KR101233451B1 - Diarylheptanoid derivatives and a composition for inducing heat shock protein comprising the same - Google Patents

Abstract

The present invention relates to a diarylheptanoid derivative and a composition for inducing a heat shock protein comprising the same, and more particularly, a novel diarylheptanoid derivative derived from a cephalum having an induction activity against a heat shock protein and a heat including the same. It relates to a composition for inducing shock protein.

Description

Diarylheptanoid derivatives and a composition for inducing heat shock protein comprising the same}

The present invention relates to a diarylheptanoid derivative and a composition for inducing a heat shock protein comprising the same, and more particularly, a novel diarylheptanoid derivative derived from a cephalum having an induction activity against a heat shock protein and a heat including the same. It relates to a composition for inducing shock protein.

Heat shock protein (HSP) is a protein expressed when cells are exposed to high temperature heat, also called stress protein. As well as heat shock, almost all types of stress induce the expression of HSP, HSP expression is a common phenomenon seen in cells exposed to stress. Historically, Ritossa first reported it in 1962, and in 1974 it became its present name. Many HSPs act as molecular chaperones in cells to prevent aggregation of proteins and to repair damaged proteins. Molecular chaperones are a collection of various proteins present in cells that prevent the aggregation of other proteins, dissolve aggregates, fold protein structures, or modify the structure of modified proteins ( refolding, degradation of damaged proteins or, in the case of severe damage, sequestration of damaged proteins into larger aggregates. Eventually, cells regulate the entire process of protein synthesis, modification, transport and degradation through the activity of molecular chaperones.

When an individual is exposed to physical or psychological stress, he or she experiences a gradual physiological change. Different types of stress can cause changes in the cellular environment that can damage proteins and DNA, and the corresponding stress response can take many forms, from the cellular level to changes in the endocrine system, nervous system and behavior. Cells damaged by stress can paradoxically show two different responses. The first is apoptosis. This is a way of cell death, which removes damaged cells to prevent inflammation. The second is the stress response. This helps cells survive by preventing their damage and promoting recovery. The research on the protective function of HSPs acting as molecular chaperones focused mainly on the repair of damaged proteins, but recently, the direction of HSP's apoptosis has been expanded.

Currently, research on HSP is being actively conducted in the field of oncology and cardiovascular diseases, and clinical trials using HSP inhibitors are underway in cancer patients. In addition, the secretion and regulation of HSP in neurons, the development and aging of the nervous system and its effects on the neuroendocrine system, the relationship between neuropsychiatric disorders and HSP, and the therapeutic use of HSP in neuropsychiatric areas Choi, Jun-ho et al., Biopsychiatry, 2007, 14 (4), 221-231).

Chodugu is also called dugu, duguja, rugu, excess, chogu, choguin, and ginger. Mature seeds of the perennial herb, Alpinia katsumadai , belonging to the family Zingiberaceae .

Chodugu is cultivated in China's South Sea region, Vietnam, etc. It has unusual aroma, tastes spicy, bitter and warm.

The appearance of the head is spherical shape with seeds, 15 ~ 27 mm in diameter. The outer side is grayish brown, divided into 3 parts by the gray-white diaphragm in the middle, and the seeds are divided. Seeds are smooth and do not fall easily. They are oval polyhedrons, 3 to 5 mm long, about 3 mm in diameter, covered with light brown membranes, and hard.

Caudal hemispheres improve the function of the nasal passages and at the same time remove moisture, warming the middle pelvis (from the diaphragm to the area above the navel) and the vomiting to prevent vomiting. The directionality is lowered down, the abdomen is full and the abdomen does not disappear or the abdomen is cold and the hiccups, vomiting, or anorexia caused by anorexia, diarrhea, diarrhea, diarrhea, and soaking It is applied to heartburn and nausea caused by the accumulation of pathological substances). Pharmacological action of chodugu has been reported as fungi, intestinal excitement, intestinal repression.

Under these backgrounds, the present inventors completed the present invention by identifying and identifying new arylheptanoid derivatives from the extracts of vulgaris and performing heat shock protein inducing activity experiments on them.

It is an object of the present invention to provide novel diarylheptanoid derivatives having heat shock protein inducing activity derived from cephalospheres.

Another object of the present invention to provide a pharmaceutical composition for the prevention and treatment of heat shock protein-induced activity-related diseases comprising the diarylheptanoid derivative.

Another object of the present invention to provide a health functional food for the prevention and improvement of heat shock protein-induced activity-related diseases comprising the diarylheptanoid derivative.

