efforts are being made to minimize these side effects, and as part of these efforts, active research is being conducted on natural products to mitigate the side effects of cancer.

[0005] Meanwhile, nutmeg (Myristica fragrans, nutmeg) is an evergreen tree belonging to the Myristicaceae family. It is made by picking the fruit, removing the seeds, drying them, removing the hard black seed coat, soaking them in lime juice overnight, and then drying them at room temperature. Nutmeg has been used to improve blood circulation and lung function and has an antibacterial effect, so it has been used to improve blood flow, treat respiratory disorders, and treat skin diseases. It is also used as a fragrance because it has aromatic components. Studies on nutmeg have reported cytotoxic effects on cancer cell lines, antibacterial and antioxidant effects, antimicrobial effects, liver detoxification effects, and inhibition of brain cholinesterase, which is related to dementia (Korean Patent Publication No. 10-1999-0034285; Korean Patent Publication No. 10-2012-0021283; Korean Patent Publication No. 10-2011-0119483).

[0006]

[0007] Accordingly, in the present invention, as a result of extensive efforts to reduce the side effects of anticancer drugs and develop a natural material with excellent anticancer effects, a novel compound derived from nutmeg extract was selected, and it was confirmed that the novel compound exhibited anticancer activity, thereby completing the present invention.

[0008]

[0009] Accordingly, the purpose of the present invention is to provide a novel compound derived from nutmeg extract.

[0010] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, or a health functional food composition for preventing or improving cancer, comprising a compound derived from a nutmeg extract as an active ingredient.

[0011]

[0012] To achieve the above-mentioned purpose,

[0013] The present invention provides a compound represented by the following chemical formula A, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

[0014] [Chemical Formula A]

[0015]

[0016] (In the above chemical formula A,

[0017] X is or , and at this time, n is an integer from 1 to 20,

[0018] At least one of R1 to R5 , and at this time, Y is O or -(CH)m- (wherein, m is 0 to 5), and R1' to R6' are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic,

[0019] The remainder of R1 to R5 are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic,

[0020] R 6, R8 and R 10 are each independently hydrogen or hydroxy,

[0021] R7 and R9 are each independently hydrogen,

[0022] R 1' Inland R 6' are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic.

[0023]

[0024] In a preferred embodiment of the present invention, the compound represented by the chemical formula A may be a compound represented by the following chemical formula 3; a compound represented by the following chemical formula 4; a compound represented by the following chemical formula 6; a compound represented by the following chemical formula 9; a compound represented by the following chemical formula 10; a compound represented by the following chemical formula 11; a compound represented by the following chemical formula 12; or a compound represented by the following chemical formula 13.

[0025] [Chemical Formula 3]

[0026]

[0027] [Chemical Formula 4]

[0028]

[0029] [Chemical Formula 6]

[0030]

[0031] [Chemical Formula 9]

[0032]

[0033] [Chemical Formula 10]

[0034]

[0035] [Chemical Formula 11]

[0036]

[0037] [Chemical Formula 12]

[0038]

[0039] [Chemical Formula 13]

[0040]

[0041]

[0042] In another preferred embodiment of the present invention, the compound represented by the chemical formula A may be a compound represented by the following chemical formula 3.

[0043] [Chemical Formula 3]

[0044]

[0045]

[0046] In addition, the present invention relates to a compound represented by the following chemical formula 14, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0047] A compound represented by the following chemical formula 15, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or

[0048] A compound represented by the following chemical formula 16, a pharmaceutically acceptable salt thereof, or an optical isomer thereof is provided.

[0049] [Chemical Formula 14]

[0050]

[0051] [Chemical Formula 15]

[0052]

[0053] [Chemical Formula 16]

[0054]

[0055]

[0056] In addition, the present invention relates to a compound represented by the following chemical formula 17, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0057] A compound represented by the following chemical formula 18, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0058] A compound represented by the following chemical formula 19, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or

[0059] A compound represented by the following chemical formula 20, a pharmaceutically acceptable salt thereof, or an optical isomer thereof is provided.

[0060] [Chemical Formula 17]

[0061]

[0062] [Chemical Formula 18]

[0063]

[0064]

[0065] [Chemical Formula 19]

[0066]

[0067] [Chemical Formula 20]

[0068]

[0069]

[0070] In addition, the present invention relates to a compound represented by the following chemical formula 21, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or

[0071] A compound represented by the following chemical formula 22, a pharmaceutically acceptable salt thereof, or an optical isomer thereof is provided.

[0072] [Chemical Formula 21]

[0073]

[0074] [Chemical Formula 22]

[0075]

[0076]

[0077] To achieve other purposes,

[0078] The present invention provides a pharmaceutical composition for preventing or treating cancer, or a composition for a health functional food for preventing or improving cancer, comprising the compound as an active ingredient.

[0079] In a preferred embodiment of the present invention, the compound is

[0080] A compound represented by the above chemical formula 3, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0081] A compound represented by the above chemical formula 4, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0082] A compound represented by the above chemical formula 6, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0083] A compound represented by the above chemical formula 10, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0084] A compound represented by the above chemical formula 11, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0085] A compound represented by the above chemical formula 12, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0086] A compound represented by the above chemical formula 14, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0087] A compound represented by the above chemical formula 15, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0088] A compound represented by the above chemical formula 17, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or

[0089] It may be a compound represented by the above chemical formula 21, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

[0090]

[0091] In the present invention, various novel compounds derived from nutmeg extract were isolated, and it was confirmed that most of the novel compounds exhibit cytotoxic effects against various cancer lines. Five compounds (3, 4, 6, 9, 11) were confirmed to exhibit high cytotoxic effects in gastric and colon cancers. In particular, the compound represented by chemical formula 3 was confirmed to not only effectively induce apoptosis through cell cycle regulation of cancer cells, but also effectively inhibit tumor growth in a xenograft mouse model, and thus can be usefully utilized as an anticancer composition.

