KR102272232B1 - Composition for preventing or treating depression comprising compound isolated from Cassia optusifolia - Google Patents

Abstract

The present invention relates to a composition for the prevention or treatment of depression comprising, as an active ingredient, cassiaside or rubrofusarin, a compound isolated from kaleidoscope, wherein the cassiaside or rubrofusarin is MAO-A (monoamine oxidase A). It has selective inhibitory activity against , so it can be usefully used for the prevention or treatment of depression.

Description

A composition for preventing or treating depression comprising a compound isolated from Cassia optusifolia

The present invention relates to a composition for the prevention or treatment of depression, comprising a compound isolated from Kyeongmyungja.

Neuropsychiatric disorders such as Parkinson's disease and dementia, schizophrenia, depression, and anxiety disorders are caused worldwide due to psychological stress from aging, excessive wealth inequality, family disintegration, feelings of alienation, and fierce competition. is an increasing trend. In the onset of these neuropsychiatric disorders, the metabolism of monoamines in the living body plays an important role, and it is known that monoamine oxidase (MAO, EC 1.4.3.4) is related as an enzyme.

Monoamine oxidase (MAO) is an enzyme that is diversely distributed in the central nervous system and peripheral tissues. It catalyzes the oxidative deamination reaction of amine compounds, resulting in monoamine compounds as neurotransmitters and hormones derived from intestinal bacteria. Breaks down amines (hormonal amines). That is, the neurotransmitter is decomposed by monoamine oxidase, and thus, the monoamine-based compound in vivo is insufficient, and neuropsychiatric disorders occur.

This monoamine oxidase (MAO) mainly uses dopamine, tyramine, epinephrine, or norepinephrne as an endogenous substrate, and selectively deaminates serotonin according to substrate specificity. It can be divided into two types: A-type (type A, MAO-A), which oxidizes, and B-type (type B, MAO-B), which selectively deaminates phenylethylamine and benzylamine. (Youdim MB et al., 2006, Nat. Rev. Neurosci., 7:295-309). Among them, MAO-A is associated with the onset of neuropsychiatric diseases such as depression and anxiety, and MAO-B is associated with the development of neurological diseases such as Alzheimer's diseases and Parkinson's diseases.

MAO inhibitors have been used to prevent or treat neuropsychiatric disorders at home and abroad, and the MAO inhibitors are MAO-A selective inhibitors, MAO-B selective inhibitors, and MAO-A/B non-selective inhibitors, and furthermore, reversible and irreversible It is classified as an inhibitor (Malcomson T et al., 2015, FEBS J.; and Mostert S et al., 2015, Chem. Med. Chem.).

With regard to MAO-A selective inhibitors, it is reported that moclobemide, brofaromine, toloxatone, amifuraline and CX157 can be used as reversible inhibitors of MAO-A. (Berlin I et al., 1990, Br. J. Clin. Pharmacol., 30:805-816; Fowler JS et al., 2010, Neuropsychopharmacology, 35:623-631; Gentili F et al., 2006, J Med. Chem., 49:5578-5586; and Lotufo-Neto F et al., 1999, Neuropsychopharmacology, 20:226-247).

However, chemically synthesized MAO-A reversible and selective inhibitors cause hepatotoxicity and postural hypotension, and have problems in that side effects such as insomnia, excitement, and convulsions occur when overdose. Therefore, there is a demand for the development of pharmaceuticals or health functional foods that are safe for long-term use and that can treat or improve depression.

Korean Patent No. 10-1902837

An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of depression comprising a compound represented by the following formula (1) as an active ingredient.

[Formula 1]

In the above formula, R ₁ and R ₂ are each independently a hydrogen atom, a hydroxyl group, a C ₁ to C ₃ lower alkyl group, a C ₁ to C ₃ lower alkoxy group, O-Glu, O-Glu-Glu or O-Glu-Glu- One or more substituents selected from Glu, wherein Glu means glucose.

Another object of the present invention is to provide a health functional food for the prevention or improvement of depression comprising the compound represented by Formula 1 as an active ingredient.

Another object of the present invention is to provide a method for inhibiting the activity of monoamine oxidase A (MAO-A) comprising treating a sample with the compound represented by Formula 1 in vitro.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating depression comprising a compound represented by the following formula (1) as an active ingredient.

[Formula 1]

In the above formula, R ₁ and R ₂ are each independently a hydrogen atom, a hydroxyl group, a C ₁ to C ₃ lower alkyl group, a C ₁ to C ₃ lower alkoxy group, O-Glu, O-Glu-Glu or O-Glu-Glu- One or more substituents selected from Glu, wherein Glu means glucose.

