KR101934630B1 - Novel lignan derivatives isolated from A. holophylla and identified and use thereof - Google Patents

Abstract

The present invention relates to a novel lignan derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising these as an active ingredient.

Description

Novel lignan derivatives isolated from A. holophylla and identified and use thereof.

The present invention relates to a novel lignan derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising these as an active ingredient.

Inflammatory reactions are caused by various inflammatory mediators and immune cells in the local blood vessels and body fluids when they are infected with tissue (cell) damage or external infectious agents (bacteria, fungi, viruses, various kinds of allergens) It exhibits a series of complex physiological responses such as substance secretion, fluid infiltration, cell migration, and tissue destruction, and external symptoms such as erythema, edema, fever, and pain. In normal cases, the inflammatory reaction removes the external infectious agent and regenerates the damaged tissue to regenerate the organism's function. However, if the antigen is not removed or the internal substance causes the inflammatory reaction to occur excessively or continuously, Some lead to diseases such as cancer.

Recently, it has been found that inflammatory reaction is one of the main mechanism causing neurodegeneration. In other words, the immune cells of the central nervous system, the small ganglion cells, can be activated by various exogenous and endogenous substances, and the activated small glioblastoma cells are activated by the inflammatory cytokines TNF-α and IL-1β, daily nitric oxide, prostaglandins, (Neo et al., J Neurochem, 81, 1285-97, 2002; Nelson, PT et al., Ann Med, 34, 491-500, 2002; Griffin, WS et al., J Neuroinflammation, 3 , 5, 2006). The production of these substances induces an immune response in the short term, but excessive production or sustained production induces neuronal death of adjacent neurons, resulting in neural degeneration. In addition, since the substances released by the nerve cells that are killing lead to activation of the cervical ganglion cells, the neural degeneration falls into a constant vicious cycle. Actually, the activity of small glial cells has been reported to be related to various degenerative neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Creutzfelt-Jakob Disease (CJD) and multiple sclerosis.

Taking into consideration the importance of neuroinflammatory responses in degenerative brain diseases, it is possible to treat neuroinflammation and degenerative brain diseases that may be caused by it by decreasing the expression level of proinflammatory mediators in these small glial cells .

Accordingly, the inventors of the present invention have conducted intensive studies and efforts to discover compounds derived from natural materials that can prevent or treat degenerative brain diseases such as neuroinflammation and / or dementia. As a result, it has been found that a series of compounds identified from fir extract, And promotes the secretion of nerve growth factor (NGF). Thus, the present invention has been completed.

It is an object of the present invention to provide a series of novel lignan derivatives or their pharmaceutically acceptable salts.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising a series of lignan derivatives or a pharmaceutically acceptable salt thereof as an active ingredient.

It is still another object of the present invention to provide a method for treating neuroinflammation or degenerative brain diseases comprising administering the pharmaceutical composition to a subject in need thereof.

It is still another object of the present invention to provide a health functional food additive for preventing or ameliorating a neuroinflammation or degenerative brain disease comprising a series of lignan derivatives or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising, as an active ingredient, a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof: to provide:

[Chemical Formula 1]

In the above formulas,

R ₁ is hydrogen, C _1-6 alkyl or β-D-Glc,

이거나,R ₂ to R ₅ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 coumaroyloxyalkyl or

Lt; / RTI &

R < ₆ > is two hydrogen or double bonded oxygen,

R < ₇ > is hydrogen or hydroxy,

R ₈ is hydrogen, C _1-6 alkyl or β-D-Glc,

R < ₉ > is hydrogen or hydroxy,

n is 0 or 1;

For example, R < ₁ > is hydrogen, methyl or beta -D-Glc,

이거나,R ₂ to R ₅ are each independently hydrogen, methyl, hydroxymethyl, coumaroyloxymethyl or

Lt; / RTI &

R < ₆ > is two hydrogen or double bonded oxygen,

R < ₇ > is hydrogen or hydroxy,

R < ₈ > is hydrogen, methyl or beta -D-Glc,

R < ₉ > is hydrogen or hydroxy,

n is 0 or 1;

Specifically, the compound

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,

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,

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,

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또는 10)

일 수 있다.9)

Or 10)

Lt; / RTI >

The present invention also provides a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases comprising, as an active ingredient, a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof:

(2)

In the above formulas,

R ₁ is? -D-Xyl or? -D-Glc,

R ₂ is hydrogen or C _1-6 alkyl.