[0092]

[0093] Figures 1a to 1c are data analyzed using circular dichroism spectroscopy (CD spectroscopy) for compounds represented by chemical formulas 1 to 8.

[0094] Figures 2a to 2c are data analyzed using circular dichroism spectroscopy (CD spectroscopy) for compounds represented by chemical formulas 10 to 13.

[0095] Figure 3 shows data analyzed using circular dichroism spectroscopy (CD spectroscopy) for compounds represented by chemical formulas 14 to 16.

[0096] Figure 4 shows data showing the main HMBC (→) and COSY (red, bold) correlations of compounds represented by chemical formulas 14 to 16.

[0097] Figure 5 shows data analyzed using circular dichroism spectroscopy (CD spectroscopy) for compounds represented by chemical formulas 17 to 20.

[0098] Figure 6 is data showing the main HMBC (→) and COSY (red, bold) correlations of compounds represented by chemical formulas 17 to 20.

[0099] Figure 7 shows data showing the main HMBC (→) and COSY (red, bold) correlations of compounds represented by chemical formula 21 or 22.

[0100] Figure 8 is a heatmap showing the survival rate (%) of cancer cell lines treated with a novel nutmeg-derived compound (10 μM). The color scale represents the percentage of viable cells relative to the untreated control, with green indicating higher cell viability and white indicating lower cell viability.

[0101] Figure 9 shows data confirming cell survival rate (%) when a novel compound (10 μM) was treated to gastric cancer cell lines and colon cancer cell lines.

[0102] Figures 10a and 10b are data confirming the cell cycle distribution of 23132 / 87 and SW48 cell lines when treated with 5 μM and 10 μM of the compounds myricone C and malavaricone C.

[0103] Figures 11a to 11c are data analyzing the cell cycle of 23132 / 87 and SW48 cell lines when treated with 5 μM and 10 μM of the compounds MyrC and Malavaricone C (MalC).

[0104] Figures 12a and 12b are data confirming the apoptosis patterns of 23132 / 87 and SW48 cell lines when treated with 5 μM and 10 μM of the compounds myricone C and malavaricone C.

[0105] Figures 13a and 13b are data confirming the distribution (%) of cell death in 23132 / 87 and SW48 cell lines when treated with 5 μM and 10 μM of the compounds myricone C and malavaricone C.

[0106] Figure 14 shows data comparing the total number of non-apoptotic cells (Q4: viable cells) and apoptotic and dead cells (Q2 and Q3) in 23132 / 87 and SW48 cell lines.

[0107] Figure 15 shows data confirming caspase-3 and -7 activity in 23132 / 87 and SW48 cell lines when treated with 5 μM and 10 μM of the compounds myricone C and malavaricone C.

[0108] Figure 16 shows data confirming the anticancer effect of administration of the Miricon C compound in a xenograft mouse model. Figure 16a is a schematic diagram showing the animal experiment process, Figure 16b is data confirming the tumor volume according to compound administration, and Figure 16c is data confirming the mouse body weight and major organ (liver, spleen, kidney) weight according to compound administration.

[0109]

[0110] Hereinafter, the present invention will be described in detail.

[0111]

[0112] The present invention relates, from a consistent perspective, to a compound represented by the following chemical formula A, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

[0113] [Chemical Formula A]

[0114]

[0115] (In the above chemical formula A,

[0116] X is or , and at this time, n is an integer from 1 to 20,

[0117] At least one of R1 to R5 , and at this time, Y is O or -(CH)m- (wherein, m is 0 to 5), and R1' to R6' are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic,

[0118] The remainder of R1 to R5 are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic,

[0119] R 6, R8 and R 10 are each independently hydrogen or hydroxy,

[0120] R7 and R9 are each independently hydrogen,

[0121] R 1' Inland R 6'are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic.

[0122]

[0123] In the present invention, the compound represented by the chemical formula A may be a compound represented by the following chemical formula 3; a compound represented by the following chemical formula 4; a compound represented by the following chemical formula 6; a compound represented by the following chemical formula 9; a compound represented by the following chemical formula 10; a compound represented by the following chemical formula 11; a compound represented by the following chemical formula 12; or a compound represented by the following chemical formula 13.

[0124] [Chemical Formula 3]

[0125]

[0126] [Chemical Formula 4]

[0127]

[0128] [Chemical Formula 6]

[0129]

[0130] [Chemical Formula 9]

[0131]

[0132] [Chemical Formula 10]

[0133]

[0134] [Chemical Formula 11]

[0135]

[0136] [Chemical Formula 12]

[0137]

[0138] [Chemical Formula 13]

[0139]

[0140]

[0141] More preferably, the compound represented by the above chemical formula A may be a compound represented by the following chemical formula 3.

[0142] [Chemical Formula 3]

[0143]

[0144]

[0145] In another aspect, the present invention relates to a compound represented by the following chemical formula 14, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0146] A compound represented by the following chemical formula 15, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or

[0147] It relates to a compound represented by the following chemical formula 16, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

[0148] [Chemical Formula 14]

[0149]

[0150] [Chemical Formula 15]

[0151]

[0152] [Chemical Formula 16]

[0153]

[0154]

[0155] In another aspect, the present invention relates to a compound represented by the following chemical formula 17, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0156] A compound represented by the following chemical formula 18, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0157] A compound represented by the following chemical formula 19, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or

[0158] It relates to a compound represented by the following chemical formula 20, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

[0159] [Chemical Formula 17]

[0160]

[0161] [Chemical Formula 18]

[0162]

[0163]

[0164] [Chemical Formula 19]

[0165]

[0166] [Chemical Formula 20]

[0167]

[0168]

[0169] In another aspect, the present invention relates to a compound represented by the following chemical formula 21, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or

[0170] It relates to a compound represented by the following chemical formula 22, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

[0171] [Chemical Formula 21]

[0172]

[0173] [Chemical Formula 22]

[0174]

[0175]

[0176] In the present invention, the compound is characterized by being isolated from a nutmeg (Myristica fragrans, nutmeg) extract, and preferably, the nutmeg extract may be a 70% (v / v) to 100% (v / v) ethanol extract.