In an embodiment of the present invention, the compound of Formula 1 may be cassiaside or rubrofusarin.

In one embodiment of the present invention, the cassia side or rubrofusarin may be isolated from Cassia optusifolia , and preferably, may be one isolated from the ethyl acetate fraction of the methanol extract of Cassia optusifolia, but is not limited thereto. Instead, it is possible to use a chemically synthesized or commercially available material by a method known in the art.

In one embodiment of the present invention, the compound may have inhibitory activity against monoamine oxidase A (MAO-A).

In addition, the present invention provides a health functional food for preventing or improving depression comprising the compound represented by Formula 1 as an active ingredient.

In addition, the present invention provides a method for inhibiting the activity of monoamine oxidase A (MAO-A) comprising treating a sample with the compound represented by Formula 1 in vitro.

Cassiaside or rubrofusarin, which is a compound isolated from the present invention, has selective inhibitory activity on monoamine oxidase A (MAO-A), and thus can be usefully used for the prevention or treatment of depression.

1 shows the chemical structural formula of cassiaside.
Figure 2 shows the chemical structural formula of rubrofusarin.
3 shows the Michaelis-Menten plot (A), Lineweaver-Burk plot (B) and secondary plot (C, D) results of cassiaside for human MAO-A.
4 shows the results of Lineweaver-Burk plot (A) and secondary plot (B, C) for human MAO-A of rubrofusarin.
5 shows the binding behavior of cassiasides docked to the catalytic sites (A, B) and non-catalytic sites (C, D) of MAO-A (cassiasides, purple bars; and FAD, black bars).
6 shows the binding pattern of rubrofusarin docked to MAO-A (A), the catalytic site (B) and the non-catalytic site (C) of MAO-A (C) ( Lubrofusarin, light green bars; harmine, black bars; and FAD, gray bars).

The present invention provides a pharmaceutical composition for preventing or treating depression comprising a compound represented by the following formula (1) as an active ingredient.

[Formula 1]

In the above formula, R ₁ and R ₂ are each independently a hydrogen atom, a hydroxyl group, a C ₁ to C ₃ lower alkyl group, a C ₁ to C ₃ lower alkoxy group, O-Glu, O-Glu-Glu or O-Glu-Glu- One or more substituents selected from Glu, wherein Glu means glucose.

The compound of Formula 1 may be cassiaside or rubrofusarin, and refers to a compound represented by Formula 2 or 3, respectively.

[Formula 2]

[Formula 3]

The cassia side or rubrofusarin may be derived from an extract or fraction of Cassia optusifolia , but is not limited thereto, and a chemically synthesized or commercially available material may be used by a method known in the art.

The extract may be obtained by extraction and separation from nature using an extraction and separation method known in the art, and the "extract" as defined in the present invention is extracted from Cassia optusifolia using an appropriate solvent. and, for example, include all of the crude extract, polar solvent-soluble extract or non-polar solvent-soluble extract of Cassia optusifolia.

As a suitable solvent for extracting the extract from Cassia optusifolia , any pharmaceutically acceptable organic solvent may be used, and water or an organic solvent may be used, but is not limited thereto, for example, Purified water, methanol, ethanol, propanol, isopropanol, alcohol having 1 to 4 carbon atoms, including butanol, acetone, ether, benzene (benzene) ), chloroform (chloroform), ethyl acetate (ethyl acetate), methylene chloride (methylene chloride), hexane (hexane) and various solvents such as cyclohexane (cyclohexane) can be used alone or in combination.

As the extraction method, any one of methods such as hot water extraction method, cold extraction method, reflux cooling extraction method, solvent extraction method, steam distillation method, ultrasonic extraction method, elution method, compression method, etc. can be selected and used. In addition, the desired extract may be further subjected to a conventional fractionation process, and may be purified using a conventional purification method. Production method of Cassia tora (Cassia optusifolia) extract of the present invention may also be used in any way that there is no limit, is known.

The compound of the present invention is a variety of chromatography, such as silica gel column chromatography, thin layer chromatography, high performance liquid chromatography, etc. from Cassia optusifolia extract. A further purified fraction may be obtained, and preferably, it may be one separated by column chromatography from the ethyl acetate fraction of the methanol extract of Kaleidoscope.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable” refers to exhibiting non-toxic properties to cells or humans exposed to the composition. The carrier may be used without limitation as long as it is known in the art, such as buffers, preservatives, soothing agents, solubilizers, isotonic agents, stabilizers, bases, excipients, lubricants, and the like.

