KR102093247B1 - Novel Meroterpene Compound, and Composition for Preventing or Treating PPAR-gamma Associated Diseases Comprising the Same - Google Patents

Abstract

The present invention relates to a novel meroterpene compound or a pharmaceutically acceptable salt thereof, and a composition for preventing, improving or treating PPAR-γ-related diseases comprising the same, the compound has no cytotoxicity and can be utilized in actual clinical practice And also acts as an agonist of PPAR-γ, exhibiting anti-inflammatory effects by suppressing the activity of NF-κB and the expression of inflammatory cytokines, as well as preventing, improving or treating various diseases involving PPAR-γ Can be utilized in

Description

Novel Meroterpene Compound, and Composition for Preventing or Treating PPAR-gamma Associated Diseases Comprising the Same

The present invention relates to a novel pharmaceutical composition or health functional food composition for preventing or treating PME-related diseases including a new merotene pen compound.

Marine microorganisms are widely regarded as promising raw materials for new bioactive precursors. In particular, the genetic complexity of endozoic algae in various marine invertebrates provides structurally unique raw materials and biologically active metabolites.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear receptor superfamily. The three PPAR isoforms (α, β / γ, δ) play an important role in the regulation of lipid production, lipid metabolism, inflammation and metabolic homeostasis. Among them, PPAR-γ is a major regulator of adipocyte differentiation, fatty acid storage and sugar metabolism, and is recognized as a target of anti-diabetic drugs. Recently, the anti-inflammatory effect of agonists of PPAR-γ has been known through various metabolic processes, which directly inhibit the expression of NF-κB, compete with NF-κB as a co-activator, p65 (RelA ; Subunit of NF-κB). Agonists of PPAR-γ have also been found to fundamentally affect the immune response through inhibition of inflammatory cytokines. Endogenous PPAR-γ agonists such as 15-deoxy-Δ ^12,14 -prostaglandin J2 (15d-PGJ ₂ ) inhibit the activity of NF-κB and other inflammatory mediators such as AP-1, ICAM, iNOS. It can protect the kidneys from ischemic damage. Thiazolidinediones (TZDs), such as rosiglitazone, are artificial PPAR-γ agonists and have been used as the basis for diabetes drug development. It is known that rosiglitazone inhibits the expression of inflammatory cytokines (TNF-α, IL-1β) and inhibits the activity of p65 during lipid polysaccharide (LPS) -induced acute kidney injury.

Meanwhile, amorphutin ( amorphutin A, B, and 2), which is a benzoic acid derivative substituted with isoprenoid, is amorpha , which is a legume. It was first isolated from the fruit of fruiticosa , and is used as a component of some seasonings. They partially function as PPAR-γ agonists and have potential anti-inflammatory and anti-diabetic properties. These agonists selectively activate PPAR-γ and inhibit side effects induced by TZD, such as weight gain, osteoporosis, cardiovascular complications, edema, and the like.

On the other hand, PPAR-γ agonists have recently received a lot of attention as a therapeutic agent for diabetes. Thiazolidinediones-based compounds such as rosiglitazone and troglitazone are typical agonists. However, the existing PPAR-γ agonist has serious problems such as weight gain and cardiovascular side effects, and it is required to develop new therapeutic drugs having excellent therapeutic effects while solving these side effects. Moreover, since PPAR-γ agonists can be developed not only for the treatment of diabetes, but also for the treatment of inflammatory diseases, anti-cancer agents, and immunomodulators, it is receiving attention as an important target for new drug development.

Korean Registered Patent No. 10-1193730 (2012.10.16 registered).

It is an object of the present invention to provide a novel meroterpene compound that acts as an agonist of PPAR-γ.

Another object of the present invention is to provide a pharmaceutical composition capable of preventing or treating PPAR-γ-related diseases more effectively, including a PPAR-γ agonist.

Another object of the present invention is to provide a health functional food composition that can more effectively prevent or improve PPAR-γ-related diseases, including PPAR-γ agonists.

In order to achieve the above object, the present invention provides a meroterpene compound represented by the following Chemical Formula 1 or 2, or a pharmaceutically acceptable salt thereof.

In order to achieve the above other object, the present invention provides a pharmaceutical composition for preventing or treating PPAR-γ-related diseases comprising a merotene compound represented by the following Chemical Formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. .

In order to achieve the above another object, the present invention is a health functional food composition for preventing or improving PPAR-γ-related diseases comprising a merotene pen compound represented by the following Chemical Formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. Provides:

[Formula 1]

[Formula 2]

In Chemical Formula 1, R ₁ is either hydrogen or (C1 to C4) alkyl, and R ₂ is (C1 to C4) alkyl.

The present invention relates to a novel compound isolated from a jellyfish-derived fungus and a composition for preventing, improving or treating PPAR-γ-related diseases comprising the same, the compound has no cytotoxicity and can be utilized clinically, and also PPAR-γ It acts as an agonist of NF-κB and inhibits the expression of inflammatory cytokines, thereby exhibiting anti-inflammatory effects, and can be utilized to prevent, improve or treat various diseases involving PPAR-γ.