[0177] In a specific embodiment of the present invention, 35 compounds were isolated from a 75% (v / v) ethanol extract of nutmeg extract, and among these, 17 new compounds represented by Chemical Formula 3, Chemical Formula 4, Chemical Formula 6, Chemical Formula 9 to Chemical Formula 22 were isolated.

[0178]

[0179] In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating cancer, or a composition for a health functional food for preventing or improving cancer, comprising the compound as an active ingredient.

[0180] Preferably, the compound is

[0181] A compound represented by the above chemical formula 3, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0182] A compound represented by the above chemical formula 4, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0183] A compound represented by the above chemical formula 6, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0184] A compound represented by the above chemical formula 10, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0185] A compound represented by the above chemical formula 11, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0186] A compound represented by the above chemical formula 12, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0187] A compound represented by the above chemical formula 14, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0188] A compound represented by the above chemical formula 15, a pharmaceutically acceptable salt thereof, or an optical isomer thereof;

[0189] A compound represented by the above chemical formula 17, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or

[0190] It may be a compound represented by the above chemical formula 21, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

[0191]

[0192] In the present invention, the compound is characterized by being isolated from a nutmeg (Myristica fragrans, nutmeg) extract, and preferably, the nutmeg extract may be a 70% (v / v) to 100% (v / v) ethanol extract.

[0193] In the present invention, the cancer may be pancreatic cancer, liver cancer, lung cancer, stomach cancer, colon cancer, prostate cancer, kidney cancer, breast cancer or ovarian cancer, and preferably stomach cancer or colon cancer.

[0194]

[0195] In a specific embodiment of the present invention, as a result of treating various cancer cell lines with novel compounds derived from nutmeg extract, it was confirmed that most of the compounds exhibited anticancer activity, and it was confirmed that the compounds represented by Chemical Formula 3, Chemical Formula 4, Chemical Formula 6, Chemical Formula 10, Chemical Formula 11, Chemical Formula 12, Chemical Formula 14, Chemical Formula 15, Chemical Formula 17, and Chemical Formula 21 had high anticancer activity.

[0196] Furthermore, five compounds (chemical formulae 3, 4, 6, 9, and 11) were confirmed to exhibit high cytotoxic effects in gastric and colon cancer. In particular, the compound represented by chemical formula 3 was confirmed to effectively induce apoptosis through cell cycle regulation in cancer cells, and the anticancer effect of administration of the compound Myricon C was confirmed in a xenograft mouse model.

[0197]

[0198] The pharmaceutical composition of the present invention can be formulated and used in various forms according to conventional methods. For example, it can be formulated in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, and can be formulated and used in the forms of topical preparations, suppositories, and sterile injectable solutions. Depending on each dosage form, pharmaceutically acceptable carriers, excipients, and diluents may be further included. In addition, it can be formulated and used in the forms of topical preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, and sterile injectable solutions according to conventional methods.

[0199] The carrier, excipient and diluent include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, etc. When formulating or formulating the pharmaceutical composition, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants that are commonly used.

[0200] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing the composition with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, etc. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin, and glycerogelatin.

[0201] The term "administration" as used herein means providing the pharmaceutical composition of the present invention to a subject by any suitable method. The pharmaceutical composition of the present invention may be administered in a therapeutically effective amount, which is an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue, animal, or human as contemplated by a researcher, veterinarian, physician, or other clinician, i.e., an amount that induces alleviation of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dosage and frequency of administration of the pharmaceutical composition of the present invention will vary depending on the desired effect. Therefore, the optimal dosage to be administered can be readily determined by those skilled in the art and can be adjusted according to various factors, including the type of disease, the severity of the disease, the content of the active ingredient and other ingredients contained in the composition, the type of formulation, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, the excretion rate of the composition, the treatment period, and concurrently used drugs. The pharmaceutical composition of the present invention may be administered to a subject by various routes. For example, it can be administered intravenously, intraperitoneally, intramuscularly, intraarterially, orally, intracardiacly, intramedullary, intrathecally, transdermally, enterally, subcutaneously, sublingually, or topically, but is not limited thereto. The pharmaceutical composition of the present invention can be administered in an amount of 1 to 10,000 mg / kg / day, and can be administered once a day or divided into several doses.

[0202]

[0203] The health functional food composition of the present invention can be used as a health functional food, food additive, or dietary supplement. When the composition of the present invention is used as a food additive, it can be appropriately used according to conventional methods, such as by adding it as is or mixing it with other foods or food ingredients.

[0204] In addition, the mixing amount of the health functional food composition may be appropriately changed depending on the intended use (prevention, health, or therapeutic treatment). For example, when manufacturing food or beverages, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw material. However, when consumed for long-term purposes for health and hygiene or health control, the composition may be added in an amount below the above range, and since there are no safety issues, the active ingredient may be used in an amount exceeding the above range.

[0205] There is no particular limitation on the type of the above food, but examples of foods to which the composition of the present invention can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, etc., and include all health foods in the conventional sense.

[0206] When the health functional food composition of the present invention is manufactured into a beverage, it may contain various flavoring agents or additional ingredients such as natural carbohydrates, as in conventional beverages. The natural carbohydrates may include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; natural sweeteners such as dextrin and cyclodextrin; and synthetic sweeteners such as saccharin and aspartame. The natural carbohydrates are contained in an amount of 0.01 to 10 wt%, preferably 0.01 to 0.1 wt%, based on the total weight of the food composition of the present invention.

[0207] The health functional food composition of the present invention may include various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc., and may include fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks, but is not limited thereto. These components may be used independently or in combination. The proportion of the above additives is not particularly limited, but is preferably included within the range of 0.01 to 0.1 wt% with respect to the total weight of the food composition of the present invention.

