KR20160001410A - A Naphthochalcone and use of the same as anticancer drug - Google Patents

Abstract

The present invention relates to naphthalene-based chalcone and uses thereof as an anticancer drug and, more specifically, to a novel naphthalene-based chalcone compound, an anticancer drug comprising the same, and a cancer prevention agent. A naphthalene-based chalcone compound is represented by chemical formula 1. In the chemical formula 1, R is a functional group selected from the group consisting of hydrogen, 6-methoxy, 4,5-dimethoxy, and 4,6-dimethoxy.

Description

Naphthalene-based chalcone and its use as an anticancer agent

The present invention relates to naphthalene-based chalcone and its use as an anticancer agent, and more particularly, to a novel compound naphthalene-based chalcone, an anticancer agent and a composition for preventing cancer.

Colon cancer is one of the diseases in which the incidence rate of diarrhea increases from the entry of advanced countries into Korea. Although early detection is the best treatment method, it still needs treatment through chemotherapy. to be.

A chalcone compound is a type of polyphenol compound known as a secondary metabolite that is found in the process of producing secondary metabolites of a plant. Many kinds of chalcone compounds have been found since they can form derivatives having various structures depending on the substituent . Some of these have been known to have anticancer effects (Yadav VR, Prasad S, Sung B, Aggarwal BB. Int Immunopharmacol. 2011 Mar; 11 (3): 295-309). The chalcone compound has the same structure as the carbon skeleton of the flavonoid-based compound as a compound having a skeleton of C6-C3-C6. Only the flavonoid compounds are composed of C6-C3-C6 carbon skeletons, whereas chalcone compounds have two C6 skeletons and ring C3 enones. The difference is in point. Since both rings constituting the chalcone compound are composed of an aromatic ring, they have a structure in which various substituents can be located. As a result, various kinds of derivatives exist depending on the kind and position of the substituent. When the substituent is hydroxy, it increases the hydrophilic property. When the substituent is methoxy, it increases the hydrophobic property. When the aromatic ring is added as the substituent, the hydrophobic property is further increased. The increase of the hydrophilicity facilitates the affinity with water constituting most of the living body, but it has a disadvantage that it makes it difficult to transmit the cell membrane constituting the cell.

Chalcone is known as a safe anticancer drug compound because of its low DNA mutagenicity due to its low binding capacity to DNA. Although chalcone is a kind of flavonoid, unlike other flavonoids, two benzene rings are connected to an open carbonyl group without ring connection. When a carbonyl group is substituted with a pyrazoline, a pyrazoline-based chalcone is formed, which is also known to exhibit anticancer activity. In nature, naphtoflavones with naphthalene groups are found. Their biological effects are known to affect cytochrome P450, but naphtalocalcon is not found in nature [4546 J. of Pharmaceutical science Vol.97, No 10.Oct. 2008].

The colony forming assay (Clonogenic assay) method of cancer cells is used for screening substances having anti-cancer effects by analyzing the effect of specific substances on cell proliferation and survival (Franken NA, Rodermond HM, Stap J , Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006; 1: 2315-9). Cell apoptosis or programmed cell death (PCD) refers to a cellular physiology (cell suicide) that induces cell death by itself (Steller, Science 1995, 267, 1445-1449). In addition to the physiological role such as the proper formation of various organs in the fetal development process of the living body, the planned cell death phenomenon (Jacobson et al., Cell, 1997, 88, 347-354) If the ligand binds to the receptor or is exposed to various cell stress stimulation signals such as ultraviolet or radioactive exposure, toxic substances, and DNA damage stimulation, serious damage to the genome of the cell will result in a biological defense system that induces cell death by itself (Li and Yuan, Current Opinion in Cell Biology 1999, 11, 261-266).

To date, various anti-cancer drugs have been known and developed, but there remain problems to be solved. One of the ways to overcome this problem is the natural materials that have been used in civilian or traditional medicine for a long time. Plants produce secondary metabolites in small quantities for their defense, one of which is flavonoids. Since the flavonoid derivatives of mannon are already known, the design of flavonoid derivatives with new skeleton is absolutely necessary for the derivation of novel substances.

[Prior Patent Literature]

Korean Patent Publication No. 10-2012-0047503

The present invention has been made in view of the above needs, and an object of the present invention is to provide a novel naphthocalcon compound.

Another object of the present invention is to provide a use of the naphthocalecone compound.