In order to solve the above problems, the present invention provides a diarylheptanoid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

In Formula 1,

R ₁ is H or OH,

R ₂ is OH,

R ₃ is O or OH,

R ₄ is H or OH,

는 이중결합 또는 단일결합이다.

Is a double bond or a single bond.

Preferably, in Chemical Formula 1,

R ₂ is an R or S array,

가 단일결합인 경우, R₃는 S 배열이다.

Is a single bond, R ₃ is an S configuration.

More preferably, the compound represented by Formula 1 is

( 1E , 5R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-1-hepten-3-one, or

It is (1 E, 3 S, 5 S) -1-phenyl-7- (4-hydroxyphenyl) -1-heptene-3,5-diol.

The present invention also provides a diarylheptanoid derivative represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

In Formula 2, R ₅ , R ₆ and R ₇ are each independently H or OH.

Preferably, in Chemical Formula 2,

Position 3 is the R or S array,

Position 7 is an R or S array.

More preferably, the compound represented by Formula 2 is a diarylheptanoid derivative or a pharmaceutically acceptable salt thereof selected from:

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1,7-bis (4-hydroxyphenyl) -2- Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,

( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 R ) -5-hydroxy-1,7-bis (4-hydroxyphenyl) -2- Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,

( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one,

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one, and

( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one.

The present invention also provides a diarylheptanoid derivative represented by the following formula (3) or a pharmaceutically acceptable salt thereof.

In Formula 3, R ₈ , R ₉ and R ₁₀ are each independently H or OH.

Preferably, the compound represented by formula 3 is 1- {2,4-dihydroxy-3- [2- (4-hydroxy-phenyl) -6-phenethyl-tetrahydro-pyran-4-yl ] -6-methoxy-phenyl} -3- (4-hydroxy-phenyl) -propenone or a pharmaceutically acceptable salt thereof.

The present invention also provides a diarylheptanoid derivative represented by the following formula (4) or a pharmaceutically acceptable salt thereof.

In Formula 4, R ₁₁ , R ₁₂ and R ₁₃ are each independently H or OH.

Preferably, the compound represented by Formula 4 is 1- [5-hydroxy-2- (4-hydroxy-phenyl) -4- (2-hydroxy-4-phenyl-butyl) -7-methoxy -Chroman-6-yl] -3- (4-hydroxy-phenyl) -propenone or a pharmaceutically acceptable salt thereof.

Diarylheptanoid derivatives of Formulas 1 to 4 of the present invention can be obtained by extractive purification from Alpinia katsumadai .

Specifically, the diarylheptanoid derivatives of Chemical Formulas 1 to 4 of the present invention are subjected to polar and nonpolar solvent fractions from methanol extracts of Alpinia katsumadai to obtain ethyl acetate fractions, and to perform column chromatography on the ethyl acetate fractions. Can be obtained by performing

Compounds of formulas (1) to (4) of the present invention may be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.

Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid may be used as the organic acid. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like can be used. It is not limited.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is preferable to produce sodium, potassium or calcium salt particularly, but not limited thereto. Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds of Formulas 1 to 4 include salts of acidic or basic groups which may be present in compounds of Formulas 1 to 4, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and the like. It can be prepared through.

In addition, the present invention provides a method for separating the diarylheptanoid derivative represented by Formula 1 to 4 comprising the following steps.

1) obtaining a methanol extract of Alpinia katsumadai ;

2) obtaining an ethyl acetate fraction from the methanol extract of the scalp; And

3) performing column chromatography on the ethyl acetate fraction of the scalp.

Step 1 is to obtain a methanol extract of Alpinia katsumadai .

As an embodiment of the present invention, the methanol extract of turmeric may be obtained by adding ultracereals to methanol, extracting three times at room temperature for 24 hours, and then concentrating under reduced pressure.

Step 2 is to obtain an ethyl acetate fraction from the methanol extract of the scalp.

In the present invention, ethyl acetate fractions of the scalp can be obtained through polar and nonpolar solvent fractions.

Specifically, in one embodiment of the present invention, distilled water is added to the methanol extract obtained above and suspended, and then dissolved by adding hexane, followed by separating only the components dissolved in the hexane layer to obtain a hexane fraction by vacuum drying, and the remaining aqueous layer. Ethyl acetate was added thereto to dissolve, and only the components dissolved in the ethyl acetate layer were separated and dried in vacuo to yield an ethyl acetate fraction, followed by the same procedure as above to obtain an n -butanol fraction and an aqueous layer.