[0208]

[0209] Hereinafter, the present invention will be described in more detail through examples.

[0210] These examples are intended solely to illustrate the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.

[0211]

[0212] Example 1: Preparation of nutmeg extract and isolation of compounds

[0213] 1-1: Preparation of nutmeg extract

[0214] Nutmeg (Myristica fragrans, nutmeg) was purchased from Kyung Hee Oriental Medicine. 5 kg of nutmeg, cut into appropriate sizes, and 24 L of 75% ethanol were mixed in an extraction vessel, cold-extracted, and the extract was filtered through a filter paper. The extraction process was repeated twice, and the solvent was then concentrated under reduced pressure and dried to obtain 205 g of the extract.

[0215]

[0216] 1-2: Isolation of compounds derived from nutmeg extract

[0217] In the present invention, a compound derived from the 75% ethanol extract of nutmeg prepared in <Example 1-1> was isolated.

[0218] The extract obtained in the above <Example 1-1> was sequentially partitioned into methylene chloride (MC) and EtOAc to obtain 100 g and 2 g of residue, respectively. The MC-soluble fraction (100 g) was fractionated on a silica gel column (hexane-EtOAc, 20:1 → 1:10) to obtain 35 fractions (1 to 35), and then the compounds in each fraction were separated using HPLC.

[0219]

[0220]

[0221] HPLC Analysis Conditions TimeAcetonitrile(0.1% formic acid)Water(0.1% formic acid)0.05.095.015.060.040.030.075.025.042.090.010.051.0100.00.055.05.095.0Column: Triart YMC C18 (Ø4.6x250 mm, 3 μm)Flow rate: 0.8 ㎖ / minInjection volume: 10 ㎕Detection wavelength: 280 nmRun time: 55 minColumn temperature: 30 ℃

[0222] Nutmeg extract-derived compound (1) No. Name Relative configuration Chemical formula 1 Myricone A or Myrifragranone B threo [Chemical formula 1] 2 Myricone B erythro [chemical formula 2] 3 Myricone C (Myricone C)threo [chemical formula 3] 4 Myricone D erythro [chemical formula 4] 5-Myricone E (Myricone E)threo [chemical formula 5] 6-Myricone F (Myricone F)threo [chemical formula 6] 7 Myricone G erythro [chemical formula 7] 8-Myrifragranone A (Myrifragranone A)threo [chemical formula 8]

[0223] Nutmeg extract-derived compound (2) No. Name Relative configuration Chemical formula 9a9b Myricone H - erythro form Myricone I - threo form erythrothreo [Chemical formula 9] 10 Myricone K erythro [chemical formula 10] 11 Myricone L-threo [chemical formula 11] 12 Myricone M (Myricone M) erythro [chemical formula 12] 13 Myricone N (Myricone N) erythro [chemical formula 13]

[0224] Nutmeg extract-derived compound (3) No. Name Chemical formula 14 Myricone O [Chemical formula 14] 15 Myricone P (chemical formula 15) 16 Myricone R [chemical formula 16]

[0225] Nutmeg extract-derived compound (4) No. Name Chemical formula 17 Myricone Q [Chemical formula 17] 18 Myricone T [chemical formula 18] 19 Myricone X [chemical formula 19] 20 Myricone Y (chemical formula 20)

[0226] Nutmeg extract-derived compound (5) No. Name Chemical formula 21 Myricone Z [Chemical formula 21] 22 Myricone W [chemical formula 22]

[0227] Nutmeg extract-derived compound (6) No. Name Chemical formula 23 Malabaricone B [Chemical formula 23] 24 malabaricone C [chemical formula 24] 25-promalabaricone B (chemical formula 25) giganteones A (chemical formula 26) 27β-sitosterol (β-sitosterol) [chemical formula 27] 283'-methoxylicarin B (3'-methoxylicarin B) [chemical formula 28] 29 Myristic acid [chemical formula 29] 30-trans-3,4,5-trimethoxycinnamic alcohol [chemical formula 30] 31 Myristicin [chemical formula 31] 32-trans-3,4-dimethoxyeinnamyl alcohol [chemical formula 32] 33 Anthriscinol [chemical formula 33] 34-methyleugenol [chemical formula 34] 35-trans-3,4-dimethoxycinnamic acid [chemical formula 35]

[0228] In the present invention, as shown in Tables 2 to 7 above, 35 compounds were separated, and among them, 18 compounds represented by Chemical Formulas 3 to 6 and Chemical Formulas 9 to 22 were confirmed to be novel compounds.

[0229] In addition, the HPLC analysis results for the compounds represented by Chemical Formulas 2 to 22 are as shown in Tables 8 to 17 below.

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242] Example 2: Anticancer activity of novel compounds derived from nutmeg extract

[0243] In order to confirm the anticancer activity of the novel compound isolated in the above <Example 1-2>, in the present invention, the novel compound was treated at a concentration of 10 μM to each of gastric cancer cell lines (AGS, 23132 / 87, SNU-719), colon cancer cell lines (SNU-81, SNU-C5, SW48), glioblastoma cell lines (SNU201, SNU466), hepatoma cell lines (HepG2), and pancreatic cancer cell lines (MiaPaCa-2), and then cell viability was measured.

[0244] AGS, SW48, HepG2, and MiaPaCa-2 were purchased from the American Type Culture Collection (ATCC, USA), the SNU cell line from the Korean Cell Line Bank (KCLB, Korea), and 23132 / 87 from the Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures GmbH (DSMZ, Germany). All cell lines were cultured in RPMI-1640 medium (HyClone, USA) supplemented with 10% FBS (Gibco, USA) and 1% penicillin-streptomycin (HyClone, USA) at 5% CO2 and 37°C.

