KR101402253B1 - Methoxychromenylchalcone or methoxychromenylphenylpropenone derivative and Use in anti-cancer agent and preparing method of the same - Google Patents

Abstract

The present invention relates to a methoxychromenylacetone or methoxy-chromenylphenylpropenone derivative and its use as an anticancer agent, and more particularly to a methoxy-chromenyl cholone or methoxy-chromenylphenylpropenone derivative, The present invention also relates to a pharmaceutical composition for an anticancer agent having an anticancer effect through an effect of inhibiting cycle progression.

Description

Methoxy chromenyl chalcone or methoxy chromenyl phenyl propene derivative and its use as an anticancer agent {Methoxychromenylchalcone or methoxychromenylphenylpropenone derivative and use of an anti-cancer agent and preparing method of the same}

The present invention relates to a methoxychromenylacetone or methoxy-chromenylphenylpropenone derivative and its use as an anticancer agent, and more particularly to a methoxy-chromenyl cholone or methoxy-chromenylphenylpropenone derivative, The present invention also relates to a pharmaceutical composition for an anticancer agent having an anticancer effect through an effect of inhibiting cycle progression.

Chalcone is a plant-derived secondary metabolite and is a compound belonging to the flavonoid family having a C6-C3-C6 skeleton. Unlike flavonoids, which are generally composed of three rings, chalcone has a structure that is slightly more fluid than a flavonoid because the two rings are linked by a, b-unsaturated carbonyl groups. The chalcone is made through the phenylpropanoid biosynthetic pathway in plants. Like other secondary metabolites, only very small amounts are found in nature in plants, so it is necessary to secure sufficient quantities to carry out biological experiments. Since chalcone also belongs to a plant-derived polyphenol compound, it has a structure capable of having substituted substituents, and thus various kinds of derivatives can be found in a natural state and artificially synthesized. Flavone, a kind of flavonoid, is a structure with three rings. One kind of benzoflavone of this derivative has a structure with one ring, which is known to inhibit the breast cancer resistance protein. Therefore, while searching for a novel compound having an anticancer effect, the present inventors have designed a compound having a new structure from a compound derived from a natural product exhibiting anticancer effect such as chalcone or benzoflavone. That is, a new compound having a fourth ring structure and a chalcone skeleton, which benzoflavones have, is designed, and they can be classified as a compound having a structure such as bromodimethoxy chromenyl chalcone core nucleus.

Korean Patent Publication No. 1020120050918 relates to a pharmaceutical composition for the prevention and treatment of cancer and angiogenesis-related diseases of benproperine derivatives,

As another related prior patent, Korean Patent Publication No. 020070048798 discloses a quinazolinone derivative and its use as a B-RAF inhibitor.

 The present invention has been made in view of the above needs, and an object of the present invention is to provide an effective anticancer agent.

In order to accomplish the above object, the present invention provides a bromodimethoxy-chromonyl chalcone derivative represented by the following formula (1).

[Chemical Formula 1]

The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases, including the above-mentioned bromodimethoxycromonyl chalcone derivative or a pharmaceutically acceptable salt thereof.

The present invention also provides a bromomethoxy-chromenyl chalcone derivative represented by the following general formula (2).

(2)

The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases, which comprises the bromomethoxy-chromenyl chalcone derivative of formula (2) or a pharmaceutically acceptable salt thereof.

The present invention also provides a 6'-bromochromenylacetic acid derivative represented by the following general formula (3).

(3)

The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases, which comprises the 6'-bromochromenylacetic acid derivative of formula (3) or a pharmaceutically acceptable salt thereof.

The present invention provides a 2,6'-dimethoxy-chromenylphenylpropenone derivative represented by the following general formula (4).

[Chemical Formula 4]

The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases, which comprises the 2,6'-dimethoxy-chromenylphenylpropenone derivative of Chemical Formula 4 or a pharmaceutically acceptable salt thereof.

The present invention provides a 4,7'-dimethoxy-chromenylphenylpropenone derivative represented by the following formula (5) having an effect of suppressing cell cycle progression of a colon cancer cell line.

[Chemical Formula 5]

The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases including the 4,7'-dimethoxy-chromenylphenylpropenone derivative of Chemical Formula 5 or a pharmaceutically acceptable salt thereof.

The present invention provides a trimethoxycromonyl chalcone derivative represented by the following formula (6).

[Chemical Formula 6]

The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases, which comprises the trimethoxy-chromenyl chalcone derivative of formula (VI) or a pharmaceutically acceptable salt thereof.

The present invention provides a 4,6'-dimethoxy chromenyl phenyl propene derivative represented by the following general formula (7).

(7)

The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases including the 4,6'-dimethoxy-chromenylphenylpropenone derivative of Chemical Formula 7 or a pharmaceutically acceptable salt thereof.

Cancer diseases that can be prevented or treated by the composition of the present invention are preferably colon cancer, but it is preferable that the cancer is cervical cancer, lung cancer, pancreatic cancer, non-small cell lung cancer, liver cancer, bone cancer, skin cancer, head cancer, Endometrial carcinoma, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, Renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, renal cell carcinoma, renal cell carcinoma, renal cell carcinoma, renal pelvic carcinoma, Spinal cord tumor, brainstem glioma, pituitary adenoma, and the like.

The composition of the present invention may be formulated into various forms such as powders, granules, tablets, capsules, oral formulations such as suspensions, emulsions, syrups and aerosols, injections of sterilized injection solutions, and the like, And can be administered via various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like.

Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further comprise a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, an antiseptic, and the like.

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, Mix and formulate. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Examples of the oral liquid preparation include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included .

Examples of preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried agents, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.

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

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex and body weight of the patient, and is generally 0.01 to 100 mg, preferably 0.1 to 10 mg per kg of body weight, It may be administered one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.

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.

In the present invention, "administration" means providing a predetermined substance to a patient in any appropriate manner, and the administration route of the composition of the present invention may be administered orally or parenterally . In addition, the composition of the present invention can be administered using any device capable of delivering an effective ingredient to a target cell.

The term "subject" in the present invention means an animal including, but not limited to, a human, a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, Mammal in one embodiment, and human in another embodiment.

The term "therapeutically effective amount " used in connection with the active ingredient in the present invention means the amount of benperin, its pharmaceutically acceptable salt or derivative thereof, which is effective in treating or preventing a subject disease.

The pharmaceutical composition of the present invention may further comprise a known anticancer agent or angiogenesis inhibitor in addition to the derivative compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and may further include other known treatments for the treatment of these diseases ≪ / RTI > Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapies, immunotherapy, and the like.

Examples of anticancer agents that may be included in the pharmaceutical composition of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, But are not limited to, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, , Cisplatin and carboplatin; Antitumor antibiotics (anti-cancer antibiotics)

but are not limited to, dactinomycin: actinomycin D, doxorubicin: adriamycin, daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin, C Bleomycin; And plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, and iridotecan, Iridotecan, and the like, but are not limited thereto.

The compounds of the present invention exhibit an inhibitory effect on G1 cell cycle progression of colon cancer cells, and thus can be usefully used as a pharmaceutical composition for the prevention and treatment of cancer diseases.

1 is a graph showing the results of chemical analysis of a bromodimethoxycromonyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop- Lt; / RTI > NMR spectra. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 2 is a graph showing the effect of the bromodimethoxycromonyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop-2-en- Lt; RTI ID = 0.0 > NMR < / RTI > (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 3 is a graph showing the effect of the bromodimethoxycromonyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop-2-en- And a high-resolution mass spectrometry spectrum. (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
FIG. 4 is a graph showing the effect of the bromodimethoxycromonyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop-2-en- It is a cell-killing induction effect in colon cancer cells. When colon cancer cells were treated with the solvent DMSO only (left) and bromodimethoxychloronicolone derivative (BrDMCC) at 20 uM concentration (right), cell cycle progress was observed after 24 hours to be. The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine
FIG. 5 is a graph showing the effect of the hydrogen atom of a bromomethoxy chromenyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop- Magnetic resonance spectroscopy. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 6 is a graph showing the effect of the carbon atom of the bromomethoxy chromenyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop- Magnetic resonance spectroscopy. (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
7 is a graph showing the relationship between the bromomethoxy chromenyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop- This is the analytical spectrum. (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
8 is a graph showing the effect of the bromomethoxy chromenyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en- Lt; / RTI > When colon cancer cells were treated with DMSO only (solvent left) and bromomethoxy chromenyl chalcone derivative (BrMCC) at 20 uM concentration (right) after 24 hours, cell cycle progress was observed . The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine
9 is a graph showing the effect of 6'-bromochromenylacetic acid derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3-methoxyphenyl) prop-2-en- Hydrogen nuclear magnetic resonance spectroscopy. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
10 is a graph showing the effect of the 6'-bromochromenylacetic acid derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3-methoxyphenyl) prop-2-en- Carbon nuclear magnetic resonance spectroscopy. (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
11 is a graph showing the effect of 6'-bromochromenylacetic acid derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3-methoxyphenyl) prop-2-en- High-resolution mass spectrometry spectrum. (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
FIG. 12 is a graph showing the effect of the 6'-bromochromenylacetic acid derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3-methoxyphenyl) prop-2-en- Inhibiting cell cycle progression of cancer cells and inducing apoptosis. HCT116 colorectal cancer cells were treated with DMSO only (solvent left) and 6'-bromochromenylacetic acid derivative (BrCC) at 20 uM concentration (right) This is a result. The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine
FIG. 13 is a graph showing the activity of the 2,6'-dimethoxy chromenyl phenyl propene derivative (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop- -one compound is a hydrogen nuclear magnetic resonance spectroscopy spectrum. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 14 is a graph showing the activity of the 2,6'-dimethoxy chromenyl phenyl propene derivative (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop- -one compound is a carbon nuclear magnetic resonance spectroscopy spectrum. (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 15 is a graph showing the molecular weight distribution of 2,6'-dimethoxy chromenyl phenyl propenone derivative (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop- -one compound. < tb >< TABLE > (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
FIG. 16 is a graph showing the effect of the 2,6'-dimethoxy chromenyl phenyl propenone derivative (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop- -one is a cell cycle arrest inhibitory effect and a cell death induction effect of colorectal cancer cells. HCT116 colorectal cancer cells were treated with 20 μM of the 2,6'-dimethoxy-chromenylphenylpropenone derivative (2,6-DMCPP) only when the solvent DMSO alone was treated (left) And the cell cycle progression was observed. The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine
FIG. 17 is a graph showing the effect of the 4,7'-dimethoxy chromenyl phenyl propenone derivative (E) -3- (7-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop- -one compound is a hydrogen nuclear magnetic resonance spectroscopy spectrum. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 18 is a graph showing the activity of the 4,7'-dimethoxy chromenyl phenyl propene derivative (E) -3- (7-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop- -one compound is a carbon nuclear magnetic resonance spectroscopy spectrum. (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 19 is a graph showing the effect of the 4,7'-dimethoxy chromenyl phenyl propene derivative (E) -3- (7-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop- -one compound. < tb >< TABLE > (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
FIG. 20 is a graph showing the effect of the 4,7'-dimethoxy chromenyl phenyl propenone derivative (E) -3- (7-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop- -one in the cell cycle progression of colorectal cancer cell lines. When the colorectal cancer cell line was treated with only the solvent DMSO (left) and the 4,7'-dimethoxy-chromenylphenylpropenone derivative was treated at a concentration of 20 uM (right), cell cycle progress was observed after 24 hours This is a result. The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine
FIG. 21 is a graph showing the effect of the compound (E) -1- (3,5-dimethoxyphenyl) -3- (6-methoxy- 2H-chromen-3-yl) prop-2-en- Hydrogen nuclear magnetic resonance spectroscopy. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
22 is a graph showing the effect of the compound (E) -1- (3,5-dimethoxyphenyl) -3- (6-methoxy- 2H-chromen-3-yl) prop-2-en- Carbon nuclear magnetic resonance spectroscopy. (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
23 is a graph showing the effect of the compound (E) -1- (3,5-dimethoxyphenyl) -3- (6-methoxy- 2H-chromen-3-yl) prop-2-en- High-resolution mass spectrometry spectrum. (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
FIG. 24 is a photograph showing the appearance of the large intestine of the trimethoxy chromenyl chalcone derivative (E) -1- (3,5-dimethoxyphenyl) -3- (6-methoxy-2H-chromen-3-yl) prop- It is a cell cycle control effect of cancer cells. The colorectal cancer cells were treated with the solvent DMSO only (left) and trimethoxy chromenyl chalcone (TMCC) derivatives at 20 uM concentration (right), and the cell cycle progress was observed after 24 hours . The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine
25 is a graph showing the effect of the 4,6'-dimethoxy chromenyl phenyl propenone derivative (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop- -one compound is a hydrogen nuclear magnetic resonance spectroscopy spectrum. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 26 is a graph showing the effect of the 4,6'-dimethoxy chromenyl phenyl propene derivative (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop- -one compound is a carbon nuclear magnetic resonance spectroscopy spectrum. (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 27 is a graph showing the effect of the 4,6'-dimethoxy chromenyl phenyl propenone derivative (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop- -one compound. < tb >< TABLE > (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
FIG. 28 is a graph showing the effect of the 4,6'-dimethoxy chromenyl phenyl propene derivative (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop- -one (DMCPP) induces apoptosis in colorectal cancer cells. When colorectal cancer cells were treated with DMSO only (solvent left) (Fig. Left) and treated with 20 uM of 4,6'-dimethoxy-chromenylphenylpropenone derivative (right), cell cycle progress was observed after 24 hours This is a result. The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine

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 examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

Example  One. Bromodimethoxychromonyl chalcone  Synthesis of derivatives

In the present invention, the bromodimethoxycromonyl chalcone derivative represented by the formula (1) was synthesized as follows using the method shown in the following reaction formula.

6-bromo-2H-chromene-3-carbaldehyde ( I ) was obtained by reacting 5-bromo-2-hydroxybenzaldehyde with acrolein in the presence of K2CO3 base according to the literature method [European Journal of Medicinal Chemistry, 2010 , 1424-1429]. (190 mg, 1 mmol) and 1- (3,5-dimethoxyphenyl) ethanone (180 mg, 1 mmol) were dissolved in 20 mL of ethanol. The mixture was cooled to room temperature in an ice water bath Deg.] C to 5 [deg.] C. Add 5 mL of 50% KOH solution slowly to the above cooling solution and stir at room temperature for about 20 hours. The reaction mixture is poured into about 100 mL of ice water, the pH is adjusted to about 3 by addition of 6N HCl, and the resulting solid is filtered. This solid was recrystallized from ethanol to obtain pure (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop-2-en-1-one.

Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

Bromomethylmethoxycromonyl chalcone derivative The hydrogen nucleus of (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop- The resonance spectroscopic spectrum and the carbon nuclear magnetic resonance spectrum are as shown in Fig. 1 and Fig. 2, respectively, and the chemical mobility is as follows.

^{1 H NMR (400MHz, DMSO-} d 6) δ 7.42 (d, 1H, H- β, J = 15.4 Hz), 7.41 (d, 1H, H-5 ', J = 2.5 Hz), 7.36 (dd, 1H , H-7 ', J = 2.5, 8.6 Hz), 7.24 (dd, 1H, H-α, J = 15.4 Hz), 7.22 (d, 2H, H-2 / H-6, J = 2.2 Hz), 7.12 (s, 1H, H- 4 '), 6.84 (d, 1H, H-8', J = 8.6 Hz), 6.80 (d, 1H, H-4, J = 2.2 Hz), 5.20 (s, 2H , H-2 '), 3.84 (s, 6H, 3-OCH3 / 5-OCH3)

¹³ C-NMR (100 MHz, DMSO-d ₆ )? 188.4 (C = O), 160.7 (C-3 / C-5), 153.4 ), 133.0 (C-7 '), 130.9 (C-3'), 130.2 (C-4 '), 130.0 (C-8 '), 112.8 (C-6'), 106.3 (C-2 / C-6), 64.9

Bromomethylmethoxycarbonyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop-2-en- Has a molecular formula of C20H17BrO4 as a new substance which is not produced. ( E ) -3- (6-bromo-pyridin-2-yl) -ethanone was used because it had a theoretical molecular weight of 401.0310 and an experimental molecular weight of 400.0312. 2 H - chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop-2-en-1-one ((E) -3- (6- bromo-2 H -chromen-3 -yl) -1- (3,5-dimethoxyphenyl) prop-2-en-1-one. High-resolution mass spectrometry of (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3,5-dimethoxyphenyl) prop-2-en- The spectrum is shown in Fig.