Step 3 is a step of performing column chromatography on the ethyl acetate fraction of the pendulum.

Specifically, the ethyl acetate fractions obtained above are separated and purified by silica gel column chromatography, reverse phase column chromatography, Sephadex LH-20 column chromatography, and semi-preparative high performance liquid chromatography (HPLC). The diarylheptanoid derivative represented by 4 can be obtained.

In addition, the present invention is a arylheptanoid derivative represented by Formula 1 to 4 or a pharmaceutically acceptable salt thereof has a heat shock protein-inducing activity and has a cell coverage effect.

Sebo protection efficacy can be used as an anticancer adjuvant, preventive or therapeutic agent for ischemic disease, and cosmetics.

Accordingly, the present invention provides an anticancer adjuvant comprising a arylheptanoid derivative represented by Formula 1 to 4 or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a composition for preventing or treating ischemic disease, including a arylheptanoid derivative represented by Formula 1 to 4 or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a cosmetic composition for preventing skin aging or improving wrinkles, including a arylheptanoid derivative represented by Chemical Formulas 1 to 4 or a pharmaceutically acceptable salt thereof.

As an example, the induction activity of heat shock proteins HSP70, HSP27, and HSF1 was examined by Western blot analysis of novel compounds 1-12 isolated from ultranovae, and treated with HSP70, HSP27 compared to the untreated control. And it was confirmed that the inducing activity of HSF1 is significantly induced.

The compounds of the present invention as a compound isolated from the pendulum, a drug that has been used as a herbal medicine for a long time, it was confirmed that there is no toxicity problem through MTT analysis.

Pharmaceutical compositions comprising a compound of Formulas 1-4 according to the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods. Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The compositions according to the invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, external preparations, suppositories or sterile injectable solutions according to conventional methods.

Specifically, when formulated, it may be formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like that are commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, or the like. Can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. As the base of the suppository, utopsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The preferred dosage of the compound according to the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compounds of the present invention can be administered in one to several times, usually in an amount of 1 to 50 mg, preferably 5 to 50 mg per kg of body weight per day.

Pharmaceutical dosage forms of the compounds according to the invention can also be used in the form of their pharmaceutically acceptable salts, and can also be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

The components included in the cosmetic composition of the present invention include components conventionally used in cosmetic compositions in addition to the compounds of the formulas (1) to (4) as active ingredients, and include, for example, conventional antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings. Phosphorus adjuvants and carriers. In addition, the cosmetic composition may further include a skin absorption promoting substance to improve its effect.

The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used as a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, a powder, a soap, , Oil, powdered foundation, emulsion foundation, wax foundation and spray, and the like. Specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane, < / RTI > butane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.

Diarylheptanoid derivatives of the formulas (1) to (4) or pharmaceutically acceptable salts thereof according to the present invention exhibit an effect of preventing, treating and ameliorating diseases related to heat shock proteins by inducing inducing activity of heat shock proteins.

Figure 1 shows the ¹ H-NMR data of the compounds 1 to 12.
2 shows ¹³ C-NMR data of Compounds 1 to 12.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for describing the present invention more specifically, and the scope of the present invention is not limited by these examples.

Example  One: Headlights ( Alpinia katsumadai A) methanol extract manufacturing

5.4 kg of Vietnamese soybean paste purchased from Gyeongdong market was added to 9 L of 100% methanol, extracted three times at room temperature for 24 hours, and concentrated under reduced pressure to obtain 788 g of methanol extract.

Example  2: Headlights  Polar and nonpolar solvents Fraction  Produce

4 L of distilled water was added to 788 g of the methanol extract obtained in Example 1, suspended, 4 L of hexane was added thereto, dissolved, and only the components dissolved in the hexane layer were separated and dried in vacuo to yield 75 g of a hexane fraction. 4 L of ethyl acetate was added to the remaining aqueous layer to dissolve, and only the components dissolved in the ethyl acetate layer were separated and dried in vacuo. This process was repeated six times to obtain 320 g of ethyl acetate fraction. The same procedure as described above gave 200 g of n -butanol fraction and 80 g of aqueous layer.

Example  3: Single Material Separation from Ethyl Acetate Fraction

150 g of the ethyl acetate fraction obtained in Example 2 was subjected to silica gel column chromatography (230-400 mesh, Merck, Germany) using a methylene chloride: methanol mixed solvent concentration gradient (95: 5 → 0: 100) to obtain 16 fractions. Divided by (F01-F16).