In order to accomplish the above object, the present invention provides a naphthalene-based chalcone compound represented by Formula 1:

[Chemical Formula 1]

In Formula 1, R is preferably a functional group selected from the group consisting of H, 6-methoxy, 4,5-dimethoxy, and 4,6-dimethoxy, but is not limited thereto.

In another embodiment of the present invention, the naphthalene-based chalcone compound is preferably a compound of formula (2), but is not limited thereto:

(2)

In Formula 2, R is preferably a functional group selected from the group consisting of 2,4-dimethoxy, and 3,5-dimethoxy.

The present invention also provides a pharmaceutical composition for anticancer therapy comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

Hereinafter, the present invention will be described.

The present inventors have designed a chalcone having a naphtho group at the same time as a pyrazoline substituted for a carbonyl group, and made a new naphthol-based chalcone into an organic synthesis. The anticancer efficacy against them was carried out through a clonogenicity test on colon cancer cell lines and found a phenomenon in which colon cancer cell lines were effectively killed, thus completing the present invention.

The compound is preferably produced by the methods described herein.

This compound can be used, for example, in pharmaceutical compositions containing a pharmaceutically acceptable carrier, prepared for storage and subsequent administration. In addition, certain embodiments relate to pharmaceutically effective amounts of the abovementioned products and compounds contained in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are those well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences (A. R. Gennaro edit. 1985) of Mack Publishing, which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes and fragrances may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and p-hydroxybenzoic acid ester can be added as a preservative. Antioxidants and suspension systems may also be used.

In particular, the composition of formula (I) or (II) may be in the form of tablets, capsules or parenteral solutions for oral administration; Suppositories for rectal administration; A sterile solution, a suspension for injection administration; As patches for skin transfer administration or adherence, and the like. The injectable solutions may be prepared in conventional forms such as liquid solutions or suspensions, solid solutions which can be suitably converted into liquid solutions or suspensions in advance, or emulsions.

Suitable excipients are, for example, water, physiological saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, hydrogen cysteine and the like. If desired, the injectable pharmaceutical composition may also contain minor amounts of non-toxic adjuvants, such as wetting agents, pH buffers, etc. Absorption accelerators (e.g., liposomes) Into an aqueous form. In addition, suspensions of the active compounds may be prepared with suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include sesame oil or other organic oils such as soy, grapefruit or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as carboxymethyl sodium cellulose, sorbitol or dextran. In some cases, the suspension may also contain a suitable stabilizer or action system to increase the solubility of the compound so that a highly concentrated solution can be prepared.

The pharmaceutical preparations for oral use can be produced by combining the active compound with a solid excipient, optionally pulverizing the resulting mixture, adding an appropriate adjuvant to obtain a tablet or sugar cores, if necessary, can do. Suitable excipients are, in particular, fillers such as sugars including lactose, sucrose, mannitol and sorbitol; Such as corn starch, wheat flour, rice flour, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, carboxymethyl sodium cellulose and / or polyvinylpyrrolidone (PVP) There are cellulosic preparations. If necessary, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate may be added. The drapery is covered with appropriate coatings. For that purpose, a concentrated sugar solution, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbapol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and also suitable organic solvents or solvent mixtures, It is also used. Dyestuffs or pigments may be added to tablets or sugar-coated tablets to define or characterize different combinations of active compounds. Such formulations may be prepared by methods known in the art (see, for example, U.S. Patent No. 5,733,888 (injectable composition), 5,726,181 (water-insoluble compound), 5,707,641 (therapeutically active protein or peptide); 5,667,809 (lipophilic agent), 5,576,012 (solubilizing polymer), 5,707,615 (antiviral formulation), 5,683,676 (granular medicament), 5,654,286 (domestic formulation), 5,688,529 5,641,515 (controlled release formulations) and 5,601,845 (elderly formulations)), all of which are incorporated by reference in their entirety as references Are incorporated herein by reference.