[0245]

[0246] Cells were seeded in 96-well plates at 5 Х 10 3 After inoculation at a density of 10 cells / well for 24 hours, the compounds were treated at appropriate concentrations (10 μM) for 48 hours. After treatment, alamarBlue reagent was added at a ratio of 1 / 10 of the treatment volume and incubated in a cell incubator at 37°C for 4 hours (protected from direct light). Then, cell viability was determined by measuring the absorbance values ​​at 570 nm and 600 nm using a microplate reader. Cell viability (%) of cells treated at specific concentrations and the half-inhibitory concentration (IC) of each natural product were calculated. 50 ) were evaluated to evaluate the anticancer effects of the candidate substances. Doxorubicin and oxaliplatin were used as positive controls for gastric cancer and colon cancer, respectively.

[0247]

[0248] All experiments were performed in triplicate, and the results are presented as the mean ± standard deviation (SD). Statistical analyses were performed using R software (version 4.2.2) (R Core Team). Differences between groups were assessed using a student's t-test or one-way ANOVA followed by a post-hoc Tukey HSD test. A p value < 0.05 was considered statistically significant.

[0249]

[0250] Survival rate (%) of cancer cell lines treated with a novel compound derived from nutmeg (10 μM) No. Comp. Gastric cancer Colorectal cancer Glioblastoma Liver cancer Pancreatic cancer AGS23132 / 87 SNU-719 SNU-81 SNU-C5 SW48 SNU201 SNU466 HepG2 MiaPaCa-21 Myrifragranone B1. 134.713.95 94.798.73 1.75 2.07 1.72.07 3.15 2 Myricone B2. 45 7.44 4.55 103.32 22.127.98 1.43 2.29 1.47 3.67 3 Myricone C0. 16 1.77 4.30 47.08 2.11 0.01 1.17 1.911.60 2.53 4 Myricone D10.158.4110.19115.6012.412.612.441.741.843.545Myricone E42.0952.1045.03125.8037.5810.170.610.582.341.646Myricone F0.511.461.3655.773.530.821.41.961.322.168Myrifragranone A2.193.922.2710.024.412.04108.1293.3995.4174.579a,9bMyricone H, I102.5095.11102.75105.3473.1286.3270.9336.0831.1945.9510Myricone K4.142.771.8516.064.942.673.280.68.704.3011Myricone L20.3219.0412.5392.5313.375.5732.750.5225.2722.0412Myricone M7.890.670.532.271.982.520.750.641.233.4614Myricone O81.4178.2171.59103.6618.7631.12100.6156.1167.0587.7815Myricone P8.491.452.146.632.623.9331.390.993.184.3217Myricone Q80.5285.0254.85113.0858.4560.21105.0745.59108.1359.9018Myricone T91.9087.08104.28102.2078.0383.45104.2586.1989.0474.7819Myricone Myricone Z6.862.404.6033.616.533.5167.760.956.057.58.

[0251]

[0252] As a result, as shown in Table 18 and Figure 8, it was confirmed that most of the novel compounds isolated from nutmeg exhibited anticancer activity. In particular, it was confirmed that five compounds (3, 4, 6, 9, and 11) exhibited excellent cytotoxic effects in gastric cancer cell lines and colon cancer cell lines.

[0253] In general, most compounds were effective starting at 10 μM treatment, but SNU81 cells appeared to be more resistant to the compounds. However, the response of these compounds to SNU81 cells was superior to that of the positive control, oxaliplatin, and the response of the compounds to SNUC5 cells was similar to that of oxaliplatin (Fig. 9).

[0254]

[0255] In addition, the IC of the compound against six cancer cell lines (AGS, 23132 / 87, SNU-719), colon cancer cell lines (SNU-81, SNU-C5, SW48) 50 To measure the values, each cell was treated with a novel compound at various concentrations (2.5 to 40 μM), and then the IC 50 The value was measured.

[0256]

[0257] IC of the compound against six cancer cell lines 50Value (μM) CompoundGastric cancerColorectal cancerAGSSNU71923132 / 87SNU81SNUC5SW48Myricone F (Formula 6)3.352.582.3910.304.043.09Myricone HI mixture (Formula 9a-9b)8.888.7810.7839.807.884.73Myricone D (Formula 4)7.275.014.1416.875.575.73Myricone C (Formula 3)3.622.932.079.842.542.55Myricone B (Formula 2)4.594.704.2516.586.856.18Myripragranone B (Formula 1) 4.07 3.99 4.09 14.64 6.32 4.30 Malavaricone C (Formula 24) 5.79 7.30 6.37 12.20 9.76 6.79 Malavaricone B (Formula 23) 6.15 5.93 4.79 9.31 4.88 4.93 Gigantenes A (Formula 26) 1.71 4.60 4.08 8.94 3.72 2.77 Positive control 1.50 2.57 0.45 41.49 12.55 2.14

[0258] IC of the compound 50 The values ​​are presented in Table 19. Among the new compounds, Myricone C and Myricone G showed the most potent anticancer activity, with the lowest IC 50 As mentioned above, the IC of myricone C and myricone G for SNU81 and SNUC5 cells 50 The values ​​were 9.84 μM and 2.54 μM, 10.30 μM and 4.04 μM, respectively, with IC of oxaliplatin 50 The IC values ​​were significantly lower than those of 41.49 μM and 12.55 μM. In contrast, the Myricone EF mixture showed the weakest effect and was lower than the most potent candidate in each cell line. 50 The values ​​were at least 1.5 times and up to 5 times higher. Among the existing compounds, gigantenes A showed overall superior activity to mirifragranone B and malavaricone C in most cell lines.

[0259] Through this analysis, a new compound, Myricone C, and an existing compound, Malavaricon C, were selected and in-depth experiments were conducted on representative cell lines of each cancer type, 23132 / 87 (gastric cancer) and SW48 (colon cancer).

[0260]

[0261] Example 3: Confirmation of the effect of the compound Myricone C on the cancer cell cycle

[0262] 3-1: Cell cycle confirmation according to treatment with Myricon C

[0263] One of the hallmarks of cancer is its ability to evade cell cycle regulation and divide rapidly. Therefore, in the present invention, the cell cycle of two cancer cell lines was analyzed in the presence or absence of either myricon C or malavaricon C.