In addition, the pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories and sterile injection solutions according to conventional methods, respectively. can Furthermore, it may be used in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel, or external preparation for skin in the form of a gel. Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the Cycotria rubra extract, for example, starch, calcium carbonate, It is prepared by mixing sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, 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 sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "administration" of the present invention means introducing a predetermined substance to an individual by an appropriate method, and the administration route of the composition may be administered through any general route as long as it can reach a target tissue. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, may be administered intrarectally, but is not limited thereto.

As used herein, the term “individual” refers to all animals including humans, rats, mice, and livestock. Preferably, it may be a mammal including a human.

As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is dependent on the patient's sex, age, body weight, health condition, type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route, and excretion rate, treatment duration, factors including drugs used in combination or concomitantly, and other fields of medicine It can be readily determined by one of ordinary skill in the art according to well-known factors. For administration, the recommended dosage may be administered once a day, or divided into several administrations.

The food composition of the present invention may include all foods in a conventional sense, and may be used interchangeably with terms known in the art, such as functional food and health functional food.

As used herein, the term "functional food" means a food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulating nutrients with respect to structure and function or physiological effects.

As used herein, the term "health functional food" refers to a food manufactured and processed by extracting, concentrating, refining, mixing, etc., a specific ingredient as a raw material or a specific ingredient contained in a food raw material for the purpose of health supplementation, It refers to a food designed and processed to sufficiently exert biological control functions such as biological defense, regulation of biological rhythm, prevention and recovery of disease, etc., by ingredients, and the composition for health food is the prevention of disease and recovery of disease. Functions related to it can be performed.

There is no limitation on the kind of food in which the composition of the present invention can be used. In addition, the composition of the present invention can be prepared by mixing known additives with other suitable auxiliary ingredients that may be included in food according to the selection of those skilled in the art. Examples of foods that can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and There are vitamin complexes and the like, and it can be prepared by adding the extract according to the present invention and its fractions as main components to juice, tea, jelly, juice, and the like.

In addition, foods that can be applied to the present invention include, for example, special nutritional foods (eg, formula milk, infant food, etc.), processed meat products, fish meat products, tofu, jelly, noodles (eg, ramen, noodles, etc.), health supplements , Seasoned foods (eg soy sauce, soybean paste, red pepper paste, mixed soy sauce, etc.), sauces, sweets (eg snacks), dairy products (eg fermented milk, cheese, etc.), other processed foods, kimchi, pickles (various kimchi, pickles, etc. ), beverages (eg, fruit, vegetable beverages, soy milk, fermented beverages, etc.), and natural seasonings (eg, ramen soup, etc.).

When the health functional food composition of the present invention is used in the form of a beverage, it may contain various sweetening agents, flavoring agents, or natural carbohydrates as additional ingredients, as in a conventional beverage. In addition to the above, the health functional food composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin , alcohol, a carbonation agent used in carbonated beverages, and the like. In addition, it may contain the pulp for the production of natural fruit juice, fruit juice beverage and vegetable beverage.

Hereinafter, the present invention will be described in more detail through examples. These examples are for explaining the present invention in more detail, and the scope of the present invention is not limited to these examples.

Example 1. Experimental materials and methods

1.1. matter

Cassiaside (cassiaside) and rubrofusarin (rubrofusarin) were separated using column chromatography from the ethyl acetate fraction of the methanol extract of kaleidoscope ( Cassia optusifolia ). The structures of cassiaside and rubrofusarin are shown in FIGS. 1 and 2, respectively.

1.2. human monoamine oxidase A (MAO-A) h MAO-A) and human monoamine oxidase B (MAO-B) h MAO-B) activity inhibition experiment

The inhibitory activity against human MAO-A and human MAO-B was ^{tested by modifying the protocol provided by the MAO-Glo TM} assay kit (Promega, Madison, WI, USA). Briefly, 12.5 μL of substrate and 12.5 μL of 4X sample or positive control (diprenyl HCl) were injected into a white opaque 96-well plate. Thereafter, human MAO-A and MAO-B enzymes were diluted with 2X reaction buffer (pH 7.4), 25 μL was injected into the well, and incubated for 1 hour. After incubation, 50 μL of reconstituted luciferin detection reagent (RLDR) was added and incubated for 20 minutes, and ALU (arbitrary light unit) was measured using a Luminometer (Spectra Max L, Molecular Devices, Sunnyvale, CA, USA). did.