Example  2. The compounds of formula Bromodimethoxychromonyl chalcone  Effect of derivatives on inhibition of cell cycle progression of colorectal cancer cells

HCT116 colorectal cancer cells were treated with a bromodimethoxy-chromenyl chalcone derivative (BrDMCC), and after 1 day, 1% trypsin-EDTA solution was added to remove cells attached to the culture container to harvest the cells, followed by addition of 70% ethanol The cells were fixed. The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

As shown in FIG. 4, when the normally-growing HCT116 colon cancer cells were treated with the bromodimethoxy-chromenyl cholorane derivative (BrDMCC) for 24 hours, the sub-G1 phase cells showed almost no change from 1.08% to 1.97%. G1 periodic cells increased from 57.74% to 72.40%, S periodic cells decreased from 12.84% to 6.19%, and G2 / M periodic cells decreased from 27.10% to 18.69%. From the above results, it was confirmed that the bromodimethoxy chromenyl chalcone derivative of the present invention inhibits the cell cycle progression of HCT116 colon cancer cells.

Example  3. Bromomethoxy chromonyl chalcone  Synthesis of derivatives

In the present invention, the bromomethoxy chromenyl chalcone derivative represented by formula (2) was synthesized as follows using the method shown in the following reaction formula.

6-bromo-2H-chromene-3-carbaldehyde ( I ) was obtained by reacting 5-bromo-2-hydroxybenzaldehyde with acrolein in the presence of K2CO3 base according to the literature method [European Journal of Medicinal Chemistry, 2010 , 1424-1429]. (180 mg, 1 mmol) and 1- (2-methoxyphenyl) ethanone (190 mg, 1 mmol) were dissolved in 20 mL of ethanol, and the temperature of the mixture was adjusted to 60 ° C. using an ice- 5 ℃. Add 5 mL of 50% KOH solution slowly to the above cooling solution and stir at room temperature for about 20 hours. The reaction mixture is poured into about 100 mL of ice water, the pH is adjusted to about 3 by addition of 6N HCl, and the resulting solid is filtered. The solid was recrystallized from ethanol to obtain pure (E) -3- (6-bromo-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en-1-one.

Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

Bromomethoxycromonyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en- And the carbon nuclear magnetic resonance spectrum are as shown in Fig. 5 and Fig. 6, respectively, and chemical mobility is as follows.

^{1 H NMR (400MHz, DMSO-} d 6) δ 7.56 (d, 1H, H-5 ', J = 2.5 Hz), 7.54 (ddd, 1H, H-4, J = 2.0, 7.5, 8.4 Hz), 7.43 (dd, 1H, H-6 , J = 2.0, 7.5 Hz), 7.36 (dd, 1H, H-7 ', J = 2.5, 8.7 Hz), 7.26 (d, 1H, H-β, J = 15.7 Hz ), 7.19 (d, 1H, H-3, J = 8.4 Hz), 7.17 (s, 1H, H-4 ', J = 15.5 Hz), 7.06 (d, 1H, H-5, J = 7.5 Hz) , 7.02 (d, IH, H-a, J = 15.7 Hz), 6.85 (d, IH, H-8 ', J = 8.7 Hz), 4.16 (s, 2H, H- 3H, 2 - OCH3)

^{13 C NMR (100MHz, DMSO-} d 6) δ 192.2 (C = O), 157.7 (C-2), 155.6 (C-9 '), 145.6 (C-β), 137.3 (C-4'), 134.7 (C-3 '), 133.0 (C-4), 132.6 (C-7'), 132.0 ), 125.0 (C-10 '), 120.6 (C-5), 117.6 (C-8'), 112.4 2-OCH3)

Bromomethoxycromonyl chalcone derivative (E) -3- (6-bromo-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en- It has the molecular formula of C19H15BrO3 as material. ( E ) -3- (6-bromo-pyridin-2-yl) -ethanone was used because it had a theoretical molecular weight of 371.0205 and an experimental molecular weight of 370.0207. 2 H - chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en-1-one ((E) -3- (6- bromo-2 H -chromen-3-yl ) -1- (2-methoxyphenyl) prop-2-en-1-one. Bromomethoxycromonyl chalcone derivative The high-resolution mass spectrometry spectrum of (E) -3- (6-bromo-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop- 7].

Example  4. The compound of formula Bromomethoxy chromonyl chalcone  Inhibits cell cycle progression and induces apoptosis of colorectal cancer cells

HCT116 Colon cancer cells were treated with bromomethoxycromonyl chalcone derivative (BrMCC), and after 1 day, 1% trypsin-EDTA solution was added to remove cells attached to the culture vessel to harvest the cells, followed by addition of 70% ethanol Cells were fixed. The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

As shown in Fig. 8, when the normally-growing HCT116 colorectal cancer cells were treated with the bromomethoxy chromenyl chalcone derivative (BrMCC) for 24 hours, the sub-G1 phase cells increased from 1.67% to 7.60%. At this time, G1 periodic cells increased from 54.87% to 60.36%, S periodic cells decreased from 10.22% to 3.66%, and G2 / M periodic cells decreased from 29.04% to 27.27%. From the above results, it was confirmed that the bromomethoxy chromenyl chalcone derivative of the present invention inhibits cell cycle progression of HCT116 colon cancer cells and induces apoptosis.