[0264] Cell cycle distribution was analyzed by DNA staining using FxCycle PI / RNase Staining Solution (Invitrogen, USA). 23132 / 87 and SW48 cell lines were cultured at 5 х 10 5 and 7 Х 10 5 After seeding in 6-well plates at a density of 10 cells / well, the cells were cultured for 24 h and starved overnight in serum-free medium. Next, the cells were treated with two concentrations of myricon C or malavaricon C, 5 and 10 μM, or with DMSO as a control, for 48 h. The cells were then harvested, fixed with 70% ethanol, and stained with PI / RNase solution. Flow cytometry (BD FACSVerse Cell Analyzer and FlowJo software; BD Biosciences, Franklin Lakes, NJ, USA) was applied to analyze the samples based on 10,000 events.

[0265]

[0266] As a result, as shown in Figures 10 and 11, overall, the compound at 10 μM significantly interfered with the cell cycle of both tested cell lines, unlike the case of 5 μM.

[0267] Furthermore, a comparison of the differences between samples treated with each compound and those treated only with DMSO as a control revealed that in 23132 / 87 cells, Myricon C (10 μM) arrested the cell cycle in the G1 phase, increasing the rate by approximately 10% compared to DMSO. Inevitably, the rates of the remaining phases decreased, particularly the G2 / M phase, which decreased by approximately 4%.

[0268] In contrast, malavaricone C had no noticeable effect on these gastric cancer cells at either concentration. In SW48 cells, treatment with 10 μM myricon C slightly decreased the proportions of G1, S, and G2 / M phases, but only the G2 / M phase was statistically significantly reduced. Meanwhile, malavaricone C increased the proportion of S phase by approximately 2% and decreased the proportions of G1 and G2 / M phases by approximately 8% and 3%, respectively. Notably, 10 μM myricone C and malavaricone C increased the sub-G1 proportion by 7% and 11%, respectively, compared to the control, DMSO.

[0269]

[0270] 3-2: Confirmation of cell cycle distribution according to the concentration of Miricon C treatment

[0271] To determine the cell cycle distribution according to the concentration of myricone C treatment, the 23132 / 87 and SW48 cell lines were treated with 5 μM and 10 μM of myricone C and malavaricone C compounds, and the cell cycle distributions were analyzed. Student's t-test was performed for statistical analysis between the two concentrations of the same compound.

[0272]

[0273] Cell cycle distribution when treated with compounds Myricone C and Malavaricone C. Cell line Compound Cycle 5 μM 10 μM %SD %SD 23 132 / 87 Malavaricone C Sub G1 1 3.07 0.55 15.08 3.36 G16 0.87 2.67 55.47 3.03 S18 100.72 19.07 0.99 G2 / M7 78 0.179 63 0.08 Myricone C Sub G19 15 1.31 10.45 2.08 G16 3.00 1.05 68.93 1.96 S21 23 0.94 14.40 1.99 G2 / M6 79 0.69 6.19 0.47 SW 48 Malavaricone C Sub G111.630.3820.171.47G153.101.2745.271.19S23.530.3224.830.33G2 / M10.210.248.300.49Miricon CSub G19.651.0224.170.98G156.631.4450.932.17S23.000.1519.300.98G2 / M8.910.246.130.47

[0274] As a result, as shown in Table 20 above, when the compound was treated at a concentration of 10 μM, it was found to be more suitable for treating the SW48 cell line. In particular, when the concentration of myricon C was increased from 5 μM to 10 μM, the sub-G1 phase ratio significantly increased from 9.65% ± 1.02% to 24.17% ± 0.98%, and the G2 phase decreased from 8.91% ± 0.24% to 6.13% ± 0.47%. Similarly, malavaricon C affected all phases of the cell cycle at 10 μM more than at 5 μM. In other words, it was confirmed that myricon C significantly affected the cell cycle of the colon cancer SW48 cell line at 10 μM.

[0275] Malavaricone C increased the proportion of S and sub-G1 phases and suppressed the remainder, whereas myricone C decreased the G2 / M phase and shifted it to the sub-G1 phase. In the case of 23132 / 87 gastric cancer, the two selected compounds showed an upward trend in the G1 phase, but a reversed trend was observed in the S and G2 / M phases.

[0276]

[0277] Example 4: Induction of apoptosis in cancer cells by the compound Myricone C

[0278] 4-1: Measurement of cell death

[0279] In the present invention, to confirm whether apoptosis of cancer cells is induced by the compound Myricon C, apoptosis was measured in cells treated with the compound using Annexin V-FITC / PI staining.

[0280] 23132 / 87 and SW48 cells were each 5 Х 10 5 and 7 Х 10 5 Cells were seeded in 6-well plates at a density of 10 cells / well and cultured for 24 h. Next, the cells were treated with two concentrations of myricon C or malavaricon C, or DMSO as a control, for 20 h. After treatment, the cells were collected and stained using the Annexin V-FITC Early Apoptosis Detection Kit (6592, Cell Signaling Technology, USA). Flow cytometry (BD FACSVerse Cell Analyzer and FlowJo software, BD Biosciences, USA) was applied to analyze the samples based on 10,000 events.

[0281]

[0282] As a result, as shown in Fig. 12, the compound treatment showed signs of inducing apoptosis in gastric and colon cancer cell lines, which was manifested by increasing the Annexin V-FITC+ / PI+ (Q2, late apoptosis and cell death) and Annexin V-FITC+ / PI- (Q3, early apoptosis) populations and decreasing the healthy population, Annexin V-FITC- / PI- (Q4).