Figure 1 shows the structural formula of amorphotin B and meroterpene compounds 1 to 6 containing the novel compounds isolated and identified in the present invention.
Figure 2 shows the results of in silico analysis of the interaction between PPAR-γ LBD and amorphutin B, or between PPAR-γ LBD and compound 1 ((A): Amorphutin B (green) is PPAR Forms a direct hydrogen bond with Ser- ³⁴² of β -sheet of -γ LBD, and helix H3 of PPAR-γ LBD (Ok: Ile ²⁸¹ , Gly ²⁸⁴ , Cys ²⁸⁵ , Arg ²⁸⁸ , Ile ³²⁶ ), Helix H4 / 5 (red) : Met ³²⁹ , Leu ³³⁰ ), Helix H2 '(orange: Leu ²⁵⁵ ), and β -sheet (yellow: Ile ³⁴¹ ) with hydrogen interaction (affinity value: -9.4 kcal / moL), (B) : Compound 1 (green) forms a direct hydrogen bond with Ser ³⁴² of β -sheet of PPAR-γ LBD, Cys ²⁸⁵ of Helix H-3 and Arg ^288, and Helix H3 of PPAR-γ LBD (yellow: Gly ²⁸⁴ , Ile ³²⁶ ), helix H4 / 5 (red: Leu ³³⁰ ), helix H6 (Met ³⁶⁴ ) and β -sheet (yellow: Ile ³⁴¹ ) with hydrogen interaction (affinity value: -8.7 kcal / moL); The docking pose of Amorphutin B and Compound 1 is Amorphutin B and human PPAR-γ protein (PDB: 4A4W) were simulated through previously reported crystal structures).
Figure 3 is a result of confirming the cytotoxicity when treated with Compound 1 to 6 (10, 30, 50μM) in Raw 264.7 macrophages and Ac2F rat hepatocytes for 24 hours.
4 is a result of confirming whether PPAR-γ activity by Compound 1 or rosiglitazone (Rosi) in Ac2F cells (luciferase expression (fold of control) was expressed as mean ± standard deviation (n = 3); control For ^** p <0.01 and ^*** p <0.001).
Figure 5 is the result of confirming the PPAR-γ protein level in the nucleus through Western blot after treating compound 1 (10 or 30 μM) or rosiglitazone (Rosi, 10 μM) in RAW 264.7 macrophages for 24 hours (transcription factor IIB (TF) The level in the nucleus of IIB) was used as a reference, and each experiment was independently performed 3 times and represented as a representative value: ^** p <0.01 for the untreated control group).
Figure 6 is the result of confirming the effect on phosphorylation of NF-κB p65 protein in RAW 264.7 macrophages of compound 1 (10 or 30 μM) and dexamethasone (DEX, 10 μM) through Western blot (β-actin; internal control, Each experiment was performed 3 times independently and represented as a representative value: ^### p <0.001 for untreated control, ^* p <0.05 for LPS-treated cells, ^** p <0.01, ^*** p <0.001 ).
7 is a result of confirming the effect on the inflammatory mediators of Compound 1 (10, 30, 50 μM) and dexamethasone (DEX, 10 μM) at the cellular level through RT-PCR (GAPDH: internal control, each experiment 3 It was performed independently and expressed as a representative value: ^## p <0.01, ^### p <0.001 for the untreated control, ^* p <0.05, ^** p <0.01, ^*** p < 0.001).
Figure 8 is the result of confirming the effect of compound 1 (10, 30, 50 μM) and dexamethasone (DEX, 10 μM) on iNOS and COX-2 in RAW 264.7 macrophages through Western blot (each experiment is independently 3 times) The results were shown as representative values: ^### p <0.001 for untreated control, ^** p <0.01 and ^*** p <0.001 for LPS treated cells).
Figure 9 (A) Nitric oxide (NO), (B) TNF-α, (C) IL-1β and (D) of compound 1 (10, 30, 50 μM) and dexamethasone (DEX, 10 μM) in Raw 264.7 macrophages ) It is the result of confirming the effect on IL-6 (each experiment was performed 3 times independently and represented as a representative value: ^### p <0.001 for untreated control, ^* p <0.05 for LPS-treated cells, ^** p <0.01 and ^*** p <0.001).

Hereinafter, the present invention will be described in more detail.

Merloterpenes are also found in marine invertebrates and microorganisms such as sponges, seaweeds, and corals. These metabolites exhibit a very wide range of biological properties, including anti-cancer, anti-inflammatory, antiviral, antimicrobial and immunomodulatory activities.

Thus, the inventors of the present invention, through a study on the jellyfish-derived fungus Penicillium chrysogenum J08NF-4, two new meroterpene compounds, chrysogenester (compound represented by the formula (3)) 1) and farnesyl-2-methyl-1-O-methylhydroquinone (5-farnesyl-2-methyl-1-O-methylhydroquinone; compound 2 represented by the formula (4)) is already known farnesyl mer terpene The compounds (compounds 3 to 6) were separated together, and the present invention was completed by confirming that the compounds are representative metabolites derived from the mevalonate pathway among hybrid biosynthesis of isoprene derived from quinone or hydroquinone.

Accordingly, the present invention provides a meroterpene compound represented by Formula 1 or 2, or a pharmaceutically acceptable salt thereof:

[Formula 1]

[Formula 2]

In Chemical Formula 1, R ₁ is either hydrogen or (C1 to C4) alkyl, and R ₂ is (C1 to C4) alkyl.

Specifically, in Formula 1, R ₁ may be either hydrogen or methyl.

More specifically, the compound represented by Formula 1 may be a compound represented by Formula 3:

[Formula 3]

In addition, the compound represented by Formula 2 may be a compound represented by Formula 4 below:

[Formula 4]

In one embodiment of the present invention, the meroterphan compounds (Compounds 1-6) have a structural motif similar to amorphutin, and thus confirm that they can act as agonists of PPAR-α in the same manner as amorphutin B. Did.

That is, the meroterpene compound may be an agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ), according to an embodiment of the present invention, the mero It was confirmed that the terpene compound acts as an agonist of PPAR-γ to suppress the phosphorylation of the NF-κB subunit and to suppress the expression of inflammatory cytokines.

The meroterpene compound exhibiting such an effect may be isolated from Penicilluim chrysogenum bacteria derived from jellyfish.

Moreover, the present invention provides a pharmaceutical composition for preventing or treating PPAR-γ-related diseases comprising a merotene compound represented by the following Chemical Formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

[Formula 2]

In Chemical Formula 1, R ₁ is either hydrogen or (C1 to C4) alkyl, and R ₂ is (C1 to C4) alkyl.

Specifically, in Formula 1, R ₁ may be either hydrogen or methyl.