Example  5. 6'- Bromochromenyl chalcone  Synthesis of derivatives

In the present invention, the 6'-bromochromenylacetic acid derivative represented by formula (3) was synthesized as follows using the method shown in the following reaction formula.

6-bromo-2H-chromene-3-carbaldehyde ( I ) was obtained by reacting 5-bromo-2-hydroxybenzaldehyde with acrolein in the presence of K2CO3 base according to the literature method [European Journal of Medicinal Chemistry, 2010 , 1424-1429]. (180 mg, 1 mmol) and 1- (3-methoxyphenyl) ethanone (190 mg, 1 mmol) were dissolved in 20 mL of ethanol, and the temperature of the mixture was adjusted to 60 ° C. using an ice- 5 ℃. Add 5 mL of 50% KOH solution slowly to the above cooling solution and stir at room temperature for about 20 hours. The reaction mixture is poured into about 100 mL of ice water, the pH is adjusted to about 3 by addition of 6N HCl, and the resulting solid is filtered. This solid was recrystallized from ethanol to obtain pure (E) -3- (6-bromo-2H-chromen-3-yl) -1- (3-methoxyphenyl) prop-2-en-1-one.

Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

The hydrogen nuclear magnetic resonance spectroscopy and the carbon nuclear magnetic resonance spectrum of the 6'-bromochromenylacetic acid derivative 257 are shown in FIG. 9 and FIG. 10, respectively, and chemical mobility is as follows.

^{1 H NMR (400MHz, DMSO-} d 6) δ 7.62 (d, 1H, H-6, J = 7.9 Hz), 7.57 (d, 1H, H-5 ', J = 2.5 Hz), 7.49 (d, 1H , H-5, J = 7.9 Hz), 7.49 (d, 1H, H-2, J = 2.7 Hz), 7.49 (d, 1H, H-β, J = 15.5 Hz), 7.36 (dd, 1H, H H-4 ', J = 2.5, 8.7 Hz), 7.33 (d, IH, H-a, J = 15.5 Hz), 7.28 J = 2.7, 7.9 Hz), 6.85 (d, 1H, H-8 ', J = 8.7 Hz), 4.26 (s, 2H, H-2'), 3.84 (s, 3H, 3 - OCH3)

¹³ C NMR (100 MHz, DMSO-d ₆ )? 189.2 (C = O), 159.5 (C-3), 155.5 C-4 '), 134.8 (C-3'), 132.6 (C-7 '), 132.0 ), 120.7 (C-6), 119.0 (C-4), 117.5 (C-8 '), 112.7 - OCH3)

The 6'-bromochromenylacetone derivative 257 has a molecular formula of C19H15BrO3 as a new substance not reported to date. ( E ) -3- (6-bromo-pyridin-2-yl) -methanone was used because it had a theoretical molecular weight of 371.0205 and an experimental molecular weight of 370.0201 in order to confirm the structure of this compound confirmed by nuclear magnetic resonance spectroscopy. 2 H - chromen-3-yl) -1- (3-methoxyphenyl) prop-2-en-1-one ((E) -3- (6- bromo-2 H -chromen-3-yl ) -1- (3-methoxyphenyl) prop-2-en-1-one. 6'-Bromochromenylan chalcone derivative The high-resolution mass spectrometry spectrum (E) of 3- (6-bromo-2H-chromen-3-yl) -1- (3-methoxyphenyl) prop- Is as shown in Fig.

Example  6. The 6'- Bromochromenyl chalcone  Inhibits cell cycle progression and induces apoptosis of colorectal cancer cells

HCT116 colorectal cancer cells were treated with 6'-bromochromenyla chalcone (BrCC), and after 1 day, 1% trypsin-EDTA solution was added to remove cells attached to the culture vessel to harvest the cells, followed by addition of 70% ethanol The cells were fixed. The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

As shown in Fig. 12, when the normally growing HCT116 colon cancer cells were treated with the 6'-bromochromenylan chalcone derivative (BrCC) for 24 hours, the sub-G1 phase cells increased from 1.67% to 8.85%. At this time, G1 periodic cells were increased from 54.87% to 66.82%, S periodic cells decreased from 10.22% to 5.50%, and G2 / M periodic cells decreased from 29.04% to 16.35%. From the above results, it can be confirmed that the 6'-bromochromenylacetic acid derivative of the present invention inhibits cell cycle progression of HCT116 colon cancer cells and induces apoptosis.

Example  7. 2,6'- Dimethoxy chromenyl phenyl propene  Synthesis of derivatives

In the present invention, the 2,6'-dimethoxy-chromenylphenylpropenone derivative represented by the general formula (4) was synthesized as follows using the following reaction scheme.

6-methoxy-2H-chromene-3-carbaldehyde ( I ) was obtained by reacting 2-hydroxy-5-methoxybenzaldehyde with acrolein in the presence of K2CO3 base according to the literature method [European Journal of Medicinal Chemistry, 2010 , 1424-1429]. (180 mg, 1 mmol) and 1- (2-methoxyphenyl) ethanone (190 mg, 1 mmol) were dissolved in 20 mL of ethanol and then the temperature of the mixture was adjusted with an ice- 5 ℃. Add 5 mL of 50% KOH solution slowly to the above cooling solution and stir at room temperature for about 20 hours. The reaction mixture is poured into about 100 mL of ice water, the pH is adjusted to about 3 by addition of 6N HCl, and the resulting solid is filtered. This solid was recrystallized from ethanol to obtain pure (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en-1-one.

Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

(E) -3- (6-methoxy-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en- The hydrogen nuclear magnetic resonance spectroscopy and the carbon nuclear magnetic resonance spectrum are as shown in Fig. 13 and Fig. 14, respectively, and the chemical mobility is as follows.

^{1 H NMR (400MHz, DMSO-} d 6) δ 7.54 (ddd, 1H, H-4, J = 1.8, 7.4, 8.4 Hz), 7.48 (dd, 1H, H-6, J = 1.8, 7.4 Hz), 7.21 (d, 1H, H- β, J = 15.5 Hz), 7.18 (d, 1H, H-3, J = 8.4 Hz), 7.06 (d, 1H, H-5, J = 7.4 Hz), 7.04 ( 1H), 6.80 (m, 1H, H-4 '), 6.80 (m, 1H, H-α, J = 15.5 Hz), 4.98 (s, 2H, H-2 '), 3.86 (s, 3H, 2 - OCH3), 3.71 (s, 3H, 6' - OCH3)

^{13 C NMR (100MHz, DMSO-} d 6) δ 191.8 (C = O), 157.7 (C-2), 153.9 (C-6 '), 148.0 (C-9'), 139.4 (C-β), 133.0 (C-4), 131.4 (C-4 '), 130.2 (C-3'), 129.4 (C-6), 128.7 , 120.5 (C-5), 116.5 (C-7 '), 116.2 (C-8'), 112.3 - OCH3), 55.4 (6 ' -OCH3)

(E) -3- (6-methoxy-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en- Has a molecular formula of C20H18O4 as a new substance not reported to date. ( E ) -3- (6-methoxy-pyridin-2-yl) -ethanone was used because it had a theoretical molecular weight of 322.1205 and a molecular weight of 322.1205 as determined by nuclear magnetic resonance spectroscopy. 2 H - chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en-1-one ((E) -3- (6- methoxy-2 H -chromen-3-yl ) -1- (2-methoxyphenyl) prop-2-en-1-one. (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (2-methoxyphenyl) prop-2-en- The high-resolution mass spectrometry spectrum is shown in Fig.

Example  8. 2,6'- Dimethoxy chromenyl phenyl propene  Derivatives of colorectal cancer cells G2 / M Cell cycle progression inhibition and cell death induction effect

HCT116 colorectal cancer cells were treated with 2,6'-dimethoxy-chromenylphenylpropenone (2,6-DMCPP) and 1 day after adding 1% trypsin-EDTA solution to remove the cells attached to the culture vessel After that, cells were fixed with 70% ethanol. The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

As shown in Fig. 16, when the 2,6'-dimethoxy-chromenylphenylpropenone derivative (2,6-DMCPP) was treated for 24 hours in normally growing HCT116 colon cancer cells, the sub- To 10.87%, while that of G1 periodic cells decreased from 57.74% to 11.89% and that of S periodic cells decreased from 12.84% to 3.58%, while those with G2 / M cycles increased from 27.10% to 71.79%. From the above results, it was confirmed that the bisracimemal chalcone derivative of the present invention inhibits G2 / M cell cycle progression of HCT116 colorectal cancer cells and induces apoptosis.

Example  9. The 4,7'- Dimethoxy chromenyl phenyl propene  Synthesis of derivatives

In the present invention, the 4,7'-dimethoxy-chromenylphenylpropenone derivative represented by the formula (5) was synthesized as follows using the method shown in the following reaction formula.

2-hydroxy-4-methoxybenzaldehyde was reacted with acrolein in the presence of K2CO3 base according to literature method [European Journal of Medicinal Chemistry, 2010 , 1424-1429] to obtain 7-methoxy-2H-chromene-3-carbaldehyde ( I ). (180 mg, 1 mmol) and 1- (4-methoxyphenyl) ethanone (190 mg, 1 mmol) were dissolved in 20 mL of ethanol and then the temperature of the mixture was adjusted with an ice water bath 5 ℃. Add 5 mL of 50% KOH solution slowly to the above cooling solution and stir at room temperature for about 20 hours. The reaction mixture is poured into about 100 mL of ice water, the pH is adjusted to about 3 by addition of 6N HCl, and the resulting solid is filtered. This solid was recrystallized from ethanol to obtain pure (E) -3- (7-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en-1-one.

Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

4,7'-Dimethoxy-chromenylphenylpropenone derivative (E) -3- (7-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en- The hydrogen nuclear magnetic resonance spectroscopy and the carbon nuclear magnetic resonance spectrum are as shown in Fig. 17 and Fig. 18, respectively, and chemical mobility is as follows.