For example, R ₁ is? -D-Xyl or? -D-Glc,

R ₂ is hydrogen or methyl.

Specifically, the compound

, 12)

, 11)

, 12)

,

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,13)

, 14)

,

또는 16)

일 수 있다.15)

Or 16)

Lt; / RTI >

의 구조식을 갖는 치환기를 의미한다.In the present invention, "? -D-Xyl "

≪ / RTI >

의 구조식을 갖는 치환기를 의미한다.In the present invention, the "? -D-Glc "

≪ / RTI >

In another aspect, the present invention also provides a compound represented by the following general formula (2): < EMI ID =

(2)

In the above formulas,

R ₁ is? -D-Xyl or? -D-Glc,

R ₂ is hydrogen or C _1-6 alkyl.

For example, R ₁ is? -D-Xyl or? -D-Glc,

R ₂ is hydrogen or methyl.

Specifically, the compound

, 12)

,11)

, 12)

,

또는 14)

일 수 있다.13)

Or 14)

Lt; / RTI >

The compounds of the present invention may be lignan derivatives isolated from fir extract or fractions thereof. For example, it can be obtained by extracting and extracting from natural, hybrid, fungal root, ground part, stem, branch, leaf, fruit or plant tissue culture of fir, etc. For example, fir is extracted with methanol and separated from a fraction obtained by successive fractionation with a series of organic solvents such as n-hexane, chloroform, ethyl acetate, and n-butanol, but not limited thereto.

The compounds according to the present invention can inhibit the production of nitrogen monoxide known as an inflammation-related factor or promote the secretion of nerve growth factor and thus can be used for the prevention or treatment of neuroinflammation or degenerative brain diseases that may be caused therefrom .

In the present invention, " neuroinflammation " may be a term collectively referred to as an inflammatory reaction occurring in the nervous system, that is, a nerve cell, a neural tissue, or the like. Small intestinal gliomas, which are immune cells present in the central nervous system, can be activated by various exogenous and endogenous substances and produce and release inflammatory factors such as nitrogen monoxide. The production of these substances induces an immune response in the short term, but it is known that excessive production or sustained production induces neuronal degeneration by inducing the death of adjacent neurons.

The term " degenerative brain disease " in the present invention refers to diseases that cause degenerative changes in nerve cells of the central nervous system and cause various symptoms, and specifically, disorders of cognitive function, learning or memory, ≪ / RTI > For example, the degenerative brain diseases which can be prevented or treated by using a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient include vascular cognitive disorder, dermentia, Alzheimer's disease Parkinson ' s disease, Lewy body disease, frontotemporal lobar degeneration, stroke, cerebral arteriosclerosis, stroke, Huntington ' s disease, Pick's the present invention relates to the use of the compounds of the present invention for the treatment of diseases such as Creutzfeldt-Jakob disease, Amyotrophic lateral sclerosis, multiple sclerosis, ischemic brain disease, cerebral infarct, corticobasal degeneration, progressive supranuclear palsy, or Down syndrome.

In the present invention, " prevention " refers to any action that inhibits or delays the onset of neuroinflammation or degenerative brain disease upon administration of the composition, and " treatment " means that the composition alleviates symptoms due to neuroinflammation or degenerative brain disease It refers to all actions that benefitfully change.

The pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may further comprise an appropriate carrier, adduct or diluent conventionally used in the production of a pharmaceutical composition. The compound of the present invention or a pharmaceutically acceptable salt thereof may be used in an amount of 0.001% by weight to 99% by weight, preferably 0.01% by weight to 50% by weight, based on the total weight of the composition, . ≪ / RTI >

The pharmaceutical composition may be any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, nonaqueous solvents, suspensions, emulsions, And may be oral or parenteral formulations of various forms. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

In another aspect, the present invention provides a method of treating neuroinflammation or degenerative brain disease comprising administering the pharmaceutical composition to a subject in need thereof.

