KR20140094962A - Composition Comprising Licochalcone A for prevention or treatment of Neurodegenarative Diseases - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating degenerative nervous diseases, wherein the pharmaceutical composition includes licochalcone A or a pharmaceutically acceptable salt of the same as an active ingredient. The composition according to the present invention has an excellent effect in controlling Hsp90 so as to induce the decomposition of Hsp90 matrix proteins which cause the degenerative nervous diseases. Accordingly, the composition can be usefully used as a medical product or a health supplementary food for treating the degenerative nervous diseases.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing or treating degenerative neurological diseases including ricocalcone A. BACKGROUND ART Composition Comprising Licochalcone A for prevention or treatment of Neurodegenerative Diseases

The present invention relates to a novel use of ricocalcone A for the prevention or treatment of neurodegenerative diseases.

As the life span of people increases and as they move into an aging society, degenerative neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Lou Gehrig's disease are increasing. Neurodegenerative diseases are caused by accumulation of beta-amyloid (Aβ) plaque (Aβ-plaque) in brain tissue and neurofibrillary tangles (NFT) appear in brain cells, Atrophy occurs and various symptoms related to it occur.

Parkinson's disease is caused by dopaminergic neurons of the substantia nigra (pars compacta) in the basal ganglia, which gradually undergo degenerative changes and cause dopamine, a neurotransmitter of the corpus striatum, (Fearney et al., 1991). It is a disease characterized by tremor, bradykinesia, and rigidity when 70-80% of the striatum is lost.

Alzheimer's disease (AD) is a complex neurodegenerative disease caused by a gradual decline in memory, behavior, language, and spatio-temporal abilities that eventually leads to death and is caused by a variety of factors. The patient's brain has neurofibrillary tangles consisting of paired helical filaments (PHFs) containing extracellular plaque beta-amyloid (Abeta) peptides and hyperphosphorylated forms of tau tangles) are accumulated.

Currently, studies to inhibit or inhibit the production of beta amyloid peptides and beta amyloid peptide-induced oxidative stress continue, but no new materials or drugs have been developed. To date, cholinesterase inhibitors (Aricept, Exelon, Reminyl, etc.) targeting cholinergic neurons and Memantine, a glutamate antagonist, have been approved by the FDA for the development of Alzheimer's disease All that is on the market now. However, as mentioned above, since these drugs only temporarily alleviate the symptoms, there is a desperate need for a drug development technology that can cure the disease sickly or inhibit the progress of the disease itself.

On the other hand, Hsp90 protein is one of the most abundant chaperones within eukaryotic cells and is responsible for stabilization and regulation of various proteins related to cell growth differentiation, survival. The substrate protein of Hsp90, called the client protein, contains over 50 cancer-causing proteins. When the Hsp90 activity is inhibited, the Hsp90 client proteins are degraded by the proteasome. Therefore, Hsp90 activity inhibitor can reduce various cancer-inducing proteins at the same time, and thus it is attracting much attention as an anticancer agent that can be applied to a wide variety of cancers. In particular, Hsp90 has been reported to be effective in treating cancer with resistance, since it simultaneously reduces various cancer-inducing proteins. In addition, it has been reported that Hsp90 protein can be used as a therapeutic agent for degenerative neurological diseases (Laura et al., 2009, 1 (2), 267- 283).

Licochalcone A (Licochalcone A) is a polyphenolic substance based on chalcone as a natural substance present in licorice, turnip, and the like. Although the physiological function of Ricocalcon A is not well known, it has long been used as a powerful antimalarial agent (Chen et al., Antimicrob Agents Chemother. 38 (7) pp.1470-1475, 1994) (Korean Patent Laid-Open No. 10-2010-0077553). However, the therapeutic effect of degenerative disease and the inhibitory effect of Hsp90 have not been disclosed.

Therefore, the present invention is a new candidate drug having an effect of preventing and treating degenerative neurological diseases, and is intended to provide a new use through the Hsp90 inhibitory effect of ricocalcone A.

In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising ricocalcone A as an active ingredient.

The present invention also provides a health food composition for preventing or ameliorating a neurodegenerative disease comprising ricocalcone A as an active ingredient.

The composition according to the present invention is excellent in the inhibitory effect of Hsp90 and induces degradation of Hsp90 substrate protein causing degenerative neurological disease through inhibition of Hsp90, thus being useful as a medicament for treating degenerative neurological diseases or a health supplement.

