KR101649981B1 - Novel Xanthone Derivatives and Composition for Treating Cancer Comprising the Same as Active Ingredient - Google Patents

Abstract

The present invention relates to a novel xanthone derivative compound and an anticancer composition comprising the compound as an active ingredient. The xanthine derivative compound of the present invention exhibits excellent anticancer activity against various human cancer cells, and the water solubility characteristics are greatly improved as compared with the? -Mangosteen compound as the parent compound. The xanthine derivative compound of the present invention can be developed as an anticancer drug having very excellent activity.

Description

[0001] The present invention relates to a novel xanthone derivative and a composition for anticancer comprising the same as an active ingredient.

The present invention relates to a novel xanthone derivative and an anticancer composition comprising the same as an active ingredient.

Mangosteen (Mangosteen, Garcinia mangostana L. Clusiaceae) is a well-known indigenous tropical fruit of Southeast Asia and has been used as a traditional medicine to treat inflammation, ulcers, skin infections, wound healing, amoebic dysentery and diarrhea (1). The major secondary metabolites of mangosteen are found to be oxidized and prenylated minerals, among which a-mangosteen is a yellow solid crystal with a Zanton core structure. This material was first isolated by W. Schmid in 1885 and its structure was correctly identified by Yates and Stout in 1958. (2), anti-inflammatory activity (3), antioxidant activity (4), anti-allergic activity (5), antibacterial activity (6), antituberculous activity (7), antifungal activity -HIV (9) and the enhancing activity of the immune system (10). Since various xanthone compounds have been of interest as useful chemical protectants and treatments (11), recent studies on synthetic chemistry and medicinal chemistry of a-mangosteen have been performed (12). In contrast, there have been reports of chemical modification of the derivatized derivatives of improved properties (13).

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

WO 2009/124909 A1

Pedraza-Chaverri, J .; C ㅱ rdenas-Rodr ㅽ guez, N .; Orozco-Ibarra, M .; P. Rez-Rojas, J.M. Food. Chem. Toxicol. 2008, 46, 3227-3239. Cui, J .; Hu, W .; Cai, Z .; Liu, Y .; Li, S.; Tao, W .; Xiang, H. Pharmacol. Biochem. Behav. 2010, 95, 166-172. (a) Tewtrakul, S .; Wattanapiromsakul, C .; Mahabusarakam, W. J. Ethnopharmacol. 2009, 121, 379-382. (b) Nakatani, K .; Nakahata, N .; Arakawa, T .; Yasuda, H .; Ohizumi. Y. Biochem. Pharmacol. 2002, 63, 73-79. Jung, H. A .; Su, B. N .; Keller, W. J .; Mehta, R. G .; Kinghorn, A.D. J. Agric. Food Chem. 2006, 54, 2077-2082. Nakatani, K .; Atsumi, M .; Arakawa, T .; Oosawa, K .; Shimura, S .; Nakahata, N .; Ohizumi, Y. Biol Pharm Bull. 2002, 25, 1137-1141. Sakagami, Y .; Iinuma, M .; Piyasena, K. G .; Dharmaratne, H.R. Phytomedicine, 2005, 12, 203-208. Suksamrarn, S .; Suwannapoch, N .; Phakhodee, W .; Thanuhiranlert, J .; Ratananukul, P .; Chimnoi, N .; Suksamrarn, A. Chem. Pharm. Bull. 2003, 51, 857-859. Kaomongkolgit, R .; Jamdee, K .; Chaisomboon, N. J. Oral Sci. 2009, 51, 401-406. Chen, S. X .; Wan, M .; Loh, B.N. Planta Med. 1996, 62, 381-382. Tang, Y. P .; Li, P. G .; Kondo, M .; Ji, H. P .; Kou, Y .; Ou, B. J. Med. Food 2009, 12, 755-763. (a) Zhang, X .; Li, X .; Ye, S .; Zhang, Y .; Tao, L .; Gao, Y .; Gong, D .; Xi, M .; Meng, H .; Zhang, M .; Gao, W .; Xu, X .; Guo, Q .; You, Q. Med. Chem. 2012, 8, 1012-1025. (b) Han, A. R .; Kim, J.A .; Lantvit, D. D.; Kardono, L. B .; Riswan, S .; Chai, H .; Carcache de Blanco, E.J .; Farnsworth, N. R .; Swanson, S. M .; Kinghorn, A.D. J. Nat. Prod. 2009, 72, 2028-2031. (c) Doi, H .; Shibata, MA .; Shibata, E .; Morimoto, J .; Akao, Y .; Iinuma, M .; Tanigawa, N .; Otsuki, Y. Anticancer Res. 2009, 29, 2485-2495. (d) Akao, Y .; Nakagawa, Y .; Iinuma, M .; Nozawa, Y. Int. J. Mol. Sci. 2008, 9, 355-370. (a) Zou, H .; Koh, J. J .; Li, J .; Qiu, S .; Aung, T.T .; Lin, H .; Lakshminarayanan, R .; Dai, X .; Tang, C .; Lim, F. H .; Zhou, L .; Tan, A. L .; Verma, C .; Tan, D.T .; Chan, H. S .; Saraswathi, P .; Cao, D .; Liu, S.; Beuerman, R.W. J. Med. Chem. 2013, 56, 2359-2373. (b) Xu, D .; Nie, Y .; Liang, X .; Ji, L .; Hu, S .; You, Q .; Wang, F .; Ye, H .; Wang, J. Nat. Prod. Commun. 2013, 8, 1101-1103. (c) Matsumoto, K .; Akao, Y .; Yi, H .; Ohguchi, K .; Ito, T .; Tanaka, T .; Kobayashi, E .; Iinuma, M .; Nozawa, Y. Bioorg. Med. Chem. 2004, 12, 5799-806. (d) Iikubo, K .; Ishikawa, Y .; Ando, N .; Umezawa, K .; Nishiyama, S. Tetrahedron Lett. 2002, 43, 291-293. (a) Ha, L. D .; Hansen, P. E .; Vang, O .; Duus, F .; Pham, H. D .; Nguyen, L.-H. D. Chem. Pharm. Bull. 2009, 57, 830-834. (b) Nishihama, Y .; Ogamino, T .; Shi, W. L .; Cha, B. Y .; Yonezawa, T .; Teruya, T .; Nagai, K .; Suenaga, K .; Woo, J.T .; Nishiyama, S. Heterocycles 2009, 77, 759-765. (c) Sudta, P .; Jiarawapi, P .; Suksamrarn, A .; Hongmanee, P .; Suksamrarn, S. Chem. Pharm. Bull. 2013, 61, 194-203. Forming structural assignment of C-6 selective alkylation, NOESY analysis of compound 6a, see Supplementary Material. Jain, A. C .; Zutshi, M. K. Tetrahedron 1973, 29, 3347-3350. Yates, P .; Bhat, H. B. Can. J. Chem. 1970, 48, 680-684. Gao, H.; Kawabata, J. Bioorg. Med. Chem. 2005, 13, 1661-1671. TMSI, BBr3, AlCl3 / NaI / pyridine and piperidine / H2O (2.5: 1) were used for the conversion of α-mangostin into γ-mangostin, Kang, M. R .; Kang, J. S .; Yang, J. W .; Kim, B. G .; Kim, J.A .; Jo, Y. N .; Lee, K .; Lee, C. W .; Lee, K.H .; Yun, J .; Kim, H. M .; Han, G .; Kang, J. S .; Park, S.K. Oncol. Lett. 2012, 3, 113-118.