^{1 H NMR (400MHz, DMSO-} d 6) δ 8.10 (d, 2H, H-2 / H-6, J = 8.7 Hz), 7.42 (d, 1H, H-β, J = 15.5 Hz), 7.18 ( d, 1H, H-α, J = 15.5 Hz), 7.14 (d, 1H, H-5 ', J = 8.4 Hz), 7.08 (s, 1H, H-4'), 7.07 (d, 2H, H -3 / H-5, J = 8.7 Hz), 6.55 (dd, 1H, H-6 ', J = 2.2, 8.4 Hz), 6.49 (d, 1H, H-8', J = 2.2 Hz), 5.14 3H, 7'-OCH3), 3.77 (s, 2H, H-2 '

¹³ C NMR (100 MHz, DMSO-d ₆ )? 187.0 (C = O), 163.1 (C-4), 161.7 (C-4 '), 130.7 (C-2 / C-6), 130.5 (C-1), 129.2 C-10 '), 113.9 (C-3 / C-5), 108.0 (C-6'), 101.3 '-OCH3)

4,7'-Dimethoxy-chromenylphenyl propenone derivative (E) -3- (7-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en- Has a molecular formula of C20H18O4 as a new substance not reported to date. This compound was identified as ( E ) -3- (7-methoxy-pyridin-2-yl) -ethanone as it had a theoretical molecular weight of 322.1205 and an experimental molecular weight of 322.1205. 2 H - chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en-1-one ((E) -3- (7- methoxy-2 H -chromen-3-yl ) -1- (4-methoxyphenyl) prop-2-en-1-one. 4,7'-Dimethoxy-chromenylphenylpropenone derivative (E) -3- (7-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en- The high-resolution mass spectrometry spectrum is shown in Fig.

Example  10. The 4,7'- Dimethoxy chromenyl phenyl propene  Derivative inhibits cell cycle progression of colorectal cancer cell line

HCT116 colorectal cancer cells were treated with 4,7'-dimethoxy-chromenylphenylpropenone derivative (4,7-DMCPP), and after 1 day, 1% trypsin-EDTA solution was added to remove cells attached to the culture vessel, After harvesting, cells were fixed with 70% ethanol. The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

As shown in Fig. 20, when the 4,7'-dimethoxy-chromenylphenylpropenone derivative (4,7-DMCPP) was treated for 24 hours in normally growing HCT116 colon cancer cells, the sub-G1 phase cells did not change , G1 periodic cells decreased from 57.74% to 62.88%, S periodic cells decreased from 12.84% to 11.69%, and G2 / M periodic cells decreased from 27.10% to 24.21%. From the above results, it was confirmed that the 4,7'-dimethoxy-chromenylphenylpropenone derivative of the present invention inhibits cell cycle progression of HCT116 colon cancer cells.

Example  11. Trimethoxy chromenyl chalcone  Synthesis of derivatives

In the present invention, the trimethoxy chromenyl chalcone derivative represented by formula (6) was synthesized as follows using the method shown in the following reaction formula.

6-methoxy-2H-chromene-3-carbaldehyde ( I ) was obtained by reacting 2-hydroxy-5-methoxybenzaldehyde with acrolein in the presence of K2CO3 base according to the literature method [European Journal of Medicinal Chemistry, 2010 , 1424-1429]. (180 mg, 1 mmol) and 1- (3,5-dimethoxyphenyl) ethanone (190 mg, 1 mmol) were dissolved in 20 mL of ethanol and then the temperature of the mixture was cooled in an ice water bath Deg.] C to 5 [deg.] C. Add 5 mL of 50% KOH solution slowly to the above cooling solution and stir at room temperature for about 20 hours. The reaction mixture is poured into about 100 mL of ice water, the pH is adjusted to about 3 by addition of 6N HCl, and the resulting solid is filtered. This solid was recrystallized from ethanol to obtain pure (E) -1- (3,5-dimethoxyphenyl) -3- (6-methoxy-2H-chromen-3-yl) prop-2-en-1-one.

Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

Hydrogen nuclear magnetic resonance of (E) -1- (3,5-dimethoxyphenyl) -3- (6-methoxy-2H-chromen-3-yl) prop-2-en- The spectroscopic spectrum and the carbon nuclear magnetic resonance spectrum are as shown in [Figure 21] and [Figure 22], respectively, and the chemical mobility is as follows.

^{1 H NMR (400MHz, DMSO-} d 6) δ 7.45 (d, 1H, H-β, J = 15.5 Hz), 7.22 (d, 2H, H-2 / H-6, J = 2.3 Hz), 7.22 ( d, 1H, H-α, J = 15.5 Hz), 7.12 (s, 1H, H-4 '), 6.82 (m, 1H, H-8'), 6.82 (m, 1H, H-7 '), 1H, H-5 '), 6.79 (d, 1H, H-4, J = 2.3 Hz) 5-OCH3), 3.72 (s, 3H, 6 ' -CH3)

^{13 C NMR (100MHz, DMSO-} d 6) δ 188.4 (C = O), 160.7 (C-3 / C-5), 153.9 (C-6 '), 148.2 (C-9'), 141.0 (C- ?), 139.6 (C-1), 132 (C-4 '), 130.6 (C-3'), 122.7 (C-8 '), 112.2 (C-5'), 106.3 (C-2 / C-6), 104.8 ), 55.4 (6 ' -OCH3)

(E) -1- (3,5-dimethoxyphenyl) -3- (6-methoxy-2H-chromen-3-yl) prop-2-en- And has a molecular formula of C21H20O5 as a new substance. High-resolution mass spectrometry was used to confirm the structure of this compound as confirmed by nuclear magnetic resonance spectroscopy. Since the theoretical molecular weight was 352.1311 and the molecular weight obtained by the experiment was 352.1312, the compound was found to be ( E ) -1- ethoxy) -3- (6-methoxy -2 H - chromen-3-yl) prop-2-en-1-one ((E) -1- (3,5-dimethoxyphenyl) -3- ( It was identified as 6-methoxy-2 H -chromen- 3-yl) prop-2-en-1-one). High-resolution mass spectrometry spectra of (E) -1- (3,5-dimethoxyphenyl) -3- (6-methoxy-2H-chromen-3-yl) prop-2-en- Is the same as [Figure 23].