In the present invention, the term " individual " refers to all animals including humans, in which the disease has developed or may cause neuroinflammation or degenerative brain diseases. By administering the pharmaceutical composition of the present invention to the individual, Or can treat the disease that has occurred efficiently. The pharmaceutical composition and neuroinflammation or degenerative brain disease are as described above.

In the present invention, " administering " is intended to introduce the pharmaceutical composition of the present invention to suspect individuals of neuroinflammation or degenerative brain disease by any suitable method, and the administration route may include various routes of oral or parenteral administration ≪ / RTI >

The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount.

The term " pharmaceutically effective amount " as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will vary depending on the species and severity, age, sex, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.

The pharmaceutical composition of the present invention is not particularly limited as long as it is a subject for neuroinflammation or degenerative brain disease, and any of them can be applied. For example, any non-human animal such as a monkey, a dog, a cat, a rabbit, a guinea pig, a rat, a mouse, a cattle, a sheep, a pig or a goat can be used. Subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and may be administered by a suitable method, including localized administration, if necessary, for localized treatment. The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and body weight of the individual, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. For example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection.

Suitable total daily doses may be determined by the treatment within the scope of sound medical judgment and are generally in the range of 0.001 to 1000 mg / kg, preferably 0.05 to 200 mg / kg, more preferably 0.1 to 100 mg / kg can be administered once or several times a day.

In another aspect, the present invention provides a health functional food additive for preventing or ameliorating a neuroinflammation or degenerative brain disease comprising, as an active ingredient, a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In the above formulas,

R ₁ is hydrogen, C _1-6 alkyl or β-D-Glc,

이거나,R ₂ to R ₅ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 coumaroyloxyalkyl or

Lt; / RTI &

R < ₆ > is two hydrogen or double bonded oxygen,

R < ₇ > is hydrogen or hydroxy,

R ₈ is hydrogen, C _1-6 alkyl or β-D-Glc,

R < ₉ > is hydrogen or hydroxy,

n is 0 or 1;

The present invention also provides a health functional food additive for preventing or ameliorating a neuroinflammation or degenerative brain disease comprising a compound represented by the following general formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient:

(2)

In the above formulas,

R ₁ is? -D-Xyl or? -D-Glc,

R ₂ is hydrogen or C _1-6 alkyl.

The nerve inflammation or degenerative brain disease is as described above.

In the present invention, the term " improvement " refers to the use of a composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient to prevent or treat symptoms of suspected or suspected diseases such as neuroinflammation or degenerative brain disease It refers to all acts that are improved or benefited.

Specifically, a compound of the present invention or a pharmaceutically acceptable salt thereof may be added to a health functional food composition for the purpose of preventing or ameliorating neuroinflammation or degenerative brain disease.

The food composition of the present invention may be in the form of pills, powders, granules, infusions, tablets, capsules or liquid preparations, and the kind of food to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be added There are no limitations, for example, various beverages, gums, tea, vitamin complex, and health supplement foods.

In addition to the compound of the present invention or its pharmaceutically acceptable salt, other ingredients may be added to the food composition, and the kind thereof is not particularly limited. For example, it may contain various herbal medicine extracts, food-acceptable food-aid additives or natural carbohydrates such as ordinary food, but is not limited thereto.

The above-mentioned " food-aid additive " is a component that can be added to food, and it can be added to make a health functional food of each formulation and can be appropriately selected and used by those skilled in the art. Examples of food-aid additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, , a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated beverage. However, the types of the food auxiliary additives of the present invention are not limited by the above examples.

Examples of the natural carbohydrate include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose and the like; And polysaccharides such as dextrin and cyclodextrin and sugar alcohols such as xylitol, sorbitol and erythritol. In addition to the above, natural flavorings (such as tau mart), stevia extracts (rebaudioside A, Etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.

The food composition of the present invention may include a health functional food. The above-mentioned "health functional food" refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids, and circles by using raw materials and components having useful functions in the human body. The term "functional" as used herein refers to the structure and function of the human body, which has a beneficial effect on health uses such as controlling nutrients or physiological actions. The health functional food of the present invention can be manufactured by a method commonly used in the art and can be prepared by adding raw materials and ingredients which are conventionally added in the art. Also, unlike general medicine, there is an advantage that there is no side effect that can occur when a medicine is used for a long time by using food as a raw material, and it is excellent in portability.