The present inventors have made efforts to produce a xanthone derivative having improved water solubility while maintaining the anticancer activity of? -Mangostin by modifying the structure of? -Mangosteen having excellent anticancer activity but having very limited water solubility characteristics. As a result, the present inventors have succeeded in synthesizing a novel xanthone derivative having an excellent water-soluble property while maintaining excellent anticancer activity and confirming its toxic activity against cancer cell lines, thereby completing the present invention.

Accordingly, an object of the present invention is to provide a novel xanthone derivative.

Another object of the present invention is to provide an anticancer composition comprising the novel xanthone derivative as an active ingredient.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a xanthone derivative compound represented by the following general formula (1).

[Chemical Formula 1]

In Formula 1,

R ₁ is H, or C ₁ -C ₅ alkyl;

R ₂ and R ₇ are independently of each other C ₁ -C ₇ linear or branched alkyl or C ₂ -C ₇ linear or branched alkenyl;

R ₃ is OH, CH ₃ COO, CO ₂ H (CH ₂ ) _n O, C ₁ -C ₅ alkoxy, TfO, CH ₂ CHCH ₂ O or H, Tf is triflate, n is an integer of 1 to 3;

R ₄ is H, halo, NH ₂ , or NO ₂ ;

R ₅ is OH, CH ₃ COO, CO ₂ H (CH ₂ ) _n O, CH ₂ CHCH ₂ O, TfO, H, or NH ₂ , Tf is triflate, Lt; / RTI >

R ₆ is C ₁ -C ₅ alkyl, CCH, or

to be:

According to a preferred embodiment of the present invention, the Zanthone derivative compound of the present invention is a compound of any one of the following compounds:

1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3,6-diyl acetate;

6,8-hydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3-yl acetate;

2 - ((6,8-hydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9-oxo -9 H-xanthene-3-yl) Oxy) acetic acid;

2,2 '- ((1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo-3,6-xanthene Diyl) bis (oxy)) diacetic acid;

3- (allyloxy) 6, 8-dihydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

3,6-bis (allyloxy) -1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

6,8-hydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3-yl trifluoromethane sulfonate Nate;

1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3,6-diyl-bis methane (trifluoromethyl Sulfonate);

3- (allyloxy) -8-hydroxy-2,6-dimethoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

3,6-bis (allyloxy) 1,7-dimethoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

3,6-dihydroxy-1,7-dimethoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

1,3-dihydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one;

1-hydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one;

3-Amino-8-hydroxy-1,7-di-isopentyl-2-methoxy -9 H - xanthene-9-one;

1,3,6- trihydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one;

1,3,6,7- tetrahydroxy-2,8-di-isopentyl-4-nitro -9 H - xanthene-9-one;

4-amino -1,3,6,7- tetrahydroxy-2,8-di-isopentyl -9 H - xanthene-9-one;

4-Chloro -1,3,6- trihydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one;

1,3,6- trihydroxy-2,8-bis (3-methyl-2-boot-en-1-yl) -7- (prop-2-in-1-yloxy) -9 H - xanthene -9-one; And

Tert-butyl 2- (4 - (((3,6,8- trihydroxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9-oxo -9 H-xanthene- 2- yl) oxy) methyl) -1 H -1,2,3- triazol-1-yl) acetate.