1.3. Kinetic Study of Human MAO-A

The present inventors performed experiments to determine the mechanism of inhibition of cassiaside and rubrofusarin on human MAO-A. Briefly, the enzymatic reactions at different concentrations of cassiaside (human MAO-A: 0, 2, 10 and 50 μM) under different concentrations of substrate were shown through Michaelis-Menten plots and Lineweaver-Burk plots. In kinetic experiments on human MAO-A, substrates at concentrations of 40, 80, and 160 μM (final concentrations: 10, 20, and 40 μM) were used.

In addition, the enzymatic reactions in various concentrations of rubrofusarin (MAO-A: 0, 1.25, 5, 20 μM) under various concentrations of substrate were shown through Michaelis-Menten plot and Lineweaver-Burk plot. In kinetic experiments on human MAO-A, substrates at concentrations of 40, 80, and 160 μM (final concentrations: 10, 20, and 40 μM) were used.

1.4. Molecular docking studies

The docking simulation of the target receptor with cassiaside or rubrofusarin was performed using AutoDock 4.2 program. The X-ray crystal structure of the human MAO-A-harmine complex (PDB ID: 2Z5X) was obtained from the RCSB Protein Data Bank (PDB). The 3D structures of cassiaside and rubrofusarin were generated using the Marvin Sketch program (v17,1,30, ChemAxon, Budapest, Hungary). Automatic docking simulations were run using AutoDockTools (ADT) to evaluate the proper bonding orientation. For docking calculations, Gasteiger charges were added by default, the rotatable bond was set to ADT, and all torsions were made rotatable. Grid maps were created with AutoGrid. The docking protocol for non-bendable or bendable ligand docking consisted of 15 independent genetic algorithms. Other parameters used are ADT defaults. Results were visualized and analyzed using Discovery Studio (v17.2, Accelrys, San Diego, CA, USA) and UCSF Chimera (http://www.cgl.ucsf.edu/chimera/).

Example 2. Inhibitory effect on human MAO-A and human MAO-B activity

The present inventors performed an experiment to measure the inhibitory effect of cassiaside and rubrofusarin on MAO-A and MAO-B using R-(-)-diprenyl HCl as a positive control. As a result, as shown in Table 1, cassiaside showed a high inhibitory effect and high selectivity for MAO-A. _{The IC 50} value of cassiaside for MAO-A was confirmed to be 11.26 μM, and it did not show an inhibitory effect on MAO-B at a concentration of 400 μM or less.

In addition, as shown in Table 2, rubrofusarin showed a high inhibitory effect and high selectivity for MAO-A rather than MAO-B. _{The IC 50} values of rubrofusarin for MAO-A and MAO-B were found to be 5.90 μM and 91.40 μM, respectively.

Example 3. Kinetic analysis results for human MAO-A

The present inventors performed enzyme kinetic experiments through Michaelis-Menten plot, Lineweaver-Burk plot, and secondary plots thereof in order to understand the mechanism of inhibition of human MAO. As a result, when cassiaside was treated, the Lineweaver-Burk plot for the activity of human MAO-A was drawn in a straight line and crossed in the second quadrant ( FIG. 3 ). In addition, a typical mixed-type inhibition pattern was also observed in the Michaelis-Menten plot. As shown in FIG. 3 , it was confirmed that the higher the concentration of cassiaside, the higher the position of the y-axis intersection (1/Vmax), and the shorter the x-axis intersection point. Accordingly, it was confirmed that cassiaside is a mixed inhibitor. Inhibition constants (K ic and K iu ) of cassiaside for human MAO-A were confirmed to be 6.26 μM and 12.32 μM, respectively, by secondary plots ( FIG. 3 and Table 1).

In addition, when rubrofusarin was treated, the Lineweaver-Burk plot for the activity of human MAO-A was drawn in a straight line and crossed in the two quadrants ( FIG. 4 ). In addition, a typical mixed-type inhibition pattern was also observed in the Michaelis-Menten plot. As shown in FIG. 4 , it was confirmed that as the concentration of rubrofusarin increased, the position of the y-axis crossing point (1/Vmax) increased, and the x-axis crossing point became shorter. Thus, it was confirmed that rubrofusarin is a mixed inhibitor. The inhibitory constants (K ic and K iu ) of rubrofusarin on human MAO-A were confirmed to be 4.38 μM and 4.22 μM, respectively, by secondary plots ( FIG. 4 and Table 2).