More specifically, the compound represented by Formula 1 may be a compound represented by Formula 3:

[Formula 3]

In addition, the compound represented by Formula 2 may be a compound represented by Formula 4 below:

[Formula 4]

As described above, the merotene compound acts as an agonist of PPAR-γ, thereby preventing or treating diseases related to PPAR-γ, wherein the PPAR-γ related diseases are inflammation, diabetes, insulin resistance, and leptin Resistance, lipid metabolic abnormality, sugar metabolic abnormality, hyperlipidemia, and may be any one selected from the group consisting of metabolic syndrome, but is not limited thereto.

In particular, the meroterpene compound can prevent or treat PPAR-γ-related diseases by inhibiting the NF-κB signal transduction pathway, thereby exhibiting an effect of inhibiting even the expression of inflammatory cytokines, thereby exhibiting an anti-inflammatory effect, thereby more effectively PPAR -γ-related diseases can be prevented or treated.

The pharmaceutical composition according to the present invention may further include a suitable carrier, excipient or diluent commonly used in the manufacture of pharmaceutical compositions.

As a carrier, excipient or diluent usable in the present invention, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, And methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil.

The pharmaceutical composition according to the present invention is formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions, respectively, according to a conventional method. You can.

In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc.These solid preparations include at least one excipient such as starch, calcium carbonate, sucrose ( sucrose) or lactose, gelatin, and the like.

Also, lubricants such as magnesium stearate and talc are used in addition to simple excipients. Liquid preparations for oral use include suspending agents, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used as diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, may be included. , But is not limited thereto.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin may be used, but are not limited thereto.

The meroterpene compound of the present invention or a salt thereof may be included in an amount of 0.001 to 30.0 parts by weight based on 100 parts by weight of the pharmaceutical composition, and when the content is less than 0.001% by weight, the effect as a PPAR-γ agonist is insignificant, 30.0% by weight If the amount exceeds%, an increase in effect due to an increase in the amount of use may cause a slight problem.

The amount of the active ingredient of the pharmaceutical composition of the pharmaceutical composition according to the present invention or the salt thereof may vary depending on the patient's age, gender, weight, and disease, but is 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg Can be administered once to several times a day.

The dosage of the meroterpene compound or its salt of the present invention can be increased or decreased depending on the route of administration, the degree of disease, sex, weight, and age. Therefore, the above dosage does not limit the scope of the present invention in any way.

The pharmaceutical composition may be administered to various mammals, such as rats, mice, livestock, and humans. Any mode of administration can be envisaged, for example, but not limited to, oral, rectal or intravenous, intramuscular, subcutaneous, bronchosuction, intrauterine dura or intracerebroventricular injection. Does not.

Since the meroterpene compound of the present invention has stability as a compound derived from fungi, it can be used in the pharmaceutical composition of the present invention.

In addition, the present invention provides a health functional food composition for preventing or improving PPAR-γ-related diseases comprising a merotene compound represented by the following Chemical Formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

[Formula 2]

In Chemical Formula 1, R ₁ is either hydrogen or (C1 to C4) alkyl, and R ₂ is (C1 to C4) alkyl.

Specifically, in Formula 1, R ₁ may be either hydrogen or methyl.

More specifically, the compound represented by Formula 1 may be a compound represented by Formula 3:

[Formula 3]

In addition, the compound represented by Formula 2 may be a compound represented by Formula 4 below:

[Formula 4]

In this case, the PPAR-γ related disease may be any one selected from the group consisting of inflammation, diabetes, insulin resistance, leptin resistance, lipid metabolism abnormality, sugar metabolism abnormality, hyperlipidemia and metabolic syndrome, but is not limited thereto.

In particular, the meroterpene compound can prevent or treat PPAR-γ-related diseases by inhibiting the NF-κB signal transduction pathway, thereby exhibiting an effect of inhibiting the expression of inflammatory cytokines, thus exhibiting an anti-inflammatory effect, thereby more effectively PPAR -γ disease can be prevented or improved.

The health functional food composition according to the present invention may be provided in the form of a health functional food or health drink, and may be used in the form of a soft or hard capsule filled with functional beverages, pills, tablets, or dry powdered ingredients. , But is not limited thereto.

Foods to which the merotene compound according to the present invention or a salt thereof can be added include, for example, various foods, candy, chocolate, beverages, chewing gum, tea, vitamin complexes, various health supplements, powders, granules, tablets, etc. It can be used in the form of pills, capsules or beverages.

The health functional food composition may further include a food-pharmaceutically acceptable carrier. In one embodiment, when the dietary supplement composition of the present invention is in the form of a beverage, there are no particular limitations on the liquid component other than containing the merotene compound or a salt thereof as an essential component in the indicated ratio, and there are no limitations. Eggplant flavoring agents or natural carbohydrates may be included as additional ingredients. At this time, examples of natural carbohydrates include monosaccharides such as glucose, fructose, disaccharides, such as maltose, sucrose, polysaccharides, such as conventional sugars and xylitol, such as dextrins, cyclodextrins, etc. And sugar alcohols such as sorbitol and erythritol. In addition, as the flavoring agent, natural flavoring agents such as taumatin, stevia extract, hebaudioside A, glycyrrhizine, and synthetic flavoring agents such as saccharin and aspartame may be used.

In addition to the above-mentioned beverages, the health functional food of the present invention includes various nutrients, vitamins, minerals, synthetic flavoring agents, flavoring agents such as natural flavoring agents, coloring agents, enhancers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, and protective colloid It may contain a thickening agent, pH adjusting agent, stabilizer, preservative, glycerin, alcohol, carbonic acid used in carbonated beverages, and the like.

The effective dose of the meroterpene compound or its salt contained in the dietary supplement composition can be used in accordance with the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene purposes or for health control purposes It may be less than the above range, it is clear that the active ingredient can be used in an amount above the above range because there is no problem in terms of safety.

Hereinafter, examples will be described in detail to help understanding of the present invention. However, the following examples are provided to more fully explain the present invention to those having average knowledge in the art, and are merely illustrative of the contents of the present invention, so the scope of the present invention is limited to the following examples. no.