FIG. 1 is a graph showing an experiment result showing the effect of inhibiting proliferation of lung cancer cell line of Ricorcon A.
Figure 2 is a photograph of the Western blot showing the inhibitory effect of Hsp90-associated protein of Ricocalcon A.
3 is a photograph showing the Hsp90 binding site of ricocalcone A. Fig.

The present invention provides a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising ricocalcone A or a pharmaceutically acceptable salt thereof as an active ingredient.

Ricoh chalcone A is one of the major flavonoids of licorice (Glycyrrhizae radix) and its chemical structure was revealed in 1975 (Saitoh & Shibata. Tetrahedron Lett. 50, pp4461-4462, 1975). The structure of Ricocalcone A is shown in the following formula (1).

[Chemical Formula 1]

The ricocalcone A of the present invention represented by the above formula (1) can be used in the form of a pharmaceutically acceptable salt, and the acid addition salt formed by a pharmaceutically acceptable free acid is useful as a salt. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.

In addition, Ricocalcone A represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

The inventors of the present invention have studied the compounds derived from natural materials inhibiting Hsp90, and found that ricocalcolone A isolated from licorice extract binds to the N-terminal ATP pocket of Hsp90 protein and inhibits it, Cancer-induced or degenerative neurologic disease-related substrate protein is induced, and the present invention has been completed.

In one embodiment of the invention, the degenerative neurological disorder is selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Kacob disease, Huntington's disease, and Lou Gehrig's disease.

The pharmaceutical composition for the prevention or treatment of degenerative neurological diseases comprising ricocalcone A or a pharmaceutically acceptable salt thereof as an active ingredient according to the present invention can be used for the treatment of neurodegenerative diseases. Accordingly, the present invention relates to a pharmaceutical composition for the prevention or treatment of degenerative neurological diseases comprising ricocalcone A or a pharmaceutically acceptable salt thereof as an active ingredient, ricocalcone A or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic agent for degenerative neurological diseases And a method for treating a degenerative neurological disease comprising administering to a subject a therapeutically effective amount of ricocalcone A or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the pharmaceutical composition for the prevention or treatment of degenerative neurological diseases comprising ricocalcone A or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated with a suitable carrier, excipient , At least one additive selected from the group consisting of disintegrants, sweeteners, coating agents, swelling agents, lubricants, lubricants, flavors, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders and lubricants .

Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.

In another embodiment of the present invention, the pharmaceutical composition for the prevention or treatment of degenerative neurological diseases comprising the above-mentioned ricocalcone A or a pharmaceutically acceptable salt thereof as an active ingredient may be administered orally or parenterally in the form of granules, powders, Pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, drops, or liquid preparations.

According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.

The preferable dose of the above-mentioned ricocalcone A may vary depending on the condition and body weight of the subject, the kind and degree of the disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.

 In the present invention, the above reference may be a mammal including humans, but is not limited to these examples.

The present invention also provides a health food composition for preventing or ameliorating a neurodegenerative disease comprising ricocalcone A as an active ingredient.

In one embodiment of the present invention, the health food composition comprises 0.01 to 90 parts by weight, 0.1 to 90 parts by weight, 1 to 90 parts by weight, or 10 to 90 parts by weight of ricocarcon A per 100 parts by weight of the total food composition But are not limited thereto.

In another embodiment of the present invention, the health food composition may further comprise at least one additive selected from the group consisting of organic acids, phosphates, antioxidants, lactose casein, dextrin, glucose, sugar and sorbitol. The organic acid can be, but is not limited to, citric acid, fumaric acid, adipic acid, lactic acid or malic acid, and the phosphate can be sodium phosphate, potassium phosphate, acid pyrophosphate or polyphosphate (polymeric phosphate) But are not limited to, natural antioxidants such as polyphenols, catechins, alpha-tocopherol, rosemary extract, licorice extract, chitosan, tannic acid or phytic acid.

In still another embodiment of the present invention, the health food composition may contain flavorings such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and aging agents (such as cheese, chocolate, etc.) ), Pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. In addition, the food composition according to one embodiment of the present invention may contain flesh for the production of natural fruit juice, fruit juice drink and vegetable drink. The proportion of such an additive is generally, but not limited to, 0 to 20 parts by weight, 5 to 20 parts by weight, or 5 to 15 parts by weight per 100 parts by weight of the composition of the present invention.