6.0 g of the eleventh fraction from the first column was subjected to reversed phase chromatography (YMC gel ODS-A, 12 nm, S-150 μm) with acetonitrile: water mixture (5: 5). After obtaining the fraction (F11.01-F11.17), 130 mg of the third fraction (F11.13) was subjected to Sephadex LH-20 column (Amersham Pharmacia Biotech) with 100% methanol to obtain Compound 2 (56.0 mg). )

In addition, 80 mg of subfraction F11.06 was subjected to silica gel column chromatography using a hexane: ethyl acetate mixed solvent concentration gradient (9: 1 → 7: 3) to obtain compound 1 (43.0 mg). Subfraction F11.10 (200 mg) and F11.13 (110 mg) were each semi-preparative HPLC (water containing methanol: 0.1% formic acid as eluent at a ratio of 82:18, flow rate 2 ml / min, Detector UV 365 nm) was carried out to obtain an isomeric mixture of compounds 8 to 10 (32.0 mg) and an isomer mixture of compounds 3 to 4 (7.8 mg), respectively.

In addition, 520 mg of subfraction F11.15 was divided into 15 fractions (F11.15.01-F11.15.15) by silica gel column chromatography using a hexane: ethyl acetate mixed solvent concentration gradient (90: 10 → 50: 50). 75 mg of fraction 10 (F11.15.10) was subjected to reverse phase column chromatography with methanol: water mixed solvent (85:15) to obtain an isomeric mixture of compounds 5 to 7. (31.0 mg) was isolated.

Each isomeric mixture is separated into each single material of compounds 3 to 10 by semi-preparative HPLC using chiral column ( n- hexane-IPA = 70:30, flow rate 1 ml / min, detector UV 365 nm). [Compound 3: 0.90 mg (0.000017% w / w), t _R 41.1 min; compound 4: 2.00 mg (0.000037% w / w), t _R 52.4 min; compound 5: 2.10 mg (0.000039% w / w), t _R 36.7 min; compound 6: 2.20 mg (0.000041% w / w), t _R 43.1 min; compound 7: 1.30 mg (0.000024% w / w), t _R 46.9 min; compound 8: 1.10 mg (0.000020% w / w), t _R 38.5 min; compound 9: 2.00 mg (0.000037% w / w), t _R 44.3 min; compound 10: 2.30 mg (0.000043% w / w), t _R 48.3 min].

Subsequently, fraction F11.15.03 (120 mg) was subjected to semi-preparative HPLC of methanol: 0.1% formic acid in water at a ratio of 87:13 to compound 11 (3.10 mg, 0.000056% w / w) and compound 12. (10.50 mg, 0.00019% w / w) was isolated.

Experimental Example  1: Confirmation of structure of isolated compound

The structures of the compounds 1 to 12 isolated in Example 3 were confirmed through NMR and spectroscopic characteristics.

The results are shown below.

Compound 1

( 1E , 5R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-1-hepten-3-one

Yellow amorphous powder

[a] ²⁵ _D -18.45 ( c 0.1, MeOH)

UV (MeOH) λ _max (log ε) 325 (4.7), 233 (4.6) nm

IR ν _max (KBr) 3312, 2929, 1717, 1541 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 319.1310 [M + Na] ⁺ (calcd for C ₁₉ H ₂₀ O ₃ Na, 319.1305)

Compound 2

(1 E, 3 S, 5 S) -1-phenyl-7- (4-hydroxyphenyl) -1-heptene-3,5-diol

Yellow amorphous powder

[a] ²⁵ _D +19.33 ( c 0.1, MeOH)

UV (MeOH) λ _max (log ε) 252 (4.4), 227 (4.2) nm

IR ν _max (KBr) 3302, 2926, 1554, 1455 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 321.1463 [M + Na] ⁺ (calcd for C ₁₉ H ₂₂ O ₃ Na, 321.1461)

Compound 3

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1,7-bis (4-hydroxyphenyl) -2- Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one

Yellow amorphous solid

[a] ²⁵ _D +9.43 ( c 0.21, MeOH)

UV (MeOH) λ _max (log ε) 348 (4.7), 288 (4.5), 217 (4.9) nm

IR ν _max (KBr) 3223, 1616, 1559, 1509, 1454 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 567.2389 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₇ , 567.2377)

Compound 4

( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 R ) -5-hydroxy-1,7-bis (4-hydroxyphenyl) -2- Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one