Example 4. Docking simulation results for human MAO-A

The present inventors performed docking simulations to prove the mechanism of inhibition of human MAO-A by cassiaside and rubrofusarin. As a result, as shown in FIG. 5 and Table 3, cassiaside was found to have binding energies of -8.42 kcal/mol and -7.59 kcal/mol in both the catalytic and non-catalytic sites of human MAO-A, respectively. These results were consistent with the kinetic results showing the mixed inhibitory effect. At the most optimized binding site of the cassiaside to the catalytic site of human MAO-A, the cassiaside formed four hydrogen bonds with the Gln215, Cys323, Ile180 and Asn181 residues of MAO-A ( FIGS. 5A and 5B ). Cassiaside also formed pi interactions with Tyr444, Tyr407, Phe352 and FAD ( FIGS. 5A and 5B ).

A similar interaction was observed in the binding between harmine and MAO-A used as a positive control. Cassiaside formed 6 hydrogen bonds with Arg172, Asp328, Glu327 and Glu329 residues at the non-catalytic site of MAO-A as well as at the catalytic site ( FIGS. 5C and 5D ). In addition, it was confirmed that cassiaside pi-interacted with Tyr175, Pro186, His187, Arg172 and Leu176 residues at the non-catalytic site of MAO-A ( FIGS. 5C and 5D ).

In addition, as shown in FIG. 6 and Table 4, it was shown that rubrofusarin has binding energies of -9.67 kcal/mol and -5.60 kcal/mol, respectively, in both the catalytic and non-catalytic sites of human MAO-A. These results were consistent with the kinetic results showing the mixed inhibitory effect. At the most optimized binding site of rubrofusarin to the catalytic site of human MAO-A, rubrofusarin formed six hydrogen bonds with the Tyr444, Asn181, Gly443 and Tyr407 residues of MAO-A (Fig. 6A and 6B). In addition, it was confirmed that rubrofusarin formed a pi-bond with the residues Ile180, Ile335, Leu337, Tyr407, and Tyr444, and formed a van der Waals bond with FAD ( FIGS. 6A and 6B ).

A similar interaction was observed in the binding between harmine and MAO-A used as a positive control. Lubrofusarin formed five hydrogen bonds with residues Gly404, Gln296, Leu298, and Met300 at the non-catalytic site of MAO-A as well as at the catalytic site ( FIGS. 6A and 6C ). In addition, it was confirmed that rubrofusarin pi-interacted with Ala302 and Pro299 residues in the non-catalytic site of MAO-A ( FIGS. 6A and 6C ).

As described above, it was confirmed that cassiaside and rubrofusarin have inhibitory activity against human MAO-A. MAO-A is related to the metabolism of norepinephrine, serotonin and tyramine, and selective inhibitors of MAO-A are known to have therapeutic effects on depression.

Accordingly, cassiaside and rubrofusarin of the present invention can be usefully used for the prevention or treatment of depression as selective inhibitors of MAO-A.

Claims (9)

A pharmaceutical composition for the prevention or treatment of depression comprising a compound represented by the following formula (1) as an active ingredient:
[Formula 1]

In the above formula,
R ₁ is a hydrogen atom or a C ₁ to C ₃ lower alkoxy group;
R ₂ is a hydrogen atom or O-Glu, wherein Glu means glucose. The method of claim 1,
The compound of Formula 1 is a composition, characterized in that cassiaside (cassiaside) or rubrofusarin (rubrofusarin). 3. The method of claim 2,
The cassia side or rubrofusarin is a composition, characterized in that isolated from the kyeomyeongja ( Cassia optusifolia ). 4. The method of claim 3,
The cassia side or rubrofusarin is a composition, characterized in that separated from the ethyl acetate fraction of the methanol extract of Kaleidoscope. The method of claim 1,
The compound is characterized in that it has inhibitory activity against MAO-A (monoamine oxidase A). A health functional food for the prevention or improvement of depression comprising a compound represented by the following formula (1) as an active ingredient:
[Formula 1]

In the above formula,
R ₁ is a hydrogen atom or a C ₁ to C ₃ lower alkoxy group;
R ₂ is a hydrogen atom or O-Glu, wherein Glu means glucose. 7. The method of claim 6,
The compound of Formula 1 is a health functional food, characterized in that cassiaside or rubrofusarin. A method of inhibiting the activity of monoamine oxidase A (MAO-A) comprising treating a sample with a compound represented by the following formula (1) in vitro:
[Formula 1]

In the above formula,
R ₁ is a hydrogen atom or a C ₁ to C ₃ lower alkoxy group;
R ₂ is a hydrogen atom or O-Glu, wherein Glu means glucose. 9. The method of claim 8,
The method of claim 1, wherein the compound of formula 1 is cassiaside or rubrofusarin.

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