According to one embodiment of the invention, the formulation of a health food composition may be in the form of solid, powder, granule, tablet, capsule, liquid or drink, although not limited thereto.

In addition, the food composition may be selected from the group consisting of confectionery, saccharides, ice cream products, dairy products, meat products, fish products, tofu or glue, edible oils, noodles, Dried products of ginseng products, kimchi pickles, dried fruits, fruits, vegetables, fruits or vegetables, cutting products, fruit juices, vegetable juices, mixed juice thereof, nuts, noodles, processed livestock products, processed marine products, , Fermented milk food, bean curd food, cereal food, fermented microorganism food, confectionery bakery, condiments, meat processing, acidic beverage, licorice, herb.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Example  1> Effect on cell proliferation Ricoh Calcorn  Review the effect of A

H1975 cells were cultured in RPMI 1640 medium containing L-glutamine, streptomycin (500 mg / ml), penicillin (100 units / ml) and 10% fetal calf serum (FBS). Cells were cultured at 37 ° C under 5% CO ₂ , and 3000 cells per well were dispensed into 96-well-plates and cultured overnight to a volume of 100 μl.

The following day, with 1% DMSO as a control, various concentrations of compound were added to each well. The cells were incubated at 37 ° C for 72 hours and cell viability was measured using the Promega Cell Titer 96 Aqueous One Solution Cell Proliferation Assay. After incubation with the added compound and the control, 20 [mu] M of assay substrate solution was added to each well, and the plates were incubated at 37 [deg.] C for an additional 1 hour. The results were measured using a Tecan infinite F200 Pro plate reader at 490 nm absorbance and the readings were expressed as a percentage of the absorbance of the treated group with DMSO only. The results are shown in Fig. Referring to FIG. 1, it was found that cell proliferation of lung cancer cell line H1975 was inhibited in proportion to the concentration of ricocalcone A.

< Example  2> Ricoh Calcorn  Of A Hsp  90 related protein inhibitory effect

H1975 cells (Gefitinib-resistant non-small cell carcinoma cell lines) were cultured in RPMI 1640 medium containing L-glutamine, streptomycin (500 mg / ml), penicillin (100 units / ml) and 10% fetal calf serum (FBS). Cells were cultured at 37 ° C, 5% CO _2, and cultured overnight in a 60 mm culture dish (5 × 10 ⁵ / dish).

On the next day, ricocalcone A, which had different concentrations of 1, 10, 30, 50 and 70 μM, was added to the positive control and 1% of DMSO as a positive control, and further cultured for 27 hours . Cells were obtained to analyze Hsp90 substrate proteolysis (Her2, EGFR, Met, Akt) and heat shock protein induction (Hsp90 and Hsp70), Western blotting each indicator protein and using actin as a loading control. The results are shown in Fig.

2, Ricocalcone A inhibited Hsp90, thereby decreasing the cancer-causing proteins Her2, EGFR, Met and Akt and increasing Hsp70.

< Example  3> Ricoh Calcorn  Of A Hsp  90 Identification of binding sites

The binding sites of ricocalcone A were identified using Autodock 4.2 modeling provided by the Scripps Research Institution, Molecular Graphics Laboratory. The central square of the N-terminal domain of Hsp90 magnified at 100_100_100 magnification and 0.375 A spacing were selected for ligand docking experiments.

The results are shown in FIG. 3, and it can be seen that, as shown in FIG. 3, ricocalcone A binds to the N-terminal ATP pocket of the Hsp90 protein.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (6)

A pharmaceutical composition for preventing or treating degenerative neurological diseases, comprising Ricorcone A or a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 1,
Wherein said ricocalcolon A binds to and inhibits Hsp90 (Heat Shock Protein 90: heat shock protein 90). The method according to claim 1,
The degenerative neurological disorder is selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Kacob disease, Huntington's disease, Or a pharmaceutically acceptable salt thereof. 4. The method according to any one of claims 1 to 3,
At least one additive selected from the group consisting of carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, lubricants, flavors, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, Or a pharmaceutically acceptable salt thereof, for the prevention or treatment of degenerative neurological diseases. 4. The method according to any one of claims 1 to 3,
The pharmaceutical composition for preventing or treating neurodegenerative diseases according to the present invention is selected from the group consisting of granules, powders, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. A health food composition for preventing or ameliorating a neurodegenerative disease comprising Ricoh chalcone A as an active ingredient.

Images