Yellow amorphous solid

[a] ²⁵ _D -10.07 ( c 0.1, MeOH)

UV (MeOH) λ _max (log ε) 347 (4.7), 288 (4.5), 216 (4.8) nm

IR ν _max (KBr) 3225, 1616, 1560, 1511, 1458 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 567.2380 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₇ , 567.2377)

Compound 5

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one

Yellow amorphous solid

[a] ²⁵ _D +6.98 ( c 0.05, MeOH)

UV (MeOH) λ _max (log ε) 350 (4.8), 289 (4.5), 217 (4.9) nm

IR ν _max (KBr) 3255, 1616, 1559, 1509, 1427 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 551.2440 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₆ , 551.2428)

Compound 6

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one

Yellow amorphous solid

[a] ²⁵ _D + 5.80 ° ( c 0.07, MeOH)

UV (MeOH) λ _max (log ε) 351 (4.8), 289 (4.5), 217 (4.9) nm

IR ν _max (KBr) 3255, 1616, 1561, 1507, 1427 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 551.2427 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₆ , 551.2428)

Compound 7

( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one

Yellow amorphous solid

[a] ²⁵ _D -7.96 ° ( c 0.11, MeOH)

UV (MeOH) λ _max (log ε) 352 (4.7), 287 (4.5), 217 (4.9) nm

IR ν _max (KBr) 3254, 1616, 1561, 1511, 1432 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 551.2434 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₆ , 551.2428)

Compound 8

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one

Yellow amorphous solid

[a] ²⁵ _D + 22.45 ° ( c 0.1, MeOH)

UV (MeOH) λ _max (log ε) 371 (4.8), 228 (4.7) nm

IR ν _max (KBr) 3260, 1615, 1558, 1510, 1437 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 567.2387 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₇ , 567.2377)

Compound 9

( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one

Yellow amorphous solid

[a] ²⁵ _D + 9.30 ° ( c 0.086, MeOH)

UV (MeOH) λ _max (log ε) 370 (4.8), 228 (4.7) nm

IR ν _max (KBr) 3258, 1615, 1558, 1512, 1438 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 567.2382 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₇ , 567.2377)

Compound 10

( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one

Yellow amorphous solid

[a] ²⁵ _D -14.93 ° ( c 0.067, MeOH)

UV (MeOH) λ _max (log ε) 371 (4.8), 227 (4.7) nm

IR ν _max (KBr) 3260, 1615, 1558, 1514, 1439 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 567.2370 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₇ , 567.2377)

Compound 11

1- {2,4-Dihydroxy-3- [2- (4-hydroxy-phenyl) -6-phenethyl-tetrahydro-pyran-4-yl] -6-methoxy-phenyl} -3- (4-hydroxy-phenyl) -propenone

Yellow amorphous solid

[a] ²⁵ _D + 12.33 ° ( c 0.146, MeOH)

UV (MeOH) λ _max (log ε) 371 (4.6), 227 (4.7) nm

IR ν _max (KBr) 3212, 1620, 1558, 1541, 1454 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 567.2377 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₇ , 567.2377)

Compound 12

1- [5-hydroxy-2- (4-hydroxy-phenyl) -4- (2-hydroxy-4-phenyl-butyl) -7-methoxy-chroman-6-yl] -3- ( 4-hydroxy-phenyl) -propenone

Yellow amorphous solid

[a] ²⁵ _D + 24.56 ° ( c 0.057, MeOH)

UV (MeOH) λ _max (log ε) 371 (4.9), 227 (4.7) nm

IR ν _max (KBr) 3244, 1618, 1559, 1542, 1513, 1473 cm ^-1

¹ H-NMR data (FIG. 1)

¹³ C-NMR data (FIG. 2)

HR-ESI-MS m / z 567.2373 [M + H] ⁺ (calcd for C ₃₅ H ₃₅ O ₇ , 567.2377)

¹ H-NMR and ¹³ C-NMR data of the compounds 1 to 12 are shown in FIGS. 1 to 2, respectively.

Experimental Example  2: investigation of heat shock protein induction activity and cytotoxicity of compounds 1 to 12

Western blot analysis was performed on the compounds 1 to 12 isolated in Example 3 to investigate the heat shock protein inducing activity of each compound.

Western blot analysis was performed as follows.