The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). In general, the compound of the present invention or a pharmaceutically acceptable salt thereof may be added in an amount of 1 to 50% by weight, preferably 5 to 10% by weight of the raw material composition, no. However, in the case of long-term ingestion intended for health and hygiene purposes or for the purpose of controlling health, the amount can also be used in the above-mentioned range.

There is no particular limitation on the kind of the food. Examples of the food to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, An alcoholic beverage, and a vitamin complex, and may include all health functional foods in a conventional sense.

The compound of the present invention or a pharmaceutically acceptable salt thereof is a substance isolated from a natural fir and is capable of inhibiting the generation of nitrogen monoxide, an inflammation-related factor, or promoting the secretion of neurotransmitters, without toxicity or side effects. Inflammatory or degenerative brain diseases.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 schematically shows a method for obtaining compounds of formulas 1-16 by extraction and fractionation from fir according to the present invention. FIG.
FIG. 2 is a graph showing the major ¹ H- ¹ H COZY (bold line) and HMBC (arrow) correlation of the compounds 11 and 14 according to the present invention.

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

Example  1: Sample preparation

In January 2012, a trunk of A. holophylla was collected from Seoul, and the plant was identified by one of the inventors, Professor Yi Jangno. A voucher specimen (SKKU-NPL 1205) is stored in the herbarium of the College of Pharmacy, Sungkyunkwan University, Suwon, Korea.

Example  2: Extraction

The fir stalks (5.0 kg) were refluxed with 80% aq. Extraction with methanol and filtration. The filtrate was distilled under reduced pressure to obtain a methanol extract (280 g), suspended in distilled water and successively fractionated with n-hexane, CHCl ₃ , EtOAc and n-butanol to obtain 23, 43, 17, ≪ / RTI >

Specific extraction and fractionation methods are illustrated in FIG.

Example  3: Isolation and identification of compounds

Using the extensive column chromatography (RP-C18 silica gel, silica gel, and HPLC column), chemical analysis of the CHCl ₃ soluble fraction (20 g) showed that the lignans of the following compounds 1, 2 and 5-10 Derivatives were isolated and identified.

Further, the following compounds 3, 4, and 11 to 16 (hereinafter, referred to as " compound 1 ") were obtained by chemical analysis of an n-butanol soluble fraction (35 g) using extensive column chromatography separation (RP- C18 silica gel, silica gel, and HPLC column) Of the lignan derivatives were isolated and identified.

The structures of the separated compounds were confirmed by various NMR analyzes such as ¹ H and ¹³ C NMR, DEPT, ¹ H- ¹ H COZY, HMQC, HMBC, and NOESY.

Example  4: Cell Survival rate Assay

Cell viability was measured using a 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide (MTT) assay. Specifically, cells cultured in 96-well plates were treated with different concentrations of lignan derivatives with or without LPS. After incubation for 24 hours, the medium was removed and MTT solution was added to the cells at a final concentration of 0.5 mg / mL and incubated for an additional 1 hour. The medium was carefully removed and 200 [mu] l of dimethylsulfoxide (DMSO) was added to each well. The optical density (OD) was measured at 570 nm with a plate reader. The cell viability was evaluated by observing the activity of viable cells reducing yellow MTT to purple formazan. The results are shown in the following Table 3 as a percentage of the control (untreated cells).