[0283]

[0284] 4-2: Comparison of apoptosis-related cell populations (Q2 and Q3) with the control group

[0285] As shown in Fig. 13, when comparing the Annexin V-FITC positive cell populations Q2 and Q3 in the treated samples with the control group DMSO, malavaricone C statistically significantly increased the Q2 population at 5 μM and the Q3 population at 10 μM in the 23132 / 87 cell line. Similarly, myricon C significantly increased the Q3 ratio at 5 μM and increased the Q2 and Q3 ratios by about 2% and 6% at 10 μM, respectively. No significant difference was found in the SW48 cells at 5 μM treatment. On the other hand, the Annexin V-FITC+ / PI+ signal was clearly increased in the 10 μM treatment with a higher concentration of the compound, especially in the case of myricon C, Q2 increased by more than 8% compared to the control group, to 22.43% ± 0.30%.

[0286]

[0287] 4-3: Analysis of intercellular differences

[0288] To determine the cell cycle distribution according to the concentration of myricone C treatment, the 23132 / 87 and SW48 cell lines were treated with 5 μM and 10 μM of myricone C and malavaricone C compounds, and the cell cycle distributions were analyzed. Student's t-test was performed for statistical analysis between the two concentrations of the same compound.

[0289]

[0290] Distribution of cell death (%) when treated with Myricone C and Malavaricone C compounds. Cell line. Compound Area. 5 μM. 10 μM. %SD. %SD. 23. 132 / 87. Malavaricone C. Q. 12. 35. 0. 37. 4. 33. 0. 10. Q. 29. 5. 4. 0. 12. 13. 23. 1. 40. Q. 35. 36. 0. 12. 6. 45. 0. 30. Q. 48. 2. 77. 0. 35. 76. 00. 1. 20. Myricone C. Q. 13. 30. 0. 24. 3. 59. 0. 17. Q. 29. 35. 0. 40. 10. 47. 0. 42. Q. 35. 76. 0. 35. 10. 97. 0. 12. Q. 48. 1. 5. 7. 0. 28. 75. 00. 0.20SW48MalabariconeCQ16.511.818.121.14Q214.500.5915.700.25Q318.101.3017.530.65Q460.900.5558.630.37MiliconeCQ17.410.834.970.52Q213.800.6522.430.30Q313.730.9218.771.07Q465.100.4953.870.77

[0291] As shown in Table 21 above, when the compound treatment concentration was doubled, Myricon C increased the Q3 population of 23132 / 87 cells from 5.76% ± 0.35% to 10.97% ± 0.12%, and the Q2 and Q3 ratios of SW48 cells from 13.80% ± 0.65% to 22.43% ± 0.30% and from 13.73% ± 0.92% to 18.77% ± 1.07%, respectively. This more than 8% increase in the Q2 population of SW48 cells was the highest among all dose-based comparisons in the experiment, indicating the strong effect of Myricon C. Notably, the changes in cell distribution due to DMSO were not statistically significant even after doubling the concentration in both cell lines.

[0292]

[0293] 4-4: Comparison of apoptotic cell populations (Q2 and Q3) and non-apoptotic cell populations (Q4)

[0294] To more clearly see the apoptotic cell populations (Q2 and Q3) and the non-apoptotic cell population (Q4), side-by-side comparative analysis was performed, as shown in Fig. 14, and the healthy population was significantly reduced in all treatments compared to the control in both cell lines. In particular, 10 μM myricon C caused the greatest reduction in Q4 distribution by 8.27% and 9.43% in 23132 / 87 and SW48 cells, respectively.

[0295] Additionally, the ratio of Q4 decreased steadily with increasing dose, and in particular, it decreased by about 11.23% when the dose was changed from 5 μM to 10 μM in SW48 cells treated with Myricon C.

[0296] Apoptotic populations include early apoptotic cells (Q3), late apoptotic cells, and dead cells (Q2). Q2 and Q3 significantly increased with increasing dose in 23132 / 87 cells treated with the compound myricone C. In SW48 cells, malavaricone C tended to increase the apoptotic and dead cell populations, but this was not statistically significant. However, 10 μM myricone C increased these populations nearly 10% more effectively than DMSO.

[0297] That is, the results of the cell death analysis using Annexin V / FITC-PI double staining confirmed that the myricon C compound could induce cell death in both gastric cancer and colon cancer cell lines, and that 10 μM was the preferred concentration.

[0298]

[0299] Example 5: Effect of Myricon C compound on caspase-3 / 7 activity in cancer cells

[0300] Apoptosis can be activated and progressed through either the intrinsic or extrinsic pathways, but in most cases, caspase-3, the executioner caspase, is involved. Therefore, we assessed the real-time activity of caspase-3 and -7 in cells treated with the compounds myricone C and malavaricone C using a caspase activity assay. Because this enzymatic activity is transient, it was analyzed at two time points: 6 and 12 hours.

[0301] Specifically, the Caspase-3 / 7 activity assay was performed by slightly modifying the manufacturer's protocol (Promega, USA). Briefly, cells were cultured at 5 х 10 3 Cells were seeded in 96-well plates at a density of 10 cells / well and cultured for 24 h. The cells were then treated with compounds at appropriate concentrations for 6 or 12 h. After treatment, the same volume of Caspase-Glo 3 / 7 reagent was added as the treated sample. The plates were then shaken and incubated at room temperature for 2 h. Enzyme activity was determined by measuring relative light units (RLU) using a Varioskan LUX Multimode Microplate Reader (Thermo Fisher Scientific, USA).

[0302]

[0303] Caspase-3 / 7 activity when treated with compounds Myricone C and Malavaricone C23132 / 87SW48MalCMyrCMalCMyrC5 μM10 μM5 μM10 μM5 μM10 μM5 μM10 μM6 h0.430.330.581.810.800.681.101.8912 h0.330.341.741.201.200.572.372.02

[0304]

[0305] As shown in Figure 15 and Table 22, in the case of gastric cancer cells, malavaricone C showed significantly lower relative luminescence units (RLU) than the DMSO control at all concentrations, with 5 μM myricon C showing the highest peak after 12 hours, and 10 μM showing the highest value only after 6 hours, which were 1.74-fold and 1.81-fold higher than DMSO, respectively.