According to another aspect of the present invention, there is provided an anticancer composition comprising as an active ingredient, a xanthone derivative compound represented by the following general formula (1) or (2).

[Chemical Formula 1]

In Formula 1,

R ₁ is H, or C ₁ -C ₅ alkyl;

R ₂ and R ₇ are independently of each other C ₁ -C ₇ linear or branched alkyl or C ₂ -C ₇ linear or branched alkenyl;

R ₃ is OH, CH ₃ COO, CO ₂ H (CH ₂ ) _n O, C ₁ -C ₅ alkoxy, TfO, CH ₂ CHCH ₂ O or H, Tf is triflate, n is an integer of 1 to 3;

R ₄ is H, halo, NH ₂ , or NO ₂ ;

R ₅ is OH, CH ₃ COO, CO ₂ H (CH ₂ ) _n O, CH ₂ CHCH ₂ O, TfO, H, or NH ₂ , Tf is triflate, Lt; / RTI >

R ₆ is C ₁ -C ₅ alkyl, CCH, or

to be:

(2)

In the above formula (2) is a C _α H = C _β H or C _α H _β -C ₂ H _2.

According to a preferred embodiment of the present invention, the xanthone derivative compound in the anticancer composition of the present invention is any one of the following compounds:

1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3,6-diyl acetate;

6,8-hydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3-yl acetate;

2 - ((6,8-hydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9-oxo -9 H-xanthene-3-yl) Oxy) acetic acid;

2,2 '- ((1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo-3,6-xanthene Diyl) bis (oxy)) diacetic acid;

3- (allyloxy) 6, 8-dihydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

3,6-bis (allyloxy) -1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

6,8-hydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3-yl trifluoromethane sulfonate Nate;

1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3,6-diyl-bis methane (trifluoromethyl Sulfonate);

3- (allyloxy) -8-hydroxy-2,6-dimethoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

3,6-bis (allyloxy) 1,7-dimethoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

3,6-dihydroxy-1,7-dimethoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;

1,3-dihydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one;

1-hydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one;

3-Amino-8-hydroxy-1,7-di-isopentyl-2-methoxy -9 H - xanthene-9-one;

5,9-dihydroxy-8-methoxy-2,2-dimethyl-7- (3-methyl-2-boot-en-1-yl) pyran-no [3,2-b] xanthene -6 (2 H )-On;

Dihydroxy-8-methoxy-2,2-dimethyl-7- (3-methylbut-2-en-1-yl) -3,4-dihydropyrano [3,2- b Gt; 6 ( 2H ) -one; < / RTI >

1,3,6- trihydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one;

1,3,6,7- tetrahydroxy-2,8-di-isopentyl-4-nitro -9 H - xanthene-9-one;

4-amino -1,3,6,7- tetrahydroxy-2,8-di-isopentyl -9 H - xanthene-9-one;

4-Chloro -1,3,6- trihydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one;

1,3,6- trihydroxy-2,8-bis (3-methyl-2-boot-en-1-yl) -7- (prop-2-in-1-yloxy) -9 H - xanthene -9-one; And

Tert-butyl 2- (4 - (((3,6,8- trihydroxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9-oxo -9 H-xanthene- 2- yl) oxy) methyl) -1 H -1,2,3- triazol-1-yl) acetate.

The xanthine derivative compound of the present invention exhibits anticancer activity against various cancer cell lines, as demonstrated in the following specific example, and can be an effective anticancer agent since water solubility characteristics are greatly improved.

&Quot; Cancer " which is a disease to be treated, improved and prevented by the composition of the present invention is an aggressive characteristic that cells divide and grow by ignoring the normal growth limit, invasive, The term " disease " refers to a disease caused by a cell having a characteristic, metastatic characteristic spreading to other parts of the body.

According to a preferred embodiment of the present invention, the cancer to be treated is selected from breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or ocular melanoma, uterine sarcoma, ovarian cancer, Endometrial cancer, small bowel cancer, endocrine cancer, thyroid cancer, pituitary cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone cancer. More preferably a colon cancer, a breast cancer, a prostate cancer, a pancreatic cancer, or a lung cancer.

According to a preferred embodiment of the present invention, the anticancer composition of the present invention comprises (i) a pharmaceutically effective amount of the above-described xanthone derivative compound; And (ii) a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The appropriate dosage of the pharmaceutical composition of the present invention may be determined by various methods depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate and responsiveness of the patient It can be prescribed. On the other hand, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg / kg (body weight) per day.

The pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, or the like.

The concentration of the active ingredient contained in the composition of the present invention is determined in consideration of the purpose of the treatment, the condition of the patient, the period of time required, the severity of the disease, and the like. The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

According to a preferred embodiment of the present invention, the anticancer composition of the present invention may be provided in the form of a functional food composition.

When the composition of the present invention is provided in the form of a food composition, the composition of the present invention may contain, in addition to the above-mentioned active ingredient, the xanthone derivative compound, a component ordinarily added during the manufacture of a food. Examples thereof include protein, carbohydrate, Fat, nutrients, flavoring agents and sweetening agents. Examples of such carbohydrates include, but are not limited to, monosaccharides such as disaccharides such as glucose and fructose, such as maltose, sucrose, oligosaccharides and the like, and polysaccharides such as dextrins, cyclodextrins, And sugar alcohols such as xylitol, sorbitol and erythritol. Natural sweeteners (tau Martin, stevia extract, rebaudioside A, glycyrrhizin, etc.) and synthetic sweetening agents (saccharin, aspartame, etc.) can be used as sweeteners. For example, when the food composition of the present invention is prepared as a drink, it may further contain citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, mulberry extract, jujube extract, licorice extract, have.