Also, various pharmaceutical compositions well known in the pharmaceutical arts are used for applications including topical, intraocular, intranasal, and intrathecal delivery. The pharmaceutical formulation may be in the form of an aqueous solution such as an ophthalmic solution or an aqueous eye drop of the active compound in the form of gelatin gum (Shedden et al., Clin. Ther., 23 (3): 440-50 (2001)) or hydrogels Ophthalmologica, 210 (2): 101-3 (1996)); Eye ointment; (See Joshi, A. 1994 J Ocul Pharmacol 10: 29-45), lipid soluble formulations (see Alm et al., Prog. Clin. Bio. Res. , 312: 447-58 (1989)) and microspheres (Mordenti, Toxicol. Sci., 52 (1): 101-6 (1999)); Also included are eye implants and the like. Such suitable pharmaceutical formulations are most frequently and preferably made into sterile, isotonic and buffered formulations for stability and convenience. The pharmaceutical compositions also include drops and sprays which are often made in a form similar to nasal secretions at various points to maintain normal ciliary movement. As is well known to those skilled in the art, suitable formulations are most frequently and preferably isotonic and have a pH of from about 5.5 to about 6.5, as disclosed, for example, in Remington ' s Pharmaceutical Sciences (18th Edition) , And also most frequently and preferably includes an antimicrobial preservative and a suitable drug stabilizer. Pharmaceutical formulations for intranasal delivery include suspensions and ointments for topical application to the ear. Common solvents for such ear formulations include glycerin and water.

When used as an anticancer agent, for example, a compound of Formula 1 or 2 or a composition containing the compound may be administered via an oral or parenteral route. Orally in the form of capsules, tablets, granules, sprays, syrups or other forms. In the case of parenteral administration, it can be administered in the form of an aqueous suspension or an oil-based preparation, or in the form of drops, suppositories, ointments, ointments, etc., and can be administered subcutaneously, intraperitoneally, intravenously, ≪ / RTI >

In one embodiment, the anti-cancer compounds can be mixed with other substances to enhance their effectiveness.

In yet another embodiment, the chemical compounds and the pharmaceutical compositions described above are administered by a particular antimicrobial method. The method comprises: (a) administration via an oral route including capsules, tablets, granules, sprays, syrups or other forms of administration; (b) administration through aqueous or non-oral routes including administration of aqueous suspensions, oily preparations, etc., or drops, suppositories, ointments, ointments, etc.; Subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection or the like; (C) topical administration; (d) rectal administration; Or (e) vaginal administration or the like, to contact with a biological tissue according to an embodiment of the present invention; (F) administration via controlled release, depot and infusion pump delivery, and the like. Detailed descriptions of embodiments and modes of administration for the dosage regimens disclosed herein include the administration of the compounds and pharmaceutical compositions disclosed herein, including intra-ocular, intranasal and intranasal routes of administration, There is a way.

In an anthropomorphic animal study, start delivering the product at a high dose level and reduce its dose until the desired effect is no longer achieved or the side effect disappears. This dose has a wide range depending on the desired effect and therapeutic evidence. Typically, the dose ranges from 10 μg / kg to 100 mg / kg, preferably from about 100 μg / kg to 10 mg / kg, per body weight. Alternatively, as can be appreciated by those skilled in the art, the dose can be calculated based on the surface area of the patient. The administration method is preferably one or two times per day orally.

Appropriate formulations, route of administration and dosage may be selected depending on the condition of the patient, depending on the physician. See, for example, Fingl et al., The Pharmacological Basis of Therapeutics (1975), which is incorporated herein by reference in its entirety. It should be noted that the method and timing of administration discontinuation, termination, or control due to toxicity or dysfunction is at the discretion of the physician. Conversely, a skilled physician will also know to adjust treatment to a higher dose level (other than toxicity) if not appropriate for the clinical response. The amount of dosage in managing the disease may vary depending on the severity of the condition to be treated and the route of administration. The severity of the disease state can be assessed, for example, by standard diagnostic assessment methods. In addition, the dose and frequency of administration will also depend on the individual age, weight, or response of the patient. A comparison program of the above-mentioned examination results can be used in the veterinary medicine field.