<Example 1> Confirmation of anti-inflammatory effect of new compounds

1. Experimental method

(1) General experiment process

IR spectra were recorded on a Jasco 410 spectrometer; UV spectra were recorded on an Optizen UV / VIS spectrophotometer, and 1D and 2D NMR spectra were recorded on a Varian UNITY 400 and Varian INOVA 500 spectrometer, respectively. The chemical shift is the peak of the residual solvent or deuterated solvent ( δ _H 3.30 at CD ₃ OD and δ _C 49.0). HRESIMS data were obtained via an Agilent 1200 UHPLC Accurate-mass Q-TOF MS spectrometer. HPLC was performed using a Gilson 307 pump, ODS column (YMC-Triat C18, 250 X 10 mm, id 5 μm) and Jasco UV-975 detector.

(2) Identification of Fungal Strain

The fungal strain P. Chrysogenum J08NF-4 marine jellyfish Nemopilema . It was isolated from nomurai , where the jellyfish were collected from the southern coast of South Korea in June 2007. Samples are from the Marine Natural Product Laboratory at Pusan National University. Specifically, after the jellyfish was washed with sterile seawater, small pieces of the surface and internal tissue were homogenized, and then inoculated into a Petri dish malt extract agar (MEA). Sterilized MEA medium contains glucose (20 g / L), malt extract (20 g / L), agar (20 g / L), peptone (1 g / L) and antibiotics (final concentration: 50 μg / mL penicillin and 50 μg / Prepared using seawater containing mL streptomycin). Then, the resulting fungal colonies were transferred to a petri dish of the same medium and incubated at 25 ° C for 10-14 days to allow colony development. As a result, a total of 12 pure fungal strains (J08NF-1 to J08NF-12) were isolated from the jellyfish, and after the fungal strain J08NF-4 was selected, it was P according to its morphology and ITS gene sequence (GeneBank accession No. KR011759). It was identified as .chrysogenum .

P. chrysogenum J08NF-4 contains 44 liters of MEA medium (75% seawater) with glucose (20 g / L), malt extract (20 g / L) and peptone (1 g / L) ) At 30 ° C. for 21 days on a shaker platform at a speed of 130 rpm.

(3) Compound extraction and separation

After 21 days of the culture period, the culture medium and mycelia were extracted with ethanol at room temperature, and the ethanol extract (18 g) was fractionated between aqueous methanol (MeOH) and n-hexane. The double aqueous MeOH layer was subjected to stepwise medium pressure liquid chromatography (MPLC; ODS-A, 120 kPa, S-30 / 50 mesh), eluting with 30% to 100% methanol to obtain 30 fractions. Next, fraction 12 (85.2 mg) was subjected to RP-HPLC (YMC-triart C18, 250 X 10 mm, 5 μm), which was eluted with 65% MeOH to obtain compound 1 (12.8 mg). . Compound 2 (5.0 mg) and Compound 3 (2.7 mg) were RP-HPLC (YMC-triart C18, 250 X 10 mm, 5 μm) and NP-HPLC (YMC-Pack SIL, 12 nm, 5 μm) in n-hexane fraction ). Other activated fractions, i.e., fractions 8, 19, 21 were also isolated via RP-HPLC (YMC-triart C18, 250 X 10 mm, 5 μm), compound 4 (1.3 g), 5 (20.6 mg) and 6 ( 10.86 mg). The NMR data of Compound 1-3 thus obtained are shown in Table 1 below.

-Chrysogenester (compound 1) : Yellow oil (MeOH); UV (MeOH) λ _max (log ε) 224 (2.72), 252 (2.73), 295 (2.18) nm; IR ν _max 2925, 2880, 2348, 1740, 1738, 1660, 1517, 1507, 1480, 1460, 1198, 458 cm ^-1 ; ¹ H (500 MHz, CD ₃ OD) and ¹³ C (100 MHz, CD ₃ OD), see Table 1 above; (+) - HRESIMS m / z 333.2056 [M + H] - (calcd for C 20 H 29 O 4, 333.2021) and [M + Na] - m / z 355.1874 (calcd for C 20 H 28 O 4 Na, 355.1885 ).

- 5-methyl-2-Parr nesil -1-O- methyl hard quinone (5- farnesyl -2-methyl-1 -O-methylhydroquinone; Compound 2): yellow oil (MeOH); UV (MeOH) λ _max (log ε) 228 (3.40), 288 (3.18) nm; IR ν _max 2926, 2864, 2340, 1723, 1653, 1510, 1455, 1395, 1197 cm ^-1 ; ¹ H (500 MHz, CD ₃ OD) and ¹³ C (100 MHz, CD ₃ OD), see Table 1 above; (-)-HRESIMS m / z 341.2486 [M-H] ^- (calcd for C ₂₃ H ₃₃ O ₂ , 341.2592).

-4-O- Methylisogrifolin ( 4-O- Methylisogrifolin ; Compound 3): yellow oil (MeOH); ¹ H (500 MHz, CD ₃ OD) and ¹³ C (100 MHz, CD ₃ OD), see Table 1 above; (-)-HRESIMS m / z 341.2486 [M-H] ^- (calcd for C ₂₃ H ₃₃ O ₂ , 341.2592).

- Parr nesil benzenediol (Farnesylbenzenediol ; Compound 4): Yellow oil (MeOH); ¹ H NMR (500 MHz, CD ₃ OD): δ 1.57 (3H, s), δ 1.58 (3H, s), δ 1.64 (3H, s), δ 1.68 (3H, s), δ 1.94 (2H, m ), δ 2.02 (5H, m), δ 2.09 (3H, s), δ 2.10 (1H, m), δ 3.22 (3H, s), δ 5.07 (1H, m), δ 5.11 (1H, m), δ 5.31 (1H, t), δ 6.51 (1H, s), δ 6.52 (1H, s); ¹³ C NMR (100 MHz, CD ₃ OD): δ 148.8, 148.3, 136.3, 135.7, 131.8, 127.0, 125.4, 125.3, 124.1, 123.1, 118.2, 116.2, 40.8, 40.8, 28.7, 27.7, 27.6, 26.0, 17.8 , 16.3, 16.2, 16.0. (+)-FABMS m / z 329 [M + H] ^- .