The present invention relates to a novel xanthone derivative compound and an anticancer composition comprising the compound as an active ingredient. The xanthine derivative compound of the present invention exhibits excellent anticancer activity against various human cancer cells, and the water solubility characteristics are greatly improved as compared with the? -Mangosteen compound as the parent compound. The xanthine derivative compound of the present invention can be developed as an anticancer drug having very excellent activity.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

I. Compound Synthesis

1. Synthesis of Compound 2 and 4-12

[Reaction 1]

[Reaction 1 above shows the process of synthesizing a-mangosteen derivatives through structural modification of compounds at C1, C3, and C6 positions. The reagents and reaction conditions in the above reaction are as follows: a) Ac ₂ O, pyridine, CH ₂ Cl ₂ , 4a 30%, 4b 20%; b) BrCH ₂ CO ₂ CH ₃ , K ₂ CO ₃ , followed by acetone and aq. 7% for KOH, 5a , 12% for 5b ; c) Allyl chloride, K ₂ CO ₃ , acetone, 59% for 6a , 20% for 6b ; d) Tf ₂ O, Et ₃ N, CH ₂ Cl ₂ 7a 5%, 7b 18%; e) CH ₃ I, K ₂ CO ₃ , acetone, 70% for 8a , 80% for 8b ; f) cat. Pd (PPh ₃ ) ₄ and K ₂ CO ₃ , MeOH, 60 ° C, 2 91%, 9 9 51%; g) H ₂ , Pd / C, 41% for MeOH 10a , 95% for 10b ; h) BnNH ₂ , Pd (OAc) ₂ , XPhos, Cs ₂ CO ₃ , DMF, μw, 160 ° C, 23%, followed by H ₂ , Pd / C, MeOH, 34%; i) DDQ, benzene, reflux, 75%; j) TsOH, benzene, reflux, 70%]

The present inventors have conducted studies to develop a compound having a novel anticancer activity through the modification of the functional group of? -Mangosteen, a natural product of polyphenols. The α-mangosteen derivatives were synthesized through various modifications at the C1, C3 and C6 positions of phenol. To synthesize the acetate of compounds 4a and 4b, a-mangosteen was treated with acetic anhydride, Et ₃ N and DMAP in CH ₂ Cl ₂ (13c). Carboxy group of the compounds 5a and 5b were introduced through the process and thus successively basic hydrolysis of methyl bromoacetate and K ₂ CO _3. As it is predicted from the preceding example for the selective alkylation at the C6 position before the position C3, aryl allyl ether of compound 6a and 6b are obtained with the compound 1-allyl bromide and process the _{K 2 CO 3 (13a, 14} ). Triflate (triflate) in analogy to compound 7a and 7b was prepared by the methanesulfonic acid anhydride, Et ₃ N and DMAP trifluoromethyl. The allyl groups of compounds 6a and 6b were used as protecting groups while the triflates of compounds 7a and 7b were displaced during aromatic substitution with subsequent hydrides or amines. After the compounds 6a and 6b were obtained, two methyl ether derivatives were obtained through methylation at the C3 and C1 positions of the phenol. By removing the protective group using allyl Pd (PPh _{3) 4} and K ₂ CO ₃ was prepared in the β- mangosteen (Compound 2) and the α- mangosteen methylated derivative C1- (Compound 9). Derivatives 10a and 10b, in which oxygen was removed at C6 and C3 / C6 positions, were obtained from mono-triflate compound 7a and bis-triflate compound 7b, respectively. During the reaction, the two prenyl groups were reduced to isopentyl groups. The amine of compound 11 was prepared from bis-triflate compound 7b via a two-step continuous process of selective introduction of diphenylmethylamine at the C6 position and complete hydrogenolysis under H ₂ , Pd / C. The known cyclic compounds 12a and 12b were prepared by treating DDQ (15) and TsOH (16), respectively.

2. Synthesis of Compound 13-16

[Reaction 2]

[Reaction 2 above shows the synthesis of alpha-mangosteen derivatives with altered C4 positions. Reaction reagents and conditions were as follows: a) H ₂ , Pd / C, MeOH, 99%; _{b) HNO 3, AcOH, 19} %; c) H ₂ , Pd / C, MeOH, 82%; d) NCS, CH ₂ Cl ₂ , 35%]

As shown in the above Reaction 2, the derivatives functionalized at the C4 position were synthesized from Compound 1. First, the hydrogenated compound 13 was prepared by catalyzed hydrogenation under H ₂ and Pd / C, followed by a nitration process using HNO ₃ and AcOH to produce the C4-nitro compound 14 in moderate yield (17 ). Here again, the C4-amino compound 15 was prepared by catalytic hydrogenation. By the known method (13b), a C4-chlorinated compound 16 was prepared.

