KR101553059B1 - Composotion comprising psammaplysin compound or the extract of Suberea sp. for preventing or treating cancer - Google Patents

Abstract

The present invention relates to a composition for preventing or treating a cancerous disease containing psammaplysin compound or a subspecies extract of subspecies Subera sp. As an active ingredient. More particularly, Suveria extract shows growth inhibitory activity against various cancer cell lines and can be used as a pharmaceutical composition useful for prevention or treatment of cancer diseases or a dry food composition.

Description

[0001] The present invention relates to a composition for preventing or treating a cancerous disease, which comprises a sampalfyin compound or a sponge sapriera extract. for preventing or treating cancer}

The present invention relates to novel Sama ply new (psammaplysin) compound or a spongy be Beria (Suberea sp . ) Extract as an active ingredient for the prevention and treatment of cancer diseases.

Cancer cells are similar in nature to normal cells in many respects, so it is not easy to remove cancer cells without damaging normal cells.

Cancer cells are distinguished from some common cells. The first is that cancer cells do not regulate cell proliferation, the second is the lack of distinctive features of the differentiation, and the third is that they penetrate the surrounding tissues and transform. In normal cells, cancer cells receive signaling by growth factors as needed, while cancer cells have low dependency on growth factors and there is no contact inhibition that growth is inhibited by contact with surrounding cells. An angiogenic factor is secreted to activate the metastasis. In addition, cancer cells do not differentiate, do not develop apoptosis or programmed cell death, and are genetically unstable. Genetic instability of cancer cells is very important in cancer progression and is known to induce tolerance to chemotherapeutic agents.

The biggest problem with chemotherapy is drug resistance, which is also a major factor in the initial successful response to anticancer drugs and ultimately failure of treatment. In recent years, efforts have been made to find the active ingredient in natural products used in the private sector in connection with the problem of overcoming these side effects.

Accordingly, the present inventors have completed the present invention by confirming that a novel psammaplysin compound or a subspecies extract of Subspira sp. Has an effect of inhibiting cell growth on various cancer cell lines.

It is an object of the present invention to provide novel samaplatinum compounds.

It is still another object of the present invention to provide a pharmaceutical composition for preventing and / or treating cancer diseases, which comprises a samaflyricin compound or a siberia extract.

It is still another object of the present invention to provide a health food composition for preventing and / or treating cancer diseases, which comprises a samaflyricin compound or a siberia extract.

The terminology used in this application is used only to describe a specific embodiment and is not intended to limit the invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In the present application, the terms "comprises" or "having" and the like are used to specify that there is a feature, a number, a step, an operation, an element, a component or a combination thereof described in the specification, But do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, or combinations thereof.

In order to accomplish the above object, the present invention provides a samaplayic compound represented by the following Chemical Formulas 1 to 4 or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1, 2]

The compounds of Formulas 1 and 2 are psammaplysin compounds having a spirooxepinisoxazoline ring system. Specifically, it is a novel compound having 4-chloro-2-methylenecyclopentane-1,3-dione group at nitrogen number 20. (1), or a form in which one hydrogen and one hydroxy group are substituted (formula (2)), and can be named as psammaplysin X and 19-hydroxypsammaplysin X, respectively.

(3)

The compound of Formula 3 is a novel samaplicin compound having an unsubstituted 2-methylenecyclopentane-1,3-dione group as a nitrogen substituent, and may be named psammaplysin Y.

[Chemical Formula 4]

The compound of formula (4) is a samaplicin compound having a hydroxyl group at the 19th carbon atom and a formamide group at the 20th carbon atom, and may be named 19-hydroxyceratinamide A.

The samaplicin compounds represented by the above Chemical Formulas (1) to (4) have remarkably excellent effects than the samaflashine compound represented by Chemical Formula (5) as can be seen in Experimental Examples described later, and doxorubicin (adriamycin ) Was found to have a similar or higher level of cancer cell growth inhibitory activity than that of the wild type.

The samaplicin compounds represented by the above Chemical Formulas (1) to (4) are new compounds that have not been available in the past. We have obtained this from the sponge, Suberea sp. However, the samaplicin compounds represented by Formulas 1 to 4 according to the present invention can be prepared by an artificial synthesis method.

Meanwhile, the novel compounds of the present invention represented by the above Chemical Formulas 1 to 4 can be prepared as pharmaceutically acceptable salts according to a conventional method in the art.

Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, an organic acid and an inorganic acid can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acid include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, , Glutaric acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt in particular, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

The pharmaceutically acceptable salts of the compounds represented by the formulas (1) to (4) include salts of acidic or basic groups which may exist in the compounds of the formulas (1) to (4), unless otherwise indicated. For example, pharmaceutically acceptable salts include the sodium, calcium, and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, (Salicylate) salts, which are known in the art and which are known in the art, such as, for example, ≪ / RTI >

The present invention provides a pharmaceutical composition for the prevention and treatment of cancer diseases, which comprises the novel compounds represented by the above Chemical Formulas 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

The cancer is preferably selected from the group consisting of colon cancer, prostate cancer, lung cancer, kidney cancer, skin cancer, gastric cancer, breast cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, Endometrioid adenocarcinoma, adenocarcinoma, adenocarcinoma, adenocarcinoma, adenocarcinoma, adenocarcinoma, endometrial adenocarcinoma, adenocarcinoma, vulvar carcinoma, vulval carcinoma, Hodgkin's disease, Cancer of the central nervous system (CNS), primary CNS lymphoma, renal cell carcinoma, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) tumor, cancer of the thyroid gland, thyroid carcinoma, adenocarcinoma, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, lymphocytic lymphoma, , Spinal cord tumor, brainstem glioma or pituitary adenoma, preferably colon cancer, prostate cancer, lung cancer, kidney cancer, skin cancer or stomach cancer.

Hereinafter, the method for obtaining the compound of the present invention will be described in detail.

The compound of the present invention is obtained by pulverizing dried Suberea sp. And pulverizing it to about 2 to 6 times, preferably 4 times the dry weight of water, C1 to C4 lower alcohol, dichloromethane, hexane, chloroform, Preferably several times, for a period of about 10 to about 48 hours, preferably about 24 hours, at a temperature of from 10 to 35, preferably from 24 to 24 hours, preferably from 2 to 5 hours, A first step of obtaining a crude extract by concentrating under reduced pressure using an extraction method such as once or once cold extraction, hot water extraction, ultrasonic extraction, and reflux extraction, preferably using a cold extraction method; The crude extract is partitioned using a polar solvent such as water and butanol, and then the organic layer is dried under reduced pressure. The organic layer is washed with water, C1 to C4 lower alcohol, dichloromethane, hexane, chloroform, methylene chloride, , A mixed solvent of water and methanol (1: 1 (v / v)) and hexane, according to polarity; The material dissolved in the polar solution layer in the second step is taken out and dried under reduced pressure, and this is dissolved in water, C1 to C4 lower alcohol, dichloromethane, hexane, chloroform, methylene chloride, ethyl acetate or a mixed solvent thereof, : A third step of performing concentration gradient reversed phase column chromatography with a mixed solvent of methanol (50:50 to 0: 100 in order) to divide into 6 fractions according to polarity; The fraction eluted with a polar solvent, preferably 80% and 90% methanol solvent, of each fraction in the third step was subjected to reverse phase high-efficiency column chromatography using a water: methanol solution as a mobile phase solvent condition to obtain the compound of the present invention 1 to 4, respectively.

The present invention provides a pharmaceutical composition for the prevention and treatment of cancer diseases comprising as an active ingredient a novel samaplicin compound represented by the above Chemical Formulas 1 to 4 or a pharmaceutically acceptable salt thereof obtained by the above production method.

In addition, the present invention provides a pharmaceutical composition comprising as an active ingredient a suveria extract obtained by the above-mentioned production method.

The extract may be dissolved in water, C1 to C4 lower alcohol, dichloromethane, hexane, chloroform, methylene chloride, ethyl acetate or a mixed solvent thereof, preferably a mixed solvent of methanol and dichloromethane, Extracts extracted once with dichloromethane.

The composition for the prevention and treatment of cancer diseases of the present invention contains 0.1 to 50% by weight of the compound or the extract, based on the total weight of the composition. However, the composition is not limited thereto, and may vary depending on the condition of the patient, the type of disease, and the progress of the disease.

Compositions comprising the compounds or extracts of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions.