-7 - Deacetoxyyanuthone ; Compound 5): Yellow oil (MeOH); ¹ H NMR (500 MHz, CD ₃ OD): δ 1.58 (3H, s), δ 1.59 (3H, s), δ 1.65 (3H, s), δ 1.66 (3H, s), δ 1.96 (2H, m ), δ 1.97 (1H, m), δ 1.97 (3H, s), δ 2.01 (2H, m), δ 2.07 (3H, m), δ 2.38 (1H, dd), δ 2.74 (1H, dd), δ 3.64 (1H, d), δ 4.49 (1H, brs), δ 5.07 (3H, m), δ 5.71 (1H, s); ¹³ C NMR (100 MHz, CD ₃ OD): δ 195.8, 159.5, 140.1, 136.1, 132.0, 125.4, 125.2, 123.7, 118.2, 68.2, 61.7, 60.6, 40.8, 40.8, 27.8, 27.8, 27.3, 26.0, 20.3 , 17.8, 16.4, 16.1. (-)-FABMS m / z 325 [M-H] ^- .

- Parr nesil quinone (Farnesylquinone; Compound 6): yellow oil (MeOH); ¹ H NMR (500 MHz, CD ₃ OD): δ 1.58 (3H, s), δ 1.60 (3H, s), δ 1.65 (3H, s), δ 1.97-2.10 (8H, m), δ 2.00 (3H , s), δ 2.00 (3H, s), δ 3.10 (2H, s), δ 5.09 (2H, m), δ 5.17 (1H, m), δ 6.48 (1H, s), δ 6.62 (1H, s ); ¹³ C NMR (100 MHz, CD ₃ OD): δ 189.3, 188.8, 149.5, 146.9, 140.4, 136.3, 134.4, 132.2, 131.8, 125.4, 125.0, 119.8, 40.8, 40.7, 28.1, 27.8, 27.3, 26.0, 17.8 , 16.3, 16.2, 15.5. (+)-FABMS m / z 345 [M + H] ^- .

(4) Cell culture and cell viability check

RAW 264.7 murine macrophages were purchased from Korean Cell Line Bank (KCLB, Seoul, Korea), and rat liver Ac2F cells were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA). The cells were cultured in a 37 ° C., 5% CO ₂ soaked incubator, 10% heat-inactivated fetal bovine serum ((FBS, Gibco), 100 units / mL penicillin (HyClone), and 100 μg / mL streptomycin ( HyClone) was maintained in high glucose Dulbecco's modified Eagle medium (DMEM / HIGH GLUCOSE, HyClone) .After incubation, the cells were seeded in 96-well culture plates and incubated for 12 hours, and the compounds obtained above were varied. Treatment was conducted at a concentration for 24 hours.

Cell viability was measured using a water soluble tetrazolium (WST) reagent (EZ-CyTox, Daeil Lab Service Co., Ltd., Seoul, Korea), wherein 10 μL of the WST reagent was added to each well. Treated and incubated for 1 hour at 37 ° C. Finally, the absorbance at 450 nm wavelength was confirmed by iMark Microplate Absorbance Reader (Bio-Rad Laboratories, Hercules, CA, USA).

(5) Luciferase Assay

A TK-PPRE X3-luciferase reporter plasmid containing three copies of the PPAR response element (PPRE) was added to the acyl CoA promoter. Christopher K. Glass (University of California, San Diego, CA, USA). The pcDNA3 expression vector and the full-length human PPAR-γ1 expression vector (pFlag-PPAR-γ1) were selected from Dr. Chatterjee (University of Cambridge, Addenbrooke's Hospital, Cambridge, UK).

For luciferase assay, effector plasmid and PPRE-X3 in 48-well plates (5 X 10 ⁴ cell / well) using Lipofectamine ^TM 2000 (Invitrogen Co., Carlsbad, CA, USA) according to the manufacturer's instructions. In addition to -TK-luciferase reporter plasmid (1 μg / well), cells of 70-80% cell density were transfected with pcDNA3 (0.1 μg / well) or pFlag-PPAR-γ1 (0.1 μg / well). One of the control cells was transfected with a plasmid containing only pcDNA3 in a blank cell and a plasmid containing PPRE in another control cell. After 4 hours of transfection, the conditioned medium was replaced with complete medium, and the cells were further incubated for an additional 10 hours. The medium was then removed, and the cells were treated with rosiglitazone or the compounds dissolved in serum-free medium for 6 hours. Thereafter, the cells were lysed and assays were performed using a ONE-Glo ^™ luciferase assay system (Luciferase Assay System; Promega, Madison, WI, USA). Luciferase activity was measured via a GloMax-Multi Microplate Multimode Reader (Promega Co., Sunny Vale, CA, USA).

(6) Reverse Transcriptase-PCR (RT-PCR)

To confirm the expression of inflammatory markers in RAW 264.7 cells by RT-PCR, total RNA is first isolated with a trizol reagent (Invitrogen, Carlsbad, CA, USA), and the first strand cDNA is combined with total RNA and M-MLV cDNA Synthesis kit (Enzynomics, Daejeon, Korea). Thereafter, cDNA products and primers of each gene were used when PCR was performed in a BIO-RAD T100 ™ Thermal Cycler PCR unit (Hercules, CA, USA) using AccuPoweruPCR PreMix (BIONEER, Seoul, Korea). At this time, specific primers used to amplify the gene fragments were as shown in Table 2 below.

gene Kinds Sequence Sequence number iNOS Forward 5'-ACC TAC CAC ACC CGA GAT GGC CAG-3 ' One Reverse 5'-AGG ATG TCC TGA ACA TAG ACC TTG GG-3 ' 2 COX-2 Forward 5'-CCG TGG GGA ATG TAT GAG CA-3 ' 3 Reverse 5'-CCA GGT CCT CGC TTA TGA TCT G-3 ' 4 IL-1β Forward 5'-GGA GAA GCT GTG GCA GCT A-3 ' 5 Reverse 5'-GCT GAT GTA CCA GTT GGG GA-3 ' 6 IL-6 Forward 5'-TGG GAA ATC GTG GAA ATG AG-3 ' 7 Reverse 5'-GAA GGA CTC TGG CTT TGT CT-3 ' 8 GAPDH
Forward 5'-TTC ACC ACC ATG GAG AAG GC-3 ' 9 Reverse 5'-GGC ATG GAC TGT GGT CAT GA-3 ' 10 TNF-α
Forward 5'-AGC ACA GAA AGC ATG ATC CG-3 ' 11 Reverse 5'-GTT TGC TAC GAC GTG GGC TA-3 ' 12