3. Synthesis of Compound 3 and 17 - 18

[Reaction 3]

[Reaction 3 above shows the synthesis of α-mangosteen with C7 position changed. The reagents and conditions of the reaction are as follows: a) morpholine (neat), 32%; b) propargylic bromide, K ₂ CO ₃ , acetone, 34%; e) t-butyl bromoacetate, NaN ₃ , then, CuSO ₄ , sodium hydroxide ascorbate, DMSO, 19%

Modifications were made at the C7 position to synthesize gamma-mangosteen and its derivatives. After several demethylation conditions were selected (18), γ-mangosteen was prepared by most effectively removing the methyl group using morpholine (neat). gamma-mangosteen (3) was prepared and then the propargyl group was introduced by mono-alkylation reaction using propargyl bromide and potassium carbonate. Finally, after synthesizing the propargyl ether of compound 17, the triazole of compound 18 was converted to the sodium azobisate and copper sulfate in DMSO by azo acetate prepared in situ by the reaction of t-butyl bromoacetate and sodium azide , Through copper-catalyzed click chemistry.

Ⅱ. Methods and Materials of Experiment

All starting materials and reagents were purchased from commercial suppliers and used without further purification. Air and humidity-specific reactions were performed under an argon atmosphere. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the specified solvent. Thin-film chromatography was performed using a 0.25 mm silica gel plate (Merk). ^{The 1} H and ¹³ C NMR spectra were recorded on a Bruker 600 MHz, Bruker 500 MHz, or JEOL 400 MHz spectrometer as a solution in deuterated chloroform (CDCl ₃ ) or methanol-d 4. ^{The 1} H NMR data is based on chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet and / or multiple resonance), proton number, (Hz). ≪ / RTI > The low resolution mass spectra were collected on a Waters LCMS system (Waters 2489 UV / visible light detector, Waters 3100 Mass, Waters 515 HPLC pump, SunFire C18 column 4.6 X 50 mm, 5 um particle size, Waters 2545 Binary Gradient Module, Waters Reagent Manager , And Waters 2767 Sample Manager).

Ⅲ. Spectroscopic data and anticancer activity of compounds

1. Spectroscopic data of the compound

(1) Hydroxy-7-methoxy-2,8-bis (3-methylbut-2-en-1-yl) H (4a) and 6,8-dihydroxy-2-methoxy-1,7-bis (3-methylbut-2- en-1-yl) -9-oxo -9 H 3-yl acetate (Compound 4b)

Acetic anhydride (25 mg, 0.24 mmol) and pyridine (29 mg, 0.37 mmol) were added to a-mangosteen (100 mg, 0.24 mmol) in CH ₂ Cl ₂ (5.0 mL). After stirring at room temperature for 30 minutes, the mixture was cooled to 0 C, poured into water (10 mL) and extracted with CH ₂ Cl ₂ (10 mL). The organic layer was washed with brine (3 mL) and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure and purified by column chromatography using hexane / ethyl acetate (5: 1) to give 4a (yellow solid, 32 mg, 30%) and compound 4b (yellow solid, 23 mg, 20% .

Compound 4a

1H NMR (CDCl3, 500 MHz) [delta] 13.5 (s, IH), 7.10 (s, IH), 6.23 (d, 2H, J = 12 Hz), 5.22-5.30 J = 8.0Hz), 3.78 (s, 3H), 3.45 (d, 2H, J = 12 Hz), 2.40 (s, 3H), 1.70-1.85 (m, 12H).

Compound 4b

2H), 4.15 (d, 2H, J = 8.0 Hz, 1H), 7.30 (s, J = 15Hz), 1.70 (s, 6H), 3.79 (d, 2H, J = ).

(3-Methylbut-2-en-1-yl) -9 (3-methylbutyl) -6,8-dihydroxy-2-methoxy- H -9-one (Compound 6a) and 3,6-bis (allyloxy) -1-hydroxy-7-methoxy- -9 H -9-one (Compound 6b)

Allyl bromide (240 mg, 2.0 mmol) and K ₂ CO ₃ (410 mg, 3.0 mmol) were added to a solution of α-mangosteen (410 mg, 1.0 mmol) in acetone (15 mL) under ambient temperature conditions. After stirring at 40 < 0 > C for 4 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The filtration residue was purified by column chromatography using hexane / ethyl acetate (5: 1) to give compound 6a (yellow solid, 260 mg, 59%) and compound 6b (yellow solid, 98 mg, 20%).

Compound 6a

1H, NMR (600 MHz, CDCl3)? 13.8 (s, IH), 6.73 (s, IH), 6.28 (M, 1H), 4.67 (ddd, 1H, J = 1.2, 2.4 and 10 Hz), 5.31-5.28 2H, J = 1.5 and 5.4 Hz), 4.13 (d, 2H, J = 6.6 Hz), 3.81 1.2 Hz), 1.78 (d, 3H, J = 1.2 Hz), 1.68 (s, 3H, J = 1.2 Hz); 13 C-NMR (150 MHz, CDCl 3) δ 182.1, 161.5, 160.6, 157.0, 155.2, 155.0, 144.1, 137.4, 136.0, 131.9, 131.8, 123.1, 121.4, 118.4, 112.0, 108.3, 103.7, 99.3, 60.8, 26.2, 25.9, 25.8, 21.4, 18.1, 17.9; LRMS (ESI < ^- >) m / z 308.1 (MH ^< ⁺ & gt ^; ).

Compound 6b

2H), 5.49 (m, 2H), 5.37 (m, 2H, < RTI ID = 0.0 & 2H), 5.25 (m, 2H), 4.65 (d, 4H, J = 4.9 Hz), 4.46 (d, 2H, J = 0.8) , 1.83 (s, 3H), 1.78 (s, 3H), 1.66 (s, 6H).