The composition comprising the compound or the extract according to the present invention may be administered orally or topically in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like, external preparation, Examples of the carrier, excipient and diluent which can be contained in the composition containing the compound or the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, , Alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil have. 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 at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The preferred dosage of the compound or extract of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the administration route and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound or the extract of the present invention is preferably administered at a dose of 0.01 mg / kg to 10 g / kg, preferably 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

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

The present invention also provides a health food composition for the prevention and treatment of cancer diseases, which comprises the novel compounds represented by the above Chemical Formulas 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the present invention relates to a health food composition for prevention and treatment of cancer diseases, which comprises the novel samaplicin compound represented by the formula (4) or a pharmaceutically acceptable salt thereof as an active ingredient, to provide. The present invention also provides a health food composition comprising as an active ingredient a suberibia extract obtained by the above-mentioned production method.

The pharmaceutical composition of the present invention can be added to a health food for the purpose of improving cancer diseases. When the composition of the present invention is used as a food additive, the pharmaceutical composition may be added as it is, or may be used together with other food or food ingredients, and suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). Generally, in the production of food or beverage, the pharmaceutical composition of the present invention is added in an amount of 0.01 to 10 parts by weight, preferably 0.05 to 1 part by weight based on the raw material. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

There is no particular limitation on the kind of the health food. Examples of foods that may include the novel compounds represented by the above Chemical Formulas 1 to 4 or pharmaceutically acceptable salts thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, , Dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.

The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.

In addition to the above, the health food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, , A carbonating agent used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

The novel samafrysin compound or siberia extract of the present invention has an effect of inhibiting the growth of various cancer cell lines and thus can be used as a pharmaceutical composition and / or a health food composition useful for the prevention and / or treatment of cancer diseases.

1 is a graph showing a hydrogen nuclear magnetic resonance spectrum of Compound 1 according to an embodiment of the present invention.
2 is a graph showing a carbon nuclear magnetic resonance spectrum of Compound 1 according to an embodiment of the present invention.
3 is a graph showing a hydrogen nuclear magnetic resonance spectrum of Compound 2 according to an embodiment of the present invention.
4 is a graph showing a carbon nuclear magnetic resonance spectrum of Compound 2 according to an embodiment of the present invention.
5 is a graph showing a hydrogen nuclear magnetic resonance spectrum of Compound 3 according to an embodiment of the present invention.
6 is a graph showing a carbon nuclear magnetic resonance spectrum of Compound 3 according to an embodiment of the present invention.
7 is a graph showing a hydrogen nuclear magnetic resonance spectrum of Compound 4 according to an embodiment of the present invention.
8 is a graph showing a carbon nuclear magnetic resonance spectrum of Compound 4 according to an embodiment of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention is capable of various modifications and various embodiments, and specific embodiments are illustrated in the drawings and will be described in detail in the detailed description. It is to be understood, however, that the invention is not to be limited to the specific embodiments, but includes all modifications, equivalents, and alternatives falling within the spirit and scope of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.

Example  : Sama Fly Shin  Separation of compounds

Example  One : Suveria ( Suberea sp .) Crude extract  Produce

The lyophilized sponges were collected from the subera sp. ( Collected in the waters near the Federated States of Micronesia Chuuk state) twice with 99% methanol and dichloromethane, once, Then, the extract was filtered and concentrated under reduced pressure to obtain 100 g of crude extract, which was used in Example 2 below.

Example  2: Separation of compounds

After separating the crude extract obtained in Example 1 with water and normal butanol, the normal butanol layer was again dried under reduced pressure, and this was mixed again with a mixed solvent of water and methanol (1: 1 (v / v)) and n-hexane And fractionated according to polarity.

Subsequently, the material dissolved in the mixed solvent of water and methanol was taken out, dried under reduced pressure, and then subjected to concentration gradient reversed phase column chromatography using a mixed solvent of water and methanol (50:50 to 0: 100 in this order) Five fractions (methanol% = 50, 60, 70, 80, 90, 100) were divided.

The purified compound was obtained by reversed phase high-efficiency column chromatography using water and methanol as a solvent, and the compound 19-hydroxyceratinamide A represented by the formula (4) of the present invention was obtained from 80% methanol solution, 1, 2 and 3, psammaplysin X, 19-hydroxypsammaplysin X and psammaplysin Y were obtained.

The structures of the separated compounds were identified and confirmed by ¹ H NMR, ¹³ C NMR, HRMS and IR. The results are shown in Figs. 1 to 8 and Tables 1 to 2 below.