PCR of the genes iNOS, COX-2, IL-1β, IL-6, and GAPDH was performed for 27 cycles consisting of denaturation at 95 ° C for 30 seconds, annealing at 57 ° C for 30 seconds, and stretching at 72 ° C for 30 seconds. PCR of TNF-α was performed during cycle 27 consisting of denaturation at 95 ° C for 30 seconds, annealing at 60 ° C for 30 seconds, and stretching at 72 ° C for 30 seconds. Thereafter, an aliquot (6 μL) of the PCR product was electrophoresed on a 1.2% agarose gel, and stained with ethidium bromide.

(7) Western Blot

Cells were collected and homogenized in lysis buffer containing a phosphatase inhibitor cocktail. Nuclear protein extraction was performed using NE-PER nuclear and cytoplasmic extraction reagents; Thermo Scientific, Rockford, IL, USA. The concentration of the protein was determined through a BCA protein assay (Thermo Scientific, Rockford, IL, USA), and after dissolving the protein equivalent in 10% SDS-polyacrylamide gel electrophoresis, polyvinylidene difluoride through electrophoresis. It was transferred to a ride (PVDF) membrane, where it was blocked for 1 hour at room temperature with Tris-buffered saline containing 0.1% Tween 20 (TBS-T) and 5% skimmed milk, and then COX. Incubated overnight at 4 ° C. with specific primary antibodies (Cell Signaling Technology, Danvers, MA, USA) that recognize -2, iNOS, PPAR-γ, NF-κB p-p65, and β-actin. Anti-rabbit horseradish-linked IgG was used as a secondary antibody, and signals were developed through the ChemiDoc ™ Touch Imaging System (Bio-Rad Laboratories, Hercules, CA, USA).

(8) Concentrations of NO and cytokines Cytokines  Released to Medium)

RAW 264.7 macrophages (1X10 ⁴ cells / well) were seeded in 96-well culture plates and cultured for 12 hours, and pretreated with various concentrations of compounds or dexamethasone for 1 hour. Thereafter, the cells were co-cultured with LPS of 25 ng / mL for 24 hours.

The NO concentration of the medium was determined through a Grease assay: Grease reagent (80 μL) was added to the medium supernatant (80 μL), and cultured at 37 ° C. in a dark condition for 20 minutes. Thereafter, absorbance was measured at 520 nm. Finally, the NO concentration was determined using a 0 to 100 μM sodium nitrite standard.

In addition, the TNF-α, IL-1β, and IL-6 expression levels of the culture medium were quantified through a sandwich-type ELISA kit (Biolegend, San Diego, CA, USA).

(9) Molecular docking study

Docking calculations were performed using AutoDock Vina 1.1.2 software (The Scripps Research Institute, La Jolla, CA, USA). The default settings and Vina scoring function have been applied.

For PPAR-γ ligand preparation, Chem3D Ultra 14.0 software (CambridgeSoft Corporation, Cambridge, MA, USA) was used to convert the 2D structure of the candidate into 3D structure data. Protein coordinates were downloaded from Protein Data Bank (accession code: 4A4W). For docking, chain A of the PPAR-γ protein was prepared in the molecular modeling software package Chimera 1.5.3 (National Institutes of Health, Bethesda, MD, USA) by removing chain B, all ligands and water molecules.

Polar hydrogen atom and grid box parameter settings were added via MGLTools 1.5.4 (The Scripps Research Institute, La Jolla, CA, USA). Analysis and visual investigation of the ligand-protein interaction of the docking pose was performed using Discovery Studio 4.3 (Accelrys Inc., San Diego, USA). The success or failure of docking was evaluated through the lowest affinity value.

(10) Statistics

The significance of the differences in each experimental group was determined through ANOVA. Results were expressed as mean ± standard deviation, the number of indicators in an independent experiment. It was judged that there was statistical significance when p- value was less than 0.05.

2. Experimental results

(1) Confirmation of structural properties of new compounds

As a result of the above experiment, chrysogen ester (compound 1) was first obtained as a yellow oil. The molecular formula of this compound is in HRESIMS spam spectrum [M + H] ^- ions (m / in _{z 333.2056 (calcd for C 20 H} 29 O 4, 333.2021)) and [M + Na] ^- ion (m / z 355.1874 ( on the basis of the _{calcd for C 20 H 28 O 4} Na, 355.1885)) was given as C ₂₀ H ₂₈ O _4. The IR absorbance band observed at 1740 cm ⁻¹ means the presence of an ester group, and the UV absorbance maxima (λ _max ) at 224, 252, and 295 nm indicate the presence of a benzene chromophore. As shown in Table 1, as a result of analyzing ¹ H and ¹³ C NMR spectral data of Compound 1, it was confirmed that the structural properties of Compound 1 are similar to farnesylbenzenediol (Compound 4). It was speculated that the aromatic moieties of compound 1 (δ _H-3 6.48 and δ _{H- 6} 6.47) exhibited the same NMR pattern as compound 4, and thus would have been linked to the isoprenyl moiety. However, the farnesyl chain of compound 1 lacks the 3-carbon isopropenyl terminus of compound 4, and has been replaced by an ester group instead. In addition, two typical olefin protons of the isoprenyl moiety (δ _{H -2 '} 5.28 and δ _{H -6'} 5.14) and an additional carbonyl signal of the ester moiety (δ _{C -10 '} 174.4) are observed. Became. The binding between the two moieties is the HMBC correlation from H-8 '(δ _H 2.24) to C-10', C-6 'and C-11', and H-8 'and H-9' (δ _H 2.35) was established by ¹ H- ¹ H Cauchy (COSY) correlation between. The relative arrangement of the two double bonds of the isoprenyl moiety was given as E according to the ROSEY correlation between H-2 'and H-4' (δ _H 2.02) and H-6 'and H-8'. Dots are compounds of the methyl carbon signal at two 14.6 (C-11 ') and 14.9 (C-12') (E configuration, δ _CH3 : 15-17 ppm; Z configuration, δ _CH3 : 23-24 ppm) It was confirmed by shift.