Depending on the condition of the particular disease to be treated, the agent can be formulated and systematically or topically administered. A variety of formulation and administration techniques are described in Remington ' s Pharmaceutical Sciences (18th Ed. 1990), Mack Publishing, Inc., Easton, Pa., The entirety of which is incorporated herein by reference. Suitable routes of administration include oral, rectal, transdermal, vaginal, mucosal delivery or intestinal administration; Intramuscular injection, subcutaneous injection, bone marrow injection, as well as non-vaginal delivery including intramuscular injection, direct intracerebral injection, intravenous injection, intraperitoneal injection, intranasal injection or intra-ocular injection. Exemplary agents may be formulated into physiologically compatible buffers such as aqueous solutions, preferably Hank's solution, Ringer's solution or physiological saline buffer. In such intraluminal administration, a suitable penetrator is used in the formulation for the boundary membrane to be permeated. Such penetrants are well known in the art. It is also within the scope of the present invention to use pharmaceutically acceptable carriers to formulate the compounds disclosed herein for the practice of the invention at dosages appropriate for systemic administration. Depending on the choice of suitable carrier and the appropriate manufacturing process, the compositions disclosed herein, particularly compositions in the form of solutions, can be administered via routes such as intravenous injection. Such compounds may be readily formulated in dosages suitable for oral administration using pharmaceutically acceptable carriers known in the art. Such carriers make it possible to formulate the compounds according to the embodiments of the present invention in a form acceptable for oral administration to the subject to be treated, such as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like.

Agents for intracellular administration can be administered using techniques well known to those skilled in the art. For example, such agents can be encapsulated in liposomes and administered as described above. When in liposomal form, all molecules present in the aqueous solution are contained in the aqueous interior. The content of the liposome is protected from the external fine environment, and the liposome is efficiently transferred to the cytoplasm because it is melted into the cell membrane. In addition, due to their hydrophobicity, small organic molecules can be administered directly into cells.

The effective amount can be determined sufficiently within the skill of a person skilled in the art, particularly based on the contents of the detailed description provided herein. In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers, including excipients and adjuvants, which aid in the processing of the active compounds into pharmaceutically usable formulations. Formulations formulated for oral administration may be in the form of tablets, dragees, capsules or solutions. The pharmaceutical composition can be produced by a known method such as, for example, mixing, dissolving, granulating, dragee-making, floating, emulsifying, encapsulating, collecting or lyophilizing processes.

The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicological properties of a particular compound or a subset of compounds that share certain chemical components can be demonstrated by measuring in vitro toxicity to cell lines such as mammalian, preferably human, cell lines. These findings often predict animal, such as mammals, and more specifically, human toxicity. In addition, the toxicity of certain compounds in animal models such as mice, rats, rabbits, dogs or monkeys can be determined using known methods. The efficacy of certain compounds can be demonstrated through several well known methods, such as in vitro methods, animal models, or clinical trials on humans. Known in vitro models exist in almost all disease states including cancer, cardiovascular disease and various immune disorders and infectious diseases, including conditions alleviated by the compounds disclosed herein. Likewise, an acceptable animal model is used to demonstrate the efficacy of a chemical to treat this condition. When choosing a model for measuring efficacy, one skilled in the art can refer to the knowledge in the art to select appropriate models, dosages and routes of administration, and prescription books and the like. Of course, human clinical trials can also be used to determine the efficacy of compounds on humans.

When used as anticancer agents, the compounds disclosed herein may be administered by oral or parenteral routes. When administered orally, it can be administered in the form of capsules, tablets, granules, sprays, syrups or other forms. When administered parenterally, it can be administered in the form of an aqueous suspension, an oil-based preparation or the like, or a drip, suppository, ointment, ointment or the like. When administered by injection, it can be administered by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, and the like. Controlled release formulations, depot formulations and infusion pump delivery systems may also be considered.

The compositions disclosed herein, which are pharmaceutical compositions, also include pharmaceutically acceptable carriers. Such compositions may be formulated for storage and subsequent administration. Acceptable carriers or diluents for therapeutic use are those which are known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences (A. R. Gennaro edit. 1985) of Mack Publishing, which is hereby incorporated by reference in its entirety. For example, such compositions may be formulated as tablets, capsules or solutions for oral administration; Suppositories for rectal or vaginal administration; It may be formulated into a sterilized solution for injection or suspension or the like. Injections may be prepared in conventional forms such as liquid solutions or suspensions, solid forms suitable for dissolving in liquids prior to injection, such as solutions or suspensions, or emulsion forms. Suitable excipients include, but are not limited to, physiological saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, hydrogen chloride cysteine and the like. In addition, if necessary, the injectable pharmaceutical composition may also contain minor amounts of non-toxic adjuvants such as wetting agents, pH buffering agents, and the like. Absorption modifiers (such as liposomes) may also be utilized if desired.

The pharmaceutically effective amount of the composition required for the dosage can be varied in consideration of the route of administration, the type of animal to be treated, and the physical characteristics of the particular animal. The dose can be determined in an amount to achieve the desired effect, but will vary depending on such factors as body weight, diet, medicament to be administered together, and other factors that would be apparent to those skilled in the pharmaceutical arts.