Compound 1 Compound 2 position δ _C , type δ _H  ( J in Hz ) δ _C , type δ _H  ( J in Hz ) One 146.3, CH 7.17, s 146.3, CH 7.18, s 2 103.5, C 103.5, C 3 149.3, C 149.3, C 4 104.1, C 104.1, C 5 37.9, CH ₂ 3.14, d (16.0) 37.9, CH ₂ 3.14, d (16.0) 3.45, d (16.0) 3.45, d (16.0) 6 119.8, C 119.8, C 7 80.1, CH 5.10, s 80.1, CH 5.10, s 8 158.4, C 158.4, C 9 159.1, C 159.1, C 10 37.5, CH ₂ 3.64, t (6.0) 37.5, CH ₂ 3.66, t (6.0) 11 30.5, CH ₂ 2.15, quin  (6.0) 31.9, CH ₂ 2.16, quin  (6.0) 12 72.0, CH ₂ 4.09, t (6.0) 72.1, CH ₂ 4.11, t (6.0) 13 152.6, C 153.2, C 14 118.7, C 118.7, C 15 134.3, CH 7.57, s 131.4, CH 7.71, s 16 138.0, C 141.9, C 17 134.3, CH 7.57, s 131.4, CH 7.71, s 18 118.7, C 118.7, C 19 35.7, CH ₂ 3.12, m 71.2, CH 5.09, brs 20 52.0, CH ₂ 3.94, m 55.8, CH ₂ 3.75, brd  (13.5) 3.98, brd  (13.5) 21 157.2, CH 7.82, brs 157.8, CH 7.90, brs 157.0, CH 7.84, brs 158.0, CH 7.91, brs 22 106.0, C 106.1, C 105.6, C 105.8, C 23 196.3, C 196.3, C 194.5, C 194.5, C 24 55.8, CH 4.54, dd  (2.0, 8.5) 55.0, CH 4.55, dd  (3.0, 8.5) 55.0, CH 4.61, dd  (2.0, 8.5) 55.1, CH 4.63, dd , (3.0, 8.5) 25 44.9, CH ₂ 2.54, dd  (2.0, 18.5) 45.3, CH ₂ 2.54, dd , (3.0, 18.5) 3.10, dd  (8.0, 18.5) 3.14, dd , (8.5, 18.5) 45.5, CH ₂ 2.49, dd  (2.0, 18.5) 45.5, CH ₂ 2.50, dd , (3.0, 18.5) 3.07, dd  (8.0, 18.5) 3.09, dd , (8.5, 18.5) 26 200.1, C 200.2, C 197.7, C 197.8, C 3- OMe 59.1, CH ₃ 3.64, s 59.1, CH ₃ 3.64 (s) 7- OH 6.12, brs 6.10 ( brs ) C9 - NH 7.91, brs 7.89 ( brs ) C20 - NH 10.36, brs 10.45 ( brs ) 10.28, brs 10.36 ( brs )

Compound 3 Compound 4 position δ _C , type δ _H  ( J in Hz ) δ _C , type δ _H  ( J in Hz ) One 146.4 CH 7.17, s 146.4 CH 7.18, s 2 103.5 C 103.4 C 3 149.3 C 149.3 C 4 104.2 C 104.1 C 5 38.0 CH ₂ 3.14, d (16.0) 37.9 CH ₂ 3.14, d (16.0) 3.46 d (16.0) 3.46, d (16.0) 6 119.8 C 119.8 C 7 80.2 CH 5.10, s 80.1 CH 5.10, s 8 158.6 C 158.5 C 9 159.1 C 159.1 C 10 37.5 CH ₂ 3.64, t (6.0) 37.5 CH ₂ 3.64, t (6.0) 11 30.5 CH ₂ 2.14, quin  (6.0) 30.4 CH ₂ 2.16, quin  (6.0) 12 72.1 CH ₂ 4.09, t (6.0) 72.0 CH ₂ 4.11, t (6.0) 13 152.7 C 152.8 C 14 118.7 C 118.5 C 15 134.5 CH 7.56, s 131.4 CH 7.65, s 16 138.3 C 143.3 C 17 134.5 CH 7.56, s 131.4 CH 7.65, s 18 118.7 C 118.5 C 19 36.0 CH ₂ 3.06, t (6.0) 71.6 CH 4.82, brs 20 51.7 CH ₂ 3.86, t (6.0) 46.2 CH ₂ 3.41, brd  (14.0) 3.56, brd  (14.0) 21 155.7 CH 7.60, s 162.4 CH 8.13, s 22 107.8 C 23 201.1 C 24 33.6 CH ₂ 2.38, d (9.0) 25 34.4 CH ₂ 2.34, d (9.0) 26 205.2 C 3- OMe 59.1 CH ₃ 3.64, s 59.1 CH ₃ 3.64, s 7- OH 6.37, brs ^b 6.23, brs ^b C9 - NH 7.93, brs ^b 7.93, brs ^b C19 - OH 6.18, brs ^b C20 - NH 10.20, brs ^b 7.43, brs ^b