Thus, as shown in Figure 1, it was confirmed that Compound 1 (Chrysogenester) has a unique structure due to the cleavage of the 3-carbon isoprenyl tail from the farnesyl chain.

On the other hand, 5-farnesyl-2-methyl-1-O-methylhydroquinone (Compound 2) was obtained as a yellow oil. The molecular formula of the compound is in its spectrum HRESIMS [M ^- H] - based on the ion (m / z (calcd for C 23 H 33 O 2, 333.2021) at 341.2486) was given as C ₂₃ H ₃₄ O _2. The ¹ H and ¹³ C NMR spectra of Compounds 2 and 3 were very similar to that of Compound 4 for additional methoxy group signals. Based on the comparison of their NMR data, compounds 2 and 3 were considered isomers and were distinguished by the HMBC correlation between methoxyl proton and aromatic carbon (C-1 in compound 2 and C-4 in compound 3). The relative arrangement of the two double bonds in the farnesyl moiety was given as E as in compound 1 above ( δ _{C- 14 '} and δ _{C- 15} : ~ 16 ppm). Thus, compound 2 was identified as 5-farnesyl-2-methyl-1-O-methylhardoquinone.

(2) Check whether Compound 1 and PPAR-γ are bound

Amorphutin B has been reported to be a partial PPAR-γ agonist with significant binding affinity to PPAR-γ LBD (EC ₅₀ 0.050 μM; rosiglitazone EC ₅₀ 0.004 μM). The crystal structure of the PPAR-γ LBD / amorphutin B complex includes two amorphutin molecules bound to chain A and chain B (inactivation) of the PPAR-γ protein. In the active structure of chain A, amorphutin B stabilizes the β-sheet region of the binding pocket of helix H3 and PPAR-γ LBD through hydrogen bonding with Ser ³⁴² . Several hydrophobic interactions around the long geranyl side chain of amorphutin B have been reported to be essential for high binding affinity to PPAR-γ. Since Compound 1 and Amorphutin B have a common structural motif, it was confirmed by in silico experiments whether or not PPAR-γ binding of Compound 1 was initiated.

As a result, as shown in FIG. 2, when Compound 1 was bound to PPAR-γ LBD, it was confirmed that it was bound under conditions similar to Amorphutin B in position and direction. The binding affinity (-8.7 kcal / moL) value of Compound 1 was similar to Amorphutin B (-9.4 kcal / moL). In addition, as shown in FIG. 2, additional hydrogen bonds of Helix H3 of Compound 1 with Cys ²⁸⁵ and Arg ^288, and additional hydrogenous contact with Helix H4 / 5 and β-sheets were confirmed. Therefore, it was found that Compound 1 acts as a PPAR-γ ligand and binds under conditions similar to Amorphutin B.

(3) Cell viability check

Prior to confirming the PPAR-γ activity in the murine Ac2F hepatocytes and RAW 264.7 macrophages of the compounds 1 to 6 identified and isolated above, cell viability in order to confirm cytotoxicity at the test concentration for setting the appropriate concentration of each compound As a result of evaluation, as shown in Fig. 3, only Compound 1 was found to have no cytotoxicity at a concentration up to 50 μM. Thus, only Compound 1, which has no cytotoxicity, was used in experiments to be performed later.

(4) Luciferase Assay  through PPAR -γ activation activity confirmation result

PPAR-γ is a ligand-activated transcription factor, and when the ligand binds to PPAR-γ, the structure of its ligand binding domain (LBD) changes to allow co-activator binding. Subsequently, the ligand / PPAR-γ complex forms a heterodimer with the retinoid X receptor (RXR), another nuclear receptor, and the heterodimeric form of the complex is a peroxisome proliferator response of DNA that initiates gene transcription. element; PPRE) region.

Based on this point, PPAR-γ activation activity was confirmed through a luciferase assay. As described above, it was transfected with a PPRE-X3-TK luc plasmid (PPRE-luc) and a PPAR-γ q expression vector. As a result of treating vehicle (negative control), compound 1 or rosiglitazone (positive control) on Ac2F cells (murine liver cell line), it was confirmed that compound 1 activates PPAR-γ concentration-dependently, as shown in FIG. 4. ; At a concentration of 20 μM, Compound 1 increased the luciferase expression level to a level similar to 5 μM of rosiglitazone, which was three times more than the control.

(5) Western Blot  Through the nucleus PPAR -γ protein level measurement result

PPAR-γ is present in the cytoplasm and nucleus, but when the ligand is bound, the PPAR-γ / ligand complex moves to the nucleus. Based on this point, the level of PPAR-γ protein activated with compound 1 in the nuclear fraction was confirmed by Western blot.

As a result, as shown in FIG. 5, when Compound 1 or rosiglitazone was treated in RAW 264.7 cells for 24 hours, 30 μM of Compound 1 significantly increased PPAR-γ levels in the nucleus (increased to about 1.7-fold) ), 10 μM of rosiglitazone showed an increase of up to 1.5 times.