3-Allyloxy-8-hydroxy-2,6-dimethoxy-1,7-bis (3-methylbut- H -9-one (Compound 8a)

K ₂ CO ₃ (66 mg, 0.48 mmol) and iodomethane (50 mg, 0.36 mmol) were added at room temperature to a solution of compound 6a (100 mg, 0.24 mmol) in acetone. After stirring at 40 < 0 > C for 12 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (5: 1) to give 8a (yellow solid, 75 mg, 70%).

1 H-NMR (400 MHz, CDCl 3)? 13.4 (s, IH), 6.71 (s, IH), 6.30 ), 5.36 (dd, 1H, J = 1.4 and 11 Hz), 4.66 (d, 2H, J = 5.4 Hz), 4.13 (d, 2H, J = 6.8 Hz), 3.88 (S, 3H), 1.34 (d, 2H, J = 6.8 Hz).

4) 3,6-bis (allyloxy) -1,7-dimethoxy-2,8-bis (3-methylbut- H -9-one (Compound 8b)

K ₂ CO ₃ (138 mg, 1 mmol) and iodomethane (112 mg, 0.8 mmol) were added at room temperature to a solution of compound 6b (80 mg, 0.16 mmol) in DMF (2 mL) After stirring at 40 < 0 > C for 12 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (9: 1) to give 8b (yellow solid, 59 mg, 80%).

2H), 5.32 (m, 2H), 5.20 (m, 2H), 5.40 (s, 2H) 2H), 4.64 (d, 2H, J = 4.7 Hz), 4.60 (d, 2H, J = 4.7 Hz), 4.13 , 3.41 (d, 2H, J = 6.8 Hz), 1.83 (s, 3H), 1.77 (s, 3H), 1.64 (d, 6H, J = 6.8 Hz).

E) 1,6-Dihydroxy-3,7-dimethoxy-2,8-bis (3-methylbut-2-en- H -Zanthen-9-one (? -Mangostin, Compound 2)

K ₂ CO ₃ (30 mg, 0.22 mmol) and tetrakis (triphenylphosphine) palladium (0) (10 mg, 8.7 μmol) were added to a solution of compound 8a (18 mg, 37 μmol) in MeOH (2 mL) Was added. After stirring at 80 [deg.] C for 5 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (2: 1) to give compound 2 (yellow solid, 15 mg, 91%).

1H NMR (600 MHz, CDCl3)? 13.4 (s, IH), 6.82 (s, IH), 6.33 (d, IH, J = 3.0 Hz), 5.28-5.25 3H), 3.35 (d, 2H, J = 7.2 Hz), 1.83-1.68 (4s, 12H) ; 13 C-NMR (CDCl 3, 150 MHz)? 181.9, 163.5, 159.7, 155.7, 155.2, 154.3, 142.5, 137.0, 132.2, 130.5, 123.1, 122.3, 112.4, 111.5, 103.8, 101.4, 88.8, 62.0, 55.8, 26.5, 25.8, 21.3, 18.2, 17.8; ^{LRMS (ESI -) m / z} 423.2 (MH +).

⑥ 3,6-Dihydroxy-1,7-dimethoxy-2,8-bis (3-methylbut-2-en- H -9-one (Compound 9)

To a solution of compound 8b (50 mg, 0.11 mmol) in MeOH (2 mL) was added K ₂ CO ₃ (68 mg, 0.5 mmol) and tetrakis (triphenylphosphine) palladium (0) ). After stirring at 60 占 폚 for 5 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (5: 1) to give compound 9 (yellow solid, 24 mg, 51%).

1H NMR (600 MHz, CDCl3)? 6.73 (d, IH, J = 2.4 Hz), 6.61 (s, IH), 5.27 2H), 4.08 (d, 2H, J = 6.6 Hz), 3.83 (s, 3H), 3.76 (s, 3H), 3.44 (d, 2H, J = 6.0 Hz), 1.78-1.55 (4s, 12H); 13 C-NMR (CDCl 3, 150 MHz) δ 176.8, 160.5, 158.8, 156.3, 154.7, 153.6, 142.5, 137.0, 131.6, 123.6, 122.1, 114.6, 110.4, 101.1, 99.0, 62.0, 61.8, 26.3, 25.8, 25.7, 22.4, 21.1, 18.1, 17.9, 14.1; ^{LRMS (ESI -) m / z} 423.2 (MH +).

?) 1,3,6-Trihydroxy-2,8-diisopentyl-7-methoxy-9 H -9-one (Compound 13)

A solution of a-mangosteen (1.0 g, 2.4 mmol) and 10% Pd / C (260 mg) in MeOH (2 mL) was placed under a hydrogen atmosphere. After stirring for 12 h, the reaction mixture was filtered through a short pad of celite and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / ethyl acetate (3: 1) to give 13 (yellow solid, 1.0 g, 99%).

(Bs, 1H), 3.83 (s, 1H), 6.28 (s, 1H), 6.25 (s, 2H), 1.49-1. 42 (m, 4H), 1.47-1. 26 (m, 1.00-0.97 (4s, 12H); 13 C-NMR (CDCl 3, 150 MHz) δ 181.9, 161.1, 159.9, 155.8, 154.5, 154.3, 142.3, 139.2, 112.2, 110.8, 103.7, 101.2, 92.5, 62.2, 60.5, 40.2, 37.9, 28.8, 28.2, 25.5, 22.5, 22.4, 20.1, 14.1; LRMS (ESI ^& lt ^{; +} & gt ^; ) m / z 415.2 (M + H ^& lt ^{; +} & gt ^; ).