Compound 1 of the present invention was obtained as an amorphous yellow solid. High-resolution ESI mass spectroscopy confirmed the molecular weight of C ₂₇ H ₂₆ Br ₄ ClN ₃ O ₈ . ¹ H NMR spectrum obtained by use of the CD ₃ OD as a solvent, but is similar to the ¹ H NMR spectrum of psammaplysin A known compound, a signal, such as _{δ H 7.66, 4.60, 3.14,} 2.62 was observed further. As a result of NMR spectrum analysis using Actone- d6 as a solvent, 4-chloro-2-methylenecyclopentane-1,3-dione group was bonded to nitrogen bonded to carbon number 20, and E / Z The isomer was found to be present in a 1: 1 ratio.

: yellow amorphous solid; ^{_{[a] 25 D -64 (c}} 0.5, acetone); UV (MeOH) [lambda] _max 311, 207 nm; (+) - LRESIMS m / z (rel int) 872 (20), 874 (65), 876 (100), 878 (82), 880 (35) [M + H] ⁺ ; (+) - HRESIMS m / z 875.8170 [M + H] ⁺ (calcd for C ₂₇ H ₂₇ ⁸¹ Br ₂ ⁷⁹ Br ₂ ClN ₃ O ₈ , 875.8181).

In the case of the compound 2 , it has a molecular formula of C ₂₇ H ₂₆ Br ₄ ClN ₃ O ₉ It was confirmed by high-resolution ESI mass spectroscopy. The signals of 隆_H 3.12 (H-19) and 3.94 (H-20) disappeared when compared to the ¹ H NMR spectrum of Compound 1 and the signals _{隆 H 5.09} (H-19) and 3.75 (H-20), a compound having a hydroxy group at the position 19 relative to the compound 1 was confirmed. This indicates that the compound represented by the above formula and the ¹³ C NMR spectrum signal δ _C 71.2 (C-19) and 55.8 (C-20)).

: pale yellow amorphous solid; ^{_{[a] 25 D -82 (c}} 0.5, acetone); UV (MeOH) [lambda] _max 309, 206 nm; ¹ (+) - LRESIMS m / z (rel int) 888 (20), 890 (60), 892 (100), 894 (77), 896 (33) [M + H] ⁺ ; (+) - HRESIMS m / z 891.8098 [M + H] ⁺ (calcd for C ₂₇ H ₂₇ ⁸¹ Br ₂ ⁷⁹ Br ₂ ClN ₃ O ₉ , 891.8130).

In the case of compound 3 ¹ H and ¹³ C NMR spectrum δ _H 7.60 _(H-21) and _{δ C 155.7 (C-21)} , 107.8 (C-22), 201.1 (C-23), 205.2 (C-26) in The presence of the 2-methylenecyclopentane-1,3-dione group in the structure was confirmed. High-resolution ESI mass spectroscopy confirmed the molecular formula of C ₂₇ H ₂₇ Br ₄ N ₃ O ₈ .

: pale yellow amorphous solid; ^{_{[a] 25 D -77 (c}} 0.5, acetone); UV (MeOH) [lambda] _max 307,207 nm; (+) - LRESIMS m / z (rel int) 838 (29), 840 (73), 842 (100), 844 (70), 846 (21) [M + H] ⁺ ; (+) - HRESIMS m / z 841.8614 [M + H] ⁺ (calcd for C ₂₇ H ₂₈ ⁸¹ Br ₂ ⁷⁹ Br ₂ N ₃ O ₈ , 841.8572).