(6) Western Blot  through NF - κB  Phosphorylation confirmation

In the nucleus, PPAR-γ regulates gene transcription through transcription promotion or transcription inhibition. During the transcription promotion process, PPAR-γ forms a heterodimer complex with RXR and recognizes PPRE at the promoter region of the target gene, which ultimately transduces the PPAR-γ target gene related to adipocyte differentiation and glucose and lipid metabolism. Leads to results. On the other hand, during the transcription inhibition process, PPAR-γ suppresses gene expression by inhibiting the NF-κB signal transduction pathway. NF-κB is a transcriptional control factor, and is an inducible transcription factor that plays an important role in immune and inflammatory reaction situations. This NF-κB consists of a total of 5 subunits (RelA / p65, c-Rel, RelB, p50, and p52), and phosphorylation of the NF-κB subunit increases or decreases the transcription of the target gene during an inflammatory reaction. Or modulates NF-κB activation, the activated NF-κB signal upregulates several inflammatory mediators (COX-2, iNOS, TNF-α, IL-1β, IL-6).

Based on this, Western blot induced with compound 1 was performed in LPS-activated RAW 264.7 cells to confirm the p65 phosphorylation level of NF-κB (signal response of NF-κB). Phosphorylation of p65 causes structural changes, which affect not only the ubiquitination and stability of p65, but also the protein-protein interactions that activate the NF-κB signaling pathway.

As a result of the experiment, as shown in FIG. 6, the level of p65 of phosphorylated NF-κB was significantly increased by LPS, but Compound 1 inhibited NF-κB p65 phosphorylation in a concentration-dependent manner. In addition, 30 μM of Compound 1 inhibited NF-κB p65 phosphorylation more strongly (up to 2.6 times) than the positive control of 10 μM of dexamethasone (suppressed to about 1.8 times). From these results and PPAR-γ inhibits the activity of NF-κ through protein-protein interaction, it can be confirmed that Compound 1 acts as an agonist of PPAR-γ that inhibits the NF-κB signal transduction pathway. there was.

(7) Results of inflammatory mediator level measurement

Transcription of inflammatory factors such as TNF-α, IL-1β, IL-6, iNOS, COX-2 can be regulated by NF-κB. Thus, mRNA levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2 in LPS-induced RAW 264.7 macrophages in order to confirm the possibility of NF-κB inhibition by Compound 1 exhibiting anti-inflammatory effects Was measured via RT-PCR.

As a result, as shown in FIG. 7, the mRNA level of the inflammatory mediators was dramatically decreased and the concentration-dependent decrease tendency was observed by pre-treatment of Compound 1. More specifically, 50 μM of Compound 1 significantly reduced iNOS, COX-2, TNF-α, IL-1β, and IL-6 by 5 times, 2 times, 2 times, 2.5 times, and 5 times, respectively, which is 10 The result was better than the pretreatment of μM dexamethasone. In particular, Compound 1 actually reduced the levels of iNOS and TNF-α to a degree similar to dexamethasone.

In addition, as a result of confirming the effect of Compound 1 once again by confirming the amount of iNOS and COX-2 proteins through Western blot, as shown in FIG. 8, Compound 1 continuously and concentration-dependently decreased iNOS levels similarly to dexamethasone. And the effect on this iNOS protein was greater than the effect on COX-2.

Next, the effect of Compound 1 on NO, TNF-α, IL-1β, and IL-6 levels was confirmed by Greek assay and ELISA, and as shown in FIG. 9, the generation of all four inflammatory mediators was remarkably, Inhibited by Compound 1 in a concentration dependent manner. In addition, Compound 1 was able to inhibit the production of NO and TNF-α, similar to dexamethasone, and this effect was consistent with the gene expression confirmation results disclosed in FIGS. 7 and 8 above.

Therefore, in sum of the above experimental results, Compound 1 of the present invention suppresses the expression of inflammatory mediators through PPAR-γ activation, and can also suppress NF-κB, thereby treating diseases related to PPAR-γ. It can be useful for having.

Since the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that this specific technique is only a preferred embodiment, whereby the scope of the present invention is not limited. Do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

<110> Pusan National University Industry-University Cooperation Foundation <120> Novel Meroterpene Compound, and Composition for Preventing or          Treating PPAR-gamma Associated Diseases Comprising the Same <130> ADP-2017-0554 <160> 12 <170> KoPatentIn 3.0 <210> 1 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 1 acctaccaca cccgagatgg ccag 24 <210> 2 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 2 aggatgtcct gaacatagac cttggg 26 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 3 ccgtggggaa tgtatgagca 20 <210> 4 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 4 ccaggtcctc gcttatgatc t 21 <210> 5 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 5 ggagaagctg tggcagcta 19 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 6 gctgatgtac cagttgggga 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 7 tgggaaatcg tggaaatgag 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 8 gaaggactct ggctttgtct 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 9 ttcaccacca tggagaaggc 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 10 ggcatggact gtggtcatga 20 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 11 agcacagaaa gcatgatccg 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 12 gtttgctacg acgtgggcta 20

Claims (15)

A merotene pen compound represented by Formula 3 or a pharmaceutically acceptable salt thereof:
[Formula 3]

delete delete The meroterpene compound of claim 1, wherein the meroterpene compound is an agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) or a pharmaceutical thereof. Acceptable salts. According to claim 1, wherein the meroterpene compound is a penicillium chrysogenum derived from jellyfish, characterized in that isolated from the bacterium Meroterpene compound or a pharmaceutically acceptable salt thereof. In the group consisting of inflammation, diabetes, insulin resistance, leptin resistance, lipid metabolism abnormality, sugar metabolism abnormality, hyperlipidemia and metabolic syndrome, which include as a active ingredient a meroterpene compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof Pharmaceutical composition for preventing or treating PPAR-γ related disease selected:
[Formula 3]

delete delete delete The pharmaceutical composition for preventing or treating PPAR-γ-related diseases according to claim 6, wherein the merotene compound prevents or treats PPAR-γ-related diseases by inhibiting a NF-κB signal transduction pathway. In the group consisting of inflammation, diabetes, insulin resistance, leptin resistance, lipid metabolism abnormality, sugar metabolism abnormality, hyperlipidemia and metabolic syndrome, which include as a active ingredient a meroterpene compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof Health functional food composition for preventing or improving PPAR-γ related diseases selected:
[Formula 3]

delete delete delete 12. The composition of claim 11, wherein the meroterpene compound prevents or improves PPAR-γ related diseases by inhibiting the NF-κB signal transduction pathway.

Images