Example  12. The compound of formula 6 Trimethoxy chromenyl chalcone  Inhibits cell cycle progression and induces apoptosis of colon cancer cell line

HCT116 colorectal cancer cells were treated with trimethoxy chromonic chalcone derivative (TMCC), and after 1 day, 1% trypsin-EDTA solution was added to remove cells attached to the culture container to harvest the cells, followed by addition of 70% ethanol Cells were fixed. The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

As shown in FIG. 24, when the normally-grown HCT116 colorectal cancer cells were treated with trimethoxy-chromenyl choline derivative (TMCC) for 24 hours, the number of sub-G1 cells increased from 1.08% to 9.9% Of cells were decreased from 57.74% to 53.65% and S periodic cells decreased from 12.84% to 2.55%, while those with G2 / M cycles increased from 27.10% to 32.40%. From the above results, it was confirmed that the bisracimemal chalcone derivative of the present invention inhibits S phase and G2 / M cell cycle progression and induces apoptosis in HCT116 colorectal cancer cells.

Example  13. 4,6'- Dimethoxy chromenyl phenyl propene  Synthesis of derivatives

In the present invention, the 4,6'-dimethoxy-chromenylphenylpropenone derivative represented by the general formula (7) was synthesized as follows using the following reaction scheme.

6-methoxy-2H-chromene-3-carbaldehyde ( I ) was obtained by reacting 2-hydroxy-5-methoxybenzaldehyde with acrolein in the presence of K2CO3 base according to the literature method [European Journal of Medicinal Chemistry, 2010 , 1424-1429]. (180 mg, 1 mmol) and 1- (4-methoxyphenyl) ethanone (190 mg, 1 mmol) were dissolved in 20 mL of ethanol and then the temperature of the mixture was adjusted to 60 ° C. using an ice- 5 ℃. Add 5 mL of 50% KOH solution slowly to the above cooling solution and stir at room temperature for about 20 hours. The reaction mixture is poured into about 100 mL of ice water, the pH is adjusted to about 3 by addition of 6N HCl, and the resulting solid is filtered. This solid was recrystallized from ethanol to obtain pure (E) -3- (6-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en-1-one.

Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

4,6'-Dimethoxy-chromenylphenyl propenone derivative (E) Synthesis of 6-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en- The hydrogen nuclear magnetic resonance spectroscopy and the carbon nuclear magnetic resonance spectrum are as shown in [Figure 25] and [Figure 26], respectively, and the chemical mobility is as follows.

^{1 H NMR (400MHz, DMSO-} d 6) δ 8.12 (d, 2H, H-2 / H-6, J = 8.8 Hz), 7.43 (d, 1H, H-β, J = 15.5 Hz), 7.28 ( d, 1H, H-α, J = 15.5 Hz), 7.08 (s, 1H, H-4 '), 7.08 (d, 2H, H-3 / H-5, J = 8.8 Hz), 6.82 (m, 1H, H-5 '), 6.82 (m, 1H, H-7'), 6.82 4-OCH3), 3.73 (s, 3H, 6 ' -OCH3)

¹³ C NMR (100 MHz, DMSO-d ₆ )? 187.6 (C = O), 163.7 (C-4), 154.4 (C-4 '), 131.4 (C-2 / C-6), 131.2 (C-1), 130.9 C-7 '), 116.7 (C-8'), 114.5 (C-3 / C-5), 112.7 '-OCH3)

(4-methoxyphenyl) prop-2-en-1-one was prepared by reacting 4,6'-dimethoxy chromenyl phenyl propene derivative Has a molecular formula of C20H18O4 as a new substance not reported to date. ( E ) -3- (6-methoxy-pyridin-2-yl) -ethanone was used because it had a theoretical molecular weight of 322.1205 and an experimental molecular weight of 322.1206. 2 H - chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en-1-one ((E) -3- (6- methoxy-2 H -chromen-3-yl ) -1- (4-methoxyphenyl) prop-2-en-1-one. 4,6'-Dimethoxy-chromenylphenyl propenone derivative (E) Synthesis of 6-methoxy-2H-chromen-3-yl) -1- (4-methoxyphenyl) prop-2-en- The high-resolution mass spectrometry spectrum is shown in Fig.

Example  14. The 4,6'- Dimethoxy chromenyl phenyl propene  Induction of colorectal cancer cells

HCT116 colorectal cancer cells were treated with 4,6'-dimethoxy-chromenylphenylpropenone derivative (DMCPP), and after 1 day, 1% trypsin-EDTA solution was added to remove cells attached to the culture container to harvest the cells, 70% ethanol was added to fix the cells. The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

As shown in Fig. 28, when the 4,6'-dimethoxy-chromenylphenylpropenone derivative was treated for 24 hours in normally growing HCT116 colon cancer cells, the number of sub-G1 cells increased from 1.67% to 41.42% G1 periodic cells decreased from 54.87% to 31.42%, S periodic cells decreased from 10.22% to 4.96%, and G2 / M periodic cells decreased from about 29.04% to 19.26%. From the above results, it was confirmed that the 4,6'-dimethoxy-chromenylphenylpropenone derivative of the present invention induces apoptosis of HCT116 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 (4)

A pharmaceutical composition for anti-cancer comprising a compound of the following formula (1) as an active ingredient.

[Chemical Formula 1] delete delete The pharmaceutical composition according to claim 1, wherein the composition has anticancer activity against colon cancer.

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