As described above, the products and compositions of the examples can be used alone or in combination of one or more, or in combination with other therapeutic agents or diagnostic agents. These products can be used in the body or in vitro. The useful dose and the most useful mode of administration will vary depending upon the age, body weight, the particular compound employed and the particular use for which these compositions or compositions are to be used. The dosage size in the management and treatment of a particular disease will depend on the severity of the condition being treated and on the route of administration and may also be formulated and administered systemically or topically, depending on the disease state and its severity. Various formulation and administration techniques are described in Remington ' s Pharmaceutical Sciences (18th Ed., 1990), Mack Publishing, Inc., Easton, Pa., The entirety of which is incorporated herein by reference.

The compounds and compositions are administered orally or parenterally in an amount of from about 0.001 mg / kg / day to about 10,000 mg / kg / day of active ingredient, preferably from about 0.1 mg / kg / day to 100 Mg / kg / day, preferably about once a day or less, preferably about 2 to 10 times a day. Alternatively, and preferably, the compounds prepared according to the methods of the examples are also administered continuously, e.g. in the form of intravenous infusions, in defined amounts. Nevertheless, as is known to those skilled in the art, in order to effectively and intensively treat a particular advanced cancer or infectious disease, depending on the situation, the anticancer compound of this embodiment should be administered in an amount exceeding or significantly exceeding the above- .

In one embodiment of the present invention, the cancer having the anticancer effect is preferably a cancer selected from the group consisting of pancreatic cancer, breast cancer, colon cancer and bone marrow cancer, but is not limited thereto.

The present invention also provides a food composition having the effect of improving cancer against the active ingredient of the compound of the present invention.

As can be seen from the present invention, the DK270 and DK553 compounds of the present invention showed a rapid decrease in the colony forming ability of the cancer cells when treated at a concentration of 5 μM or more, and the DK271, DK550, DK552 and DK554 compounds were treated at a concentration of 10 μM or more It was observed that the colony forming ability of cancer cells was abruptly decreased. From these facts, the DK270, DK271, DK550, DK552, DK553, and DK554 naphthalene compounds of the present invention have an effect of inhibiting the proliferation of cancer cells and can be used as anticancer drug candidates.

1 is a schematic of a method for synthesizing a naphthalene-based chalcone.
2 is a hydrogen-nuclear magnetic resonance spectrum of DK270.
3 is a carbon-nuclear magnetic resonance spectrum of DK270.
4 is a mass spectrometry spectrum of DK270.
5 is a hydrogen-nuclear magnetic resonance spectrum of DK271.
6 is a carbon-nuclear magnetic resonance spectrum of DK271.
7 is a mass spectrometry spectrum of DK271.
8 is a hydrogen-nuclear magnetic resonance spectrum of DK550.
9 is a carbon-nuclear magnetic resonance spectrum of DK550.
10 is a mass spectrometry spectrum of DK550.
11 is a hydrogen-nuclear magnetic resonance spectrum of DK552.
12 is a carbon-nuclear magnetic resonance spectrum of DK552.
13 is a mass spectrometry spectrum of DK552.
14 is a hydrogen-nuclear magnetic resonance spectrum of DK553.
15 is a carbon-nuclear magnetic resonance spectrum of DK553.
16 is a mass spectrometry spectrum of DK553.
17 is a hydrogen-nuclear magnetic resonance spectrum of DK554.
18 is a carbon-nuclear magnetic resonance spectrum of DK554.
19 is a mass spectrometry spectrum of DK554.
20 shows the results of inhibiting cancer cell formation by naphthalene-based chalcone, DK270, 271, 550, 552, 553 and 554.
21 is a synthesis process of naphthalene-based chalcone, DK270.
22 is a process for synthesizing naphthalene-based chalcone, DK552.

The present invention will now be described in more detail by way of non-limiting examples. The following examples are intended to illustrate the invention and the scope of the invention is not to be construed as being limited by the following examples.