8) 1,3,6,7-Tetrahydroxy-2,8-diisopentyl-4-nitro-9 H -9-one (Compound 14) < RTI ID = 0.0 >

To the compound 13 (210 mg, 0.48 mmol) was added nitric acid / acetic acid (1:50, 1.5 mL) dropwise at 0 ° C. After eseo 0 ℃ stirred for 20 minutes, the reaction mixture was neutralized with a saturated NaHCO ₃ solution and extracted with ethyl acetate. The combined organic layers were washed with brine, and concentrated under reduced pressure and dried on MgSO _4. The residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (3: 1) to give compound 14 (yellow solid, 42 mg, 19%).

1H NMR (CDCl3, 600 MHz)? 12.3 (s, IH), 7.07 (s, IH), 6.39 (s, IH), 5.23 , 2H), 2.73-2.71 (m, 2H), 1.80-1.58 (m, 2H), 1.47-1.40 (m, 4H), 1.01-0.98 (4s, 12H); (CDCl3, 150 MHz)? 178.8, 168.4, 163.5, 159.4, 155.7, 150.1, 130.7, 122.3, 114.3, 105.1, 93.4, 90.1, 82.3, 78.0, 52.2, 37.3, 33.9, 32.2, 28.6, 28.0, 21.6, 21.5, 21.4, 19.8; ^{LRMS (ESI -) m / z} 482.2 (MH +).

⑨ 4-Amino-1,3,6,7-tetrahydroxy-2,8-diisopentyl-9 H -9-one (Compound 15)

Compound 14 and 10% Pd / C (14 mg) in MeOH (2 mL) were placed under a hydrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was filtered through a short pad of celite and concentrated under reduced pressure to give compound 15 (yellow solid, 46 mg, 82%).

(CDCl3, 600 MHz) [delta] 13.5 (s, IH), 6.82 (s, IH), 3.84 (s, 3H), 3.34-3.31 -1.71 (m, 2H), 1.65-1.59 (m, 2H), 1.48-1.43 (m, 4H), 1.00-0.96 (4s, 12H); (CDCl3, 150 MHz) δ 182.0, 157.1, 155.4, 154.4, 147.7, 142.5, 139.5, 131.0, 128.8, 112.0, 110.2, 102.6, 101.1, 62.1, 40.9, 40.2, 38.0, 28.8, 28.2, 25.5, 22.7, 22.6, 22.5, 20.6; ^{LRMS (ESI -) m / z} 428.2 (MH +).

⑩ 4-Chloro-1,3,6-trihydroxy-2,8-diisopentyl-7-methoxy-9 H -9-one (Compound 16)

To a solution of a-mangosteen (205 mg, 0.5 mmol) in THF (10 mL) was added N-chlorosuccinimide (93 mg, 0.7 mmol) at room temperature. After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate, and dried on MgSO _4. The combined extracts were concentrated under reduced pressure and purified by column chromatography using hexane / ethyl acetate (2: 1) to give 16 (77 mg, 35%).

1H NMR (600 MHz, CDCl3)? 13.6 (s, IH), 6.94 (s, IH), 6.32 (bs, 2H), 5.26-5.24 (d, 2H, J = 6.0 Hz), 3.80 (s, 3H), 3.42 (d, 2H, J = 7.2 Hz), 1.81-1.67 (4s, 12H); 13 C-NMR (CDCl 3, 150 MHz)? 181.7, 159.1, 155.9, 155.4, 154.8, 149.6, 143.0, 137.2, 133.3, 132.3, 122.8, 121.3, 111.9, 110.4, 104.0, 101.8, 96.4, 62.1, 26.5, 25.8, 22.0, 18.2, 17.8; ^{LRMS (ESI -) m / z} 443.1 (MH +).

11) 1,3,6,7-Tetrahydroxy-2,8-bis (3-methylbut-2-en-1-yl) H -Xanthen-9-one (y-mangosteen, compound 3)

A mixture of a-mangosteen (200 mg, 0.5 mmol) in morpholine (2 mL) and water (1 mL) was placed in a sealed tube. The reaction mixture was heated at 140 < 0 > C for 2 days. The reaction mixture was cooled and poured into ice-cooled 1N HCl and brine mixture. The mixture was extracted with ethyl acetate. The combined organic layers are washed with brine, dried on anhydrous MgSO _4. The solution was concentrated under reduced pressure and purified by column chromatography to give compound 3 (yellow solid, 65 mg, 32%). The spectroscopic data was the same as the data (1) already reported.