[0306] In colon cancer cells, low concentrations of malavaricone C exhibited signals similar to DMSO at both time points, with 10 μM exhibiting significantly lower signals after 6 hours and similar signals to the control after 12 hours. Myricon C exhibited a similar trend to gastric cancer cells, with the signal increasing significantly over time from 6 to 12 hours at the same concentration. However, the low concentration exhibited a peak only after 12 hours, while the high concentration exhibited a peak after 6 hours. These values ​​were 1.89- and 2.37-fold higher than those of DMSO, respectively.

[0307] Based on the above evidence and the fact that RLU values ​​are proportional to caspase-3 / 7 activity, it can be concluded that myricon C (5 μM - 10 μM) significantly increased caspase activity in 23132 / 87 and SW48 cells between 6 and 12 h, leading to apoptosis. In contrast, malavaricon C did not affect this enzymatic reaction under the tested conditions.

[0308]

[0309] Example 6: Confirmation of anticancer effects of administration of the compound Myricone C in a xenograft mouse model.

[0310] Female BALB / c / nu / nu mice (5 weeks old) were used in the in vivo model.

[0311] As shown in the schematic diagram of Fig. 16a, mice were subcutaneously injected with 23132 / 87 and SW48 cells at a concentration of 5 Х10 6 Dog / mouse and 3 Х106 The mice were injected at a density of 10 mg / kg / day. When the tumors reached a minimum width of 3 mm, the mice were divided into three groups and injected intraperitoneally with myricone C (10 mg / kg), malavaricone C (10 mg / kg), and control DMSO (2% in saline solution) on different days. Tumor volume and body weight were measured twice a week. On day 27, the mice were sacrificed, and major organs (liver, spleen, kidney) and tumor tissues were collected and stored for further analysis. Tumor volume was calculated using the following formula: Volume (mm 3 ) = (length) Х(width) 2 Х1 / 2.

[0312]

[0313] Monitoring of tumor volume and body weight throughout the experiment revealed that tumor volume gradually increased in all groups. However, in the case of gastric cancer, tumor volume was confirmed to be the smallest from day 13 of Myricon C administration, and tumor growth was also inhibited in colon cancer compared to the control group (Fig. 16b). Furthermore, body weight and the weights of major organs, including the liver, spleen, and kidney, remained stable throughout the experimental period (Fig. 16c).

[0314]

[0315] The novel compounds isolated in the present invention were confirmed to exhibit cytotoxic effects against various cancer cells, and five compounds (3, 4, 6, 9, and 11) were confirmed to exhibit high cytotoxic effects in gastric and colon cancers. In particular, the compound represented by chemical formula 3 was confirmed to not only effectively induce apoptosis through cell cycle regulation of cancer cells but also effectively inhibit tumor growth in a xenograft mouse model, and thus can be usefully utilized as an anticancer composition.

Claims

1. A compound represented by the following chemical formula A, a pharmaceutically acceptable salt thereof, or an optical isomer thereof: [Chemical Formula A] (In the above chemical formula A, X is or , and at this time, n is an integer from 1 to 20, At least one of R1 to R5 , and at this time, Y is O or -(CH)m- (wherein, m is 0 to 5), and R1' to R6' are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic, The remainder of R1 to R5 are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic, R 6, R8 and R 10 are each independently hydrogen or hydroxy, R7 and R9 are each independently hydrogen, R 1' Inland R 6' are each independently hydrogen, hydroxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-10 allyl, or substituted or unsubstituted C3-10 heterocyclic.

2. In paragraph 1, The compound represented by the above chemical formula A is a compound represented by the following chemical formula 3; A compound represented by the following chemical formula 4; A compound represented by the following chemical formula 6; A compound represented by the following chemical formula 9; A compound represented by the following chemical formula 10; A compound represented by the following chemical formula 11; A compound represented by the following chemical formula 12; or A compound characterized by being a compound represented by the following chemical formula 13: [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 6] [Chemical Formula 9] [Chemical Formula 10] [Chemical Formula 11] [Chemical Formula 12] [Chemical Formula 13] .

3. In paragraph 1, A compound characterized in that the compound represented by the above chemical formula A is a compound represented by the following chemical formula 3: [Chemical Formula 3] .

4. A compound represented by the following chemical formula 14, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; A compound represented by the following chemical formula 15, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or A compound represented by the following chemical formula 16, a pharmaceutically acceptable salt thereof, or an optical isomer thereof: [Chemical Formula 14] [Chemical Formula 15] [Chemical Formula 16] .

5. A compound represented by the following chemical formula 17, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; A compound represented by the following chemical formula 18, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; A compound represented by the following chemical formula 19, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or A compound represented by the following chemical formula 20, a pharmaceutically acceptable salt thereof, or an optical isomer thereof: [Chemical Formula 17] [Chemical Formula 18] [Chemical Formula 19] [Chemical Formula 20] .

6. A compound represented by the following chemical formula 21, a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or A compound represented by the following chemical formula 22, a pharmaceutically acceptable salt thereof, or an optical isomer thereof: [Chemical Formula 21] [Chemical Formula 22] .

7. A pharmaceutical composition for preventing or treating cancer, comprising a compound of any one of claims 1 to 6 as an active ingredient.

8. In paragraph 7, A pharmaceutical composition for preventing or treating cancer, characterized in that the cancer is pancreatic cancer, liver cancer, lung cancer, stomach cancer, colon cancer, prostate cancer, kidney cancer, breast cancer or ovarian cancer.

9. A health functional food composition for preventing or improving cancer, comprising a compound of any one of claims 1 to 6 as an active ingredient.

10. In paragraph 9, A health functional food composition for preventing or improving cancer, characterized in that the cancer is pancreatic cancer, liver cancer, lung cancer, stomach cancer, colon cancer, prostate cancer, kidney cancer, breast cancer or ovarian cancer.

Images