Example  One. Naphthalene series Calcont  Compound ( DK270 - DK554 ) Synthesis of

DK270 , DK271 Synthesis of

Dimethoxybenzaldehyde (10 mmol, 1.66 g) equivalent to 2-hydroxy-1-acetonaphthone (10 mmol, 1.86 g) is dissolved in 50 mL of ethanol and the temperature is lowered to 3 ° C. using a cooling water bath. To this cold reaction mixture slowly add 10 mL of 50% (w / v) KOH aqueous solution, raise the temperature to room temperature and stir for 24 hours. The reaction mixture is diluted with 100 ml of ice water and acidified with 6N HCl hydrochloric acid (pH = 3-4), confirming that the reaction is complete using thin film chromatography. The solid formed was filtered under reduced pressure to give Intermediate Compound 2 which was used in the next reaction. Dissolve Compound 2 (5 mmol, 1.74 g) in 30 mL of ethanol, add excess hydrazine monohydrate (1 mL of 64-65% solution, 13 mmol), and reflux at 90 ° C for 6 hours. After cooling the reaction mixture to room temperature, the formed solid was filtered under reduced pressure and recrystallized in ethanol to obtain the target compound DK-270 (see FIG. 21). m.p 145-146 [deg.] C.

Other compounds DK-271 was also synthesized using DK-270, except that 3,5-dimethoxybenzaldehyde was used instead of 2,4-dimethoxybenzaldehyde as starting material. mp; DK271; 112-114 DEG C

DK550 , DK552 , DK553 , DK554 Synthesis of

Dissolve 1-naphthaldehyde (10 mmol, 1.56 g) equivalent to 6-methoxy-2-hydroxyacetophenone (10 mmol, 1.66 g) in 50 mL of ethanol and cool the solution to 3 ° C. using a cooling water bath. To this cold reaction mixture slowly add 10 mL of 50% (w / v) KOH aqueous solution, raise the temperature to room temperature and stir for 48 hours. The reaction mixture is diluted with 100 ml of ice water and acidified with 6N HCl hydrochloric acid (pH = 3-4), confirming that the reaction is complete using thin film chromatography. The formed solid was filtered under reduced pressure to give Intermediate Compound 1 which was used in the next reaction. Dissolve compound 1 (5 mmol, 1.59 g) in 30 mL of ethanol, add excess hydrazine monohydrate (1 mL of 64-65% solution, 13 mmol) and reflux at 90 ° C for 6 hours. After the reaction mixture was cooled to room temperature, the formed solid was filtered under reduced pressure and recrystallized in ethanol to obtain the desired compound DK-552 (see FIG. 22). m.p 165-168 (438-440K)

Meanwhile, the 552 compound of the present invention used 6-methoxy-2-hydroxyacetophenone, whereas 553 was 4,5-dimethoxy-2-hydroxyacetophenone instead of this compound, 554 was 4,6-dimethoxy- Was synthesized using the same procedure as in the above 552 except that 2-hydroxyacetophenone was used as a starting material. DK550; 100-104 < 0 > C, DK553; 116-120 < 0 > C, DK554; 191-194 占 폚.

Example  2. Naphthalene series Calcont  Compound ( DK270 - DK5554 ) Identification

Nuclear magnetic resonance spectroscopy was used to identify the synthesized naphthalene - based chalcone compounds. The instrument used for this was Bruker Avance400 (Karlsruhe, Germany), DK553 and DK554 were dissolved in chloroform, DK270, DK271, DK550 and DK552 were dissolved in dimethylsulfoxide and placed in a 2.5-mm NMR tube. Detailed experimental methods followed well - known hydrogen - nuclear magnetic resonance spectroscopy and carbon - nuclear magnetic resonance spectroscopy [Magn. Reson. Chem. 51: 593]. Mass spectrometry was also carried out in parallel to confirm the naphthalene-based chalcone synthesized. The mass spectrometer used in the experiment was a JMS700 spectrometer (JEOL, Tokyo, Japan).

DK270 was named 1- [5- (2,4-dimethoxyphenyl) -pyrazolin-3-yl] naphthalen-2-ol and its molecular formula was C21H20N2O3. Mass determined by mass spectrometry was 318.1366. The hydrogen-nuclear magnetic resonance spectrum of DK270 is shown in FIG. 2, the carbon-nuclear magnetic resonance spectrum is shown in FIG. 3, and the mass spectrometry spectrum is shown in FIG.

The name of DK271 is 1- [5- (3,5-dimethoxyphenyl) -pyrazolin-3-yl] naphthalen-2-ol and its molecular formula is C21H20N2O3 and its mass is 348.1470. The hydrogen-nuclear magnetic resonance spectrum of DK271 is shown in FIG. 5, the carbon-nuclear magnetic resonance spectrum is shown in FIG. 6, and the mass spectrometry spectrum is shown in FIG.