First, the protein in lysate was separated by SDS-PAGE, followed by electrophoresis on nitrocellulose membrane (GE Healthcare, UK), followed by blotting with the specified antibodies, followed by ECL detection system (Thermo scientific, USA). Visualized. As the antibodies, Anti-HSF1, Anti-Hsp27, Anti-Hsp70, and β-actin obtained from Santa Cruz Biotechnology were used.

Meanwhile, cytotoxicity was examined by performing MTT analysis on the compounds 1 to 12 isolated in Example 3.

MTT assay was performed by analyzing cytotoxicity on cells using 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT; Sigma).

The heat shock protein induction activity and cytotoxicity test results are shown in Table 1 below.

compound Fold increase ^b IC ₅₀ ( μ M) ^c HSP70 HSP27 HSF1 3 and 4 ^a 1.373 ± 0.012 1.403 ± 0.023 1.438 ± 0.032 47.4 5 - 7 ^a 1.313 ± 0.047 1.250 ± 0.011 1.090 ± 0.005 39.8 8 - 10 ^a 1.229 ± 0.009 1.270 ± 0.031 1.316 ± 0.053 45.7 11 ^a 1.350 ± 0.061 1.404 ± 0.072 1.338 ± 0.146 40.9 12 ^a 1.271 ± 0.026 1.242 ± 0.016 1.200 ± 0.030 42.1 NOTE: Protein expression is analyzed in the form of isomeric mixtures.
b: HSP70, HSP27 and HSF1 in NCI-H460 cells after normalization with β-actin signal
Quantitative result for immunoblotting. Data was collected from three samples 24 hours after treatment.
Expressed as the mean ± standard deviation of three independent experiments performed. Untreated control cells
Statistically significant compared to quantitative values of HSP70, HSP27 or HSF1 levels
Indicates difference (p <0.05)
c: IC ₅₀ value represents the concentration (μ M) is cell growth in NCI-H460 cells was inhibited 50%.

Claims (14)

Compounds or pharmaceutically acceptable salts thereof selected from:
( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1,7-bis (4-hydroxyphenyl) -2- Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,
( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 R ) -5-hydroxy-1,7-bis (4-hydroxyphenyl) -2- Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,
( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,
( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,
( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3-phenyl-2-propen-1-one,
( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one,
( 2E ) -1- {2,4-dihydroxy-3-[(1 R , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one, and
( 2E ) -1- {2,4-dihydroxy-3-[(1 S , 2 E , 5 S ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-2 -Hepten-1-yl] -6-methoxyphenyl} -3- (4-hydroxyphenyl) -2-propen-1-one.
1- {2,4-Dihydroxy-3- [2- (4-hydroxy-phenyl) -6-phenethyl-tetrahydro-pyran-4-yl] -6-methoxy-phenyl} -3- (4-hydroxy-phenyl) -propenone or a pharmaceutically acceptable salt thereof.
1- [5-hydroxy-2- (4-hydroxy-phenyl) -4- (2-hydroxy-4-phenyl-butyl) -7-methoxy-chroman-6-yl] -3- ( 4-hydroxy-phenyl) -propenone or a pharmaceutically acceptable salt thereof.
Obtaining a methanol extract of Alpinia katsumadai ;
Obtaining an ethyl acetate fraction from the methanol extract of the scalp; And
The method for separating the compound of any one of claims 1 to 3 comprising performing column chromatography on the ethyl acetate fraction of the head of the head.
An anticancer adjuvant comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
A composition for preventing or treating ischemic disease, comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
A cosmetic composition for preventing skin aging or improving wrinkles, comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
An anticancer adjuvant comprising the following compound or a pharmaceutically acceptable salt thereof:
( 1E , 5R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-1-hepten-3-one, or
(1 E, 3 S, 5 S) -1-phenyl-7- (4-hydroxyphenyl) -1-heptene-3,5-diol.
A composition for the prophylaxis or treatment of ischemic diseases comprising the following compounds or pharmaceutically acceptable salts thereof:
( 1E , 5R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-1-hepten-3-one, or
(1 E, 3 S, 5 S) -1-phenyl-7- (4-hydroxyphenyl) -1-heptene-3,5-diol.
A cosmetic composition for preventing skin aging or improving wrinkles, including the following compound or a pharmaceutically acceptable salt thereof:
( 1E , 5R ) -5-hydroxy-1- (4-hydroxyphenyl) -7-phenyl-1-hepten-3-one, or
(1 E, 3 S, 5 S) -1-phenyl-7- (4-hydroxyphenyl) -1-heptene-3,5-diol. delete delete delete delete

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