Example  5: Measurement of nitrogen monoxide (NO) Assay

The inhibitory effect of the lignan derivatives of the present invention on LPS-induced nitric oxide synthesis was studied using mouse BV2 glial cells. The BV2 cells in a 96-well plate at ⁴ × 10 4 cells / 100 ng to under the dispensing zone and / absence of the compounds of the present invention the density of the well / mL LPS for 24 hours. The nitrite concentration in the culture medium was measured using a grease reagent (5% phosphoric acid solution of Griess reagent, 1% sulfanilamide and 0.1% N-1-naphthylethylenediamine dihydrochloride) (nitrite level) was measured. 50 μl of supernatant was mixed with an equal volume of grease reagent and the OD was measured at 570 nm. A; (NOS nitric oxide synthase) inhibitors, N ^G - monomethyl - methyl -L- arginine nitric oxide synthase of the known (N-methyl-L-arginine -Mono ^G; L-NMMA) was used as a positive control.

compound IC ₅₀ ([mu] M) Cell viability (%) compound IC ₅₀ ([mu] M) Cell viability (%) One 393.35 112.06 ± 8.29 10 66.36 100.23 + - 4.55 2 470.00 108.03 + - 9.00 11 338.72 96.95 + - 10.98 3 324.81 114.22 + - 4.28 12 > 500 102.30 ± 11.19 4 319.72 96.92 + 12.04 13 187.50 92.73 + - 11.57 5 9.51 81.70 ± 14.67 14 > 500 101.52 ± 10.56 6 9.49 71.55 + - 6.81 15 > 500 118.42 + - 8.81 7 195.92 104.14 ± 8.65 16 281.25 109.42 + - 4.57 8 392.79 104.96 ± 10.55 L-NMMA ^c 21.82 114.08 ± 2.96 9 50.00 105.08 + - 9.89

As can be seen in Table 2, compounds 5, 6, 9, and 10 showed moderate activity at 20 μM with IC ₅₀ values of 9.51, 9.49, 50.00 alc 66.36 μM without significant cytotoxicity. Other compounds were weak or did not show activity. The IC ₅₀ of L-NMMA used as a positive control was 21.82 μM.

Example  6: Nerve Growth Factor ( NGF ) And cells Survival rate Assay

C6 glioma cells were treated with 20 [mu] M of the compound of the present invention to measure nerve growth factor (NGF) release into the culture medium.

, And dividing the C6 cells in a 24-well plate at a density of 1 × 10 ⁵ cells / well in order to specifically measure the level of NGF. Twenty-four hours later, the cells were treated with various concentrations of LNE for 24 hours in serum-free DMEM and antibiotics. The culture supernatant was collected from the culture plate and used for NGF assay. NGF concentration was measured using an ELISA development kit. 6-Shogaol, a known inducer of NGF production, was used as a positive control. NGF levels released are shown in Table 3 below as a percentage of control (untreated cells).

NGF release effect of compound (number of repeats = 3) compound NGF release (%) Cell viability (%) compound NGF release (%) Cell viability (%) One 135.73 + - 9.52 100.90 + - 0.40 10 102.47 + 5.05 99.74 ± 3.29 2 142.99 ± 10.86 96.95 + - 2.66 11 104.64 ± 12.36 109.50 ± 1.90 3 135.24 + - 6.27 103.30 ± 1.05 12 133.76 ± 10.69 102.99 ± 0.19 4 135.61 ± 12.75 99.90 + - 5.94 13 136.79 + - 10.81 113.99 + - 4.95 5 108.84 + 13.32 81.66 + - 7.70 14 144.93 + - 10.27 112.46 + - 7.33 6 121.36 ± 17.40 88.64 + - 2.44 15 97.15 ± 13.05 106.34 ± 3.88 7 124.36 + - 16.76 112.74 ± 5.76 16 104.14 ± 8.65 108.13 + - 0.78 8 138.84 ± 9.96 111.12 ± 5.82 6-Shogaol 168.58 + - 7.16 125.80 0.93 9 117.97 ± 12.80 98.99 ± 3.28

As shown in Table 3, the compound of the present invention did not show a cytotoxic effect at 20 μM and showed a positive control 6-Shogaol level of NGF-releasing effect.

Example  7: Cytotoxicity test

The cytotoxic activity of compounds 1 to 16 was evaluated against A549, SK-OV-3, SK-MEL-2 and HCT-116 cell lines using the SRB bioassay method. Etoposide (≥98%; Sigma Chemical Co.) was used as a positive control. As a result, the compounds of the present invention were evaluated to be inactive (IC ₅₀ > 10 μM) against A549, SK-OV-3, SK-MEL-2 and HCT-116.

Claims (14)

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