The name of DK550 is 2- [5- (naphthalen-1-yl) -pyrazolin-3-yl] phenol and its molecular formula is C19H16N2O and its mass is 288.1264. The hydrogen-nuclear magnetic resonance spectrum of DK550 is shown in FIG. 8, the carbon-nuclear magnetic resonance spectrum is shown in FIG. 9, and the mass spectrometry spectrum is shown in FIG.

The name of DK552 is 3-methoxy-2- [5- (naphthalen-1-yl) -pyrazolin-3-yl] phenol and its molecular formula is C20H18N2O2 and its mass is 318.1369. The hydrogen-nuclear magnetic resonance spectrum of DK552 is shown in FIG. 11, the carbon-nuclear magnetic resonance spectrum is shown in FIG. 12, and the mass spectrometry spectrum is shown in FIG.

DK553 is named 4,5-dimethoxy-2- [5- (naphthalen-1-yl) -pyrazolin-3-yl] phenol and its molecular formula is C21H20N2O3 and its mass is 348.1472. The hydrogen-nuclear magnetic resonance spectrum of DK553 is shown in FIG. 14, the carbon-nuclear magnetic resonance spectrum is shown in FIG. 15, and the mass spectrometry spectrum is shown in FIG. D

The name of K554 is 3,5-dimethoxy-2- [5- (naphthalen-1-yl) -pyrazolin-3-yl] phenol and its molecular formula is C21H20N2O3 and its mass is 348.1474. The hydrogen-nuclear magnetic resonance spectrum of DK554 is shown in FIG. 17, the carbon-nuclear magnetic resonance spectrum is shown in FIG. 18, and the mass spectrometry spectrum is shown in FIG. The results obtained by the hydrogen-nuclear magnetic resonance method are shown in Tables 1 and 2.

The results obtained by the carbon-nuclear magnetic resonance method are shown in Table 3.

Example  3. Naphthalene series Calcont  Compound ( DK270 - DK554 ) Of colon cancer cells Colony  Production inhibitory effect

HCT116 colon cancer cells were purchased from the American Type Culture Collection (ATTC) and cultured in DMEM (Invitrogen Life Technologies) containing 10% fetal bovine serum (Invitrogen Life Technologies) and Antibiotic-Antimycotic solution (Invitrogen Life Technologies) The cells were cultured in a 5% CO ₂ incubator at 37 ° C in a 100-mm cell culture dish at a seeding density of 1 × 10 ⁶ once every two days. DK270, DK550, DK552, DK553, and DK554 naphthalene-based compounds of the present invention were assayed for inhibition of cell proliferation through the colony forming assay of cancer cells. HCT116 colon cancer cells were divided into 3,000 cells per well in a 24-well culture dish and treated with 0, 5, 10 and 20 μM of the compound of the present invention, and after 7 days, 6% glutaraldehyde and 0.5 % Crystal violet solution (1: 1) was added to the cells, followed by reaction for 15 minutes to stain the remaining cells. As a result, as shown in FIG. 20, the DK270 and DK553 compounds of the present invention showed a rapid decrease in the colony forming ability of the cancer cells when treated at a concentration of 5 μM or more, and the DK271, DK550, DK552 and DK554 compounds It was observed that the colony forming ability of cancer cells was drastically reduced. From these facts, it has been confirmed that the DK270, DK271, DK550, DK552, DK553, and DK554 naphthalene compounds of the present invention have an effect of inhibiting the proliferation of colon cancer cells.

Having described specific portions of the present invention in detail, it will be apparent to those skilled in the art that this specific description is only a preferred embodiment and that the scope of the present invention is not limited thereby. It will be obvious. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (5)

The naphthalene-based chalcone compound represented by Formula (1)

[Chemical Formula 1]
Wherein R is a functional group selected from the group consisting of H, 6-methoxy, 4,5-dimethoxy, and 4,6-dimethoxy. The compound according to claim 1, wherein the naphthalene-based chalcone compound is a compound represented by formula (2):

(2)
In Formula 2, R is a functional group selected from the group consisting of 2,4-dimethoxy, and 3,5-dimethoxy. A pharmaceutical composition for anticancer therapy comprising the compound of any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The composition of claim 3, wherein the cancer is a colon cancer. A food composition for improving or alleviating cancer comprising the compound of any one of claims 1 to 2 as an active ingredient.

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