2. Results of anticancer activity measurement

The antitumor activity of the newly synthesized Zanthone derivatives was evaluated by using 5 types of human cancer cell lines, NCI-H460 (lung cancer cell), SW-620 (colorectal cancer cell), AsPC-1 (pancreatic cancer cell), MDA- And B16F10 (skin cancer cells) were measured using an XTT kit, and the results were summarized in Table 1 to Table 3 as IC ₅₀ values. Adriamycin and a-mangosteen were used as reference compounds, and these compounds showed potent anticancer activities as expected. This anticancer activity measurement was carried out under the standardized assay conditions described in the known prior art (19). In more detail, anticancer activity was measured by the following method. Human cancer cells were plated in 96-well plates at 1 × 10 ⁴ cells / well, cultured overnight, and then treated with each compound for 48 hours. Cytotoxicity assays were performed using an XTT kit (Roche Applied Science Mannheim, Penzberg, Upper Bavaria, Germany). The XTT labeling mixture contained 50 times the volume of 1 mg / mL sodium 3'- [1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (4-methoxy-6-nitro) benzenesulfonic acid hydrate , And 1 volume of 0.383 mg / ml N-methyldibenzopyrazine methyl sulfate. The thus-prepared XTT labeling mixture was added to the culture and incubated at 37 ° C for 2 hours. Absorbance was measured at 490 nm and 650 nm was used as the reference wavelength.

The in vitro anticancer activity (proliferation inhibitory activity against cancer cells) of 15 compounds (4-12) changed at positions 1, 3 and 6 of α-mangosteen is shown in Table 1. All phenol groups were tested for their effect on cancer cell viability. Among these compounds induced by acylation, alkylation and substitution, compounds 4a, 4b, 6a, 7b, 9, and 11 had IC ₅₀ values in the range of 10-20 μM, indicating good levels of anticancer activity. On the other hand, other derivatives showed only minimal cancer cell proliferation inhibitory effect. These SAR data suggest that the phenolic groups, especially the C3 and C6 positions, play an important role in the cytotoxic activity of the xanthone compounds on cancer cells.

After confirming the importance of the phenol groups in efficacy, several different substituents were introduced at the C4 position to alter the pKa of the C3-position phenol (Table 2). Compound 13, which is a reduced form of a-mangosteen, showed strong anticancer activity while the nitro-derivative (Compound 14) and amino-derivative (Compound 15) also showed a significant degree of anticancer activity (Compound 15, SW-620 ≪ / RTI > IC ₅₀ for cell lines). Similarly, the chloro-derivative, Compound 16, exhibited good anticancer activity (IC ₅₀ 9.59 [mu] M for the SW-620 cell line).

To assess the importance of substitution on the C7 position, the anticancer activity of compounds 3, 17 and 18 was tested (Table 3). Synthetic [gamma] -mangosteen (Compound 3) showed activity similar to that of natural [alpha] -Mangosteen, but Compound 17 and 18 had no anticancer activity completely.

The kinetic solubility of these synthesized derivatives was measured using a 5% DMSO solution at pH 6.8 (Table 4). A more detailed description of the kinetic solubility measurement method is as follows: Stock solutions were prepared at a concentration of 10 mM in 5% DMSO: 95% PBS buffer. The stock solution was diluted with 5% DMSO: 95% PBS buffer to reduce the moral concentration across the plate. Each plate was read in a vertical direction at a laser intensity of 635 nm at 90% to generate a count per well to generate initial data. All initial data was processed using BMG LABTECH NEPHELOstar Galaxy Evaluation software. The solubility limit was determined by a significant increase in signal / noise ratio. Selected derivative compounds 4a, 6a, 11, 14, and 16 exhibiting moderate anticancer activity showed a much greater increase in kinetic solubility compared to a-mangosteen several times.

compound Solubility compound Solubility One 20 ± 0.9 9 104 ± 4 3 94 ± 3 11 138 ± 6 4a 148 ± 5 13 78 ± 2 4b 122 ± 2 14 339 ± 5 6a 149 ± 2 16 381 ± 7

To summarize the results of the experiments of the present invention, we have synthesized novel xanthone derivatives based on a-mangosteen. Alpha-mangosteen could be effectively modified with beta-mangosteen and gamma-mangosteen. As a result of the anticancer activity screening using five human cancer cell lines, compounds having strong anticancer activities such as compounds 4a, 6a, 9, 13, 15, and 16 were identified.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (7)

delete The following xanthone derivative compounds:
1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3,6-diyl acetate;
6,8-hydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3-yl acetate;
3- (allyloxy) 6, 8-dihydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;
3,6-dihydroxy-1,7-dimethoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;
3-Amino-8-hydroxy-1,7-di-isopentyl-2-methoxy -9 H - xanthene-9-one;
1,3,6,7- tetrahydroxy-2,8-di-isopentyl-4-nitro -9 H - xanthene-9-one; or
4-Chloro -1,3,6- trihydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one.
delete A composition for anticancer therapy for lung cancer, colon cancer, pancreatic cancer, breast cancer or skin cancer which comprises the following Zanthone derivative compound as an active ingredient:
1-hydroxy-7-methoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3,6-diyl acetate;
6,8-hydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H -9-oxo - xanthene-3-yl acetate;
3- (allyloxy) 6, 8-dihydroxy-2-methoxy-1,7-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;
3,6-dihydroxy-1,7-dimethoxy-2,8-bis (3-methyl-2-boot-en-1-yl) -9 H - xanthene-9-one;
3-Amino-8-hydroxy-1,7-di-isopentyl-2-methoxy -9 H - xanthene-9-one;
1,3,6,7- tetrahydroxy-2,8-di-isopentyl-4-nitro -9 H - xanthene-9-one; or
4-Chloro -1,3,6- trihydroxy-2,8-di-iso-pentyl-7-methoxy--9 H - xanthene-9-one.
delete 5. The composition of claim 4, wherein the composition is a pharmaceutical composition.
5. The composition of claim 4, wherein the composition is a functional food composition.