In the case of the compound 4, the signals of δ _H 8.13 (H-21) and δ _C 162.4 (C-21) were characteristic in the ¹ H and ¹³ C NMR spectra, confirming the presence of the formamide group . The presence of the hydroxymethine signal (δ _H 4.82 (H-19)) and δ _H 3.41 and 3.56 (H-20) appearing in the ¹ H NMR spectrum confirmed the structure of the above structure, resolution This is consistent with the molecular formula of C ₂₂ H ₂₃ Br ₄ N ₃ O ₈ identified by ESI mass spectroscopy.

: pale yellow amorphous solid; ^{_{[a] 25 D -62 (c}} 0.5, acetone); UV (MeOH) [lambda] _max 305, 208 nm; (+) - LRESIMS m / z (rel int) 774 (20), 776 (67), 778 (100), 780 (68), 782 (21) [M + H] ⁺ ; (+) - HRESIMS m / z 777.8254 [M + H] + (calcd for C 22 H 24 81 Br 2 79 Br 2 N 3 O 8, 777.8258).

Experimental Example  : Measurement of Cancer Cell Growth Inhibitory Activity

Experimental Example  1: Cell culture

(Colon cancer), PC-3 (prostate cancer), ACHN (kidney cancer), MDA-MB-231 (breast cancer), NUGC-3 (gastric cancer) NCI-H23 (lung cancer) (National Cancer Institute (NCI)) was used. Culture medium containing RPMI 1640 and 10% calf serum was used.

Experimental Example  2: Measurement of cancer cell growth inhibitory activity

In order to measure the cell growth inhibitory effect of the compounds 1 to 4 obtained in Example 2 on human cancer cell lines, experiments were carried out as follows (Skehan, P .; Storeng, R .; Scudiero, D .; Monks, A .; McMahon, J .; Vistica, D .; Warren, JT;.. Bokesch, H .; Kenny, S .; Boyd, MR J. Natl Cancer Inst 1990, 82 , 1107-1112.).

In addition, the same experiment was performed on compound 5 of the following formula (5) as a negative control and doxorubicin (adriamycin) which is a known anticancer drug known as a positive control.

[Chemical Formula 5]

Each cell line was loaded onto a 96-well plate and the working solution was treated to final concentrations of 30, 10, and 3 μg / ml. After 48 hours incubation, the plate treated with the drug was fixed with 50 μl / well of 50% TCA. The fixed plate was left at 4 ° C for 60 minutes and then washed with tap water 4 to 5 times. The washed plate was dried, and 100 μl / well of SRB solution (0.4% sulforhodamine B in 1% acetic acid) was added and left for 30 minutes. The unbound dye was washed with 0.1% acetic acid, dried, and dissolved in 100 μl / well of 10 mM Tris base (pH 10.5). Absorbance was measured at 540 nm using a Versa max microplate reader (Molecular Devices), and the absorbance was calculated as a percentage of the solvent-treated group. The GI ₅₀ values of the test materials were calculated using Graphpad prism v4.0 software.

As a result, the compounds 1 and 2 of the present invention were found to have more effective anticancer activity than the compound 5 used as a negative control in various human cancer cell lines, as shown in Table 3. In particular, it was confirmed that the growth inhibitory activity was similar or higher than that of doxorubicin (adriamycin), a known anticancer agent used as a positive control for kidney cancer cell line (ACHN) and breast cancer cell line (MDA-MB-231) .

compound cell line (GI ₅₀ mu M) HCT-15 PC-3 ACHN MDA-MB-231 NUGC-3 NCI-H23 One 3.3 2.3 3.3 1.2 3.5 6.4 2 3.5 2.1 2.5 0.8 4.0 3.5 5 7.4 3.7 10.3 3.9 4.0 7.0 Doxorubicin 1.4 0.52 2.0 1.8 0.51 1.9

While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, It will be apparent to those skilled in the art that changes may be made.

Claims (11)

A psammaplysin compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

A semaplexic compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof:
(2)

A semaplanic compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof:
(3)

A semaplexic compound represented by the following formula (4) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 4]

A pharmaceutical composition for the prophylaxis or treatment of cancer diseases, which comprises a semaplexic compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.
6. The method of claim 5,
Wherein the samaflassin compound is obtained from a sponge animal.
delete 6. The method of claim 5,
Wherein the cancer disease is renal cancer or breast cancer.
6. The method of claim 5,
Wherein the cancer disease is breast cancer.
A pharmaceutical composition for the prevention or treatment of breast cancer diseases comprising a semaplexic compound according to claim 2 or a pharmaceutically acceptable salt thereof.
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