KR20200113728A - Metal organic frameworks compound and anticancer agents with that - Google Patents

Abstract

The present invention relates to a metal-organic framework compound and an anticancer agent comprising the same, wherein the metal-organic framework is represented by following chemical formula 1: [M_2(L1)_2(μ-L2)]·x(H_2O). The present invention has an effect of providing the anticancer agent including the metal-organic framework having excellent anticancer activity.

Description

Metal organic frameworks compound and anticancer agents with that}

The present invention relates to an anticancer agent comprising a metal-organic framework compound and a metal-organic framework (MOF).

The metal-organic framework compound is a highly porous crystalline material having a cage structure by metal ions coordinated to an organic compound. MOF compounds can be used to selectively adsorb gases such as hydrogen, nitrogen, carbon dioxide and methane gas, so over the past few decades, energy related gases such as H ₂ and CH ₄ storage, CO ₂ capture / separation, hydrocarbon separation, It has attracted a lot of attention in a wide range of applications such as catalysis and proton conduction.

All of these applications are closely dependent on the MOF's intrinsic physicochemical properties such as surface area, void dimension, void volume, void shape, surface functionality, framework stability and the presence of open metal locations. The high surface area and the fabrication of rigid skeletons are a prerequisite for researching new materials. There are several examples of the structural deformation of the flexible MOF skeleton, especially in response to gas adsorption to tetrapole carbon dioxide. The MOF's flexible movement can lead to an efficient gas separation system. This is because structural modifications of MOF can only occur for certain gas molecules. On the other hand, if the MOF shows a dynamic process under low pressure (<1 bar), the gas separation system will be more cost effective. Therefore, research on a flexible MOF moving at low pressure is in progress.

In addition, recently, due to the high porosity and regular structural properties of MOF, its use has been extended to the fields of biology and medicine, and its use in sophisticated and diverse fields such as drug delivery and biological imaging has been attempted.

On the other hand, there has been no attempt to develop anticancer drugs using MOF.

Meanwhile, in the case of conventional studies, the central metal of the MOF compound is mostly copper, and it is necessary to expand the central metal to develop MOFs having various physical properties.

Korean patent application 10-2015-0111597 Korean patent application 10-2018-0009101

Accordingly, the present invention was to develop an anticancer agent including a metal-organic framework.

The present invention was intended to develop a metal-organic framework that can be used as an anticancer agent.

In order to achieve the above object, the present invention provides an anticancer agent comprising a metal-organic framework of the following formula (1).

[Formula 1]

[M ₂ (L1) ₂ (μ-L2)]·x(H ₂ O)

In the above formula, M is Cu, Zn or Co,

L1 is a hydrocarbon group having two carboxylate groups,

L2 is a bis(4-pyridyl) compound or a derivative thereof

x is an integer from 1 to 10.

The present invention provides a metal-organic framework of the following formula (1).

[Formula 1]

[M ₂ (L1) ₂ (μ-L2)]·x(H ₂ O)

In the above formula, M is Co,

L1 is a hydrocarbon group having two carboxylate groups,

L2 is a bis(4-pyridyl) compound or a derivative thereof

x is an integer from 1 to 10.

The present invention has the effect of providing an anticancer agent including a metal-organic framework having excellent anticancer activity. The present invention has an effect of providing a metal-organic framework compound having excellent anticancer activity and the like. The metal-organic framework compound of the present invention has the advantage of excellent anticancer activity and very safe. In addition, the metal-organic framework compound, which is an effective substance of the anticancer agent of the present invention, can be prepared under relatively mild conditions using water as a solvent, unlike organic compounds synthesized through several steps or natural products obtained through long-term extraction. There is an effect that can be provided in a very economical way.

1 shows the structural formula of the metal-organic framework compound of the present invention.
2 is a crystal structure of a metal-organic framework compound of the present invention. [Cu ₂ (Glu) ₂ (bpy)] (a), [Cu ₂ (Glu) ₂ (bpa)] (b), [Cu ₂ (Glu) ₂ (bpe)] (c) each containing water molecules , And [Cu ₂ (Glu) ₂ (bpp)] (d) are shown.
Figure 3 shows the results of the anticancer effect of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) on ovarian cancer.
Figure 4 shows the results of the anticancer effect on brain cancer (U87) of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O).
Figure 5 shows the results of the anticancer effect of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) on brain cancer (LN229).
Figure 6 shows the cell viability results of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) for Astrocytes.
7 shows the results of apoptosis of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O).

The present invention provides an anticancer agent comprising a porous metal-organic framework.

The inventors of the present invention have found that the metal-organic framework compound of the present invention has excellent antibacterial activity, and have applied for a patent for the result of repeated research. (Patent Application No. 10-2018-0009101) Among them, it was found that the metal-organic framework compound of the present invention has an anticancer effect, and the present invention was completed.

The present invention provides an anticancer agent comprising a metal-organic framework compound of Formula 1 below.

[Formula 1]

[M ₂ (L1) ₂ (μ-L2)] x(H ₂ O)

In the above formula, M is Cu, Zn or Co,

L1 is a hydrocarbon group having two carboxylate groups,

L2 is a bis(4-pyridyl) compound or a derivative thereof

x is an integer from 1 to 10.

The metal-organic framework is harmless to the human body because water molecules are crystallized.

The metal of the metal-organic framework compound of the present invention is copper, zinc or cobalt.

L1 of the present invention is a hydrocarbon group containing two carboxylate groups. The L1 is preferably the same as the following formula (2).

[Formula 2]

^- OOC-R-COO ^-

In the above formula, R is a bond or a straight or branched hydrocarbon group having 1 to 7 carbon atoms which may have a single bond or a double bond.

L1 is more preferably malonat, succinate, fumarate, glutarate, adipate or muconate.

The metal of the metal-organic framework compound of the present invention is an L2 ligand to which bis(4-pyridyl) or a derivative thereof is bound. The bis(4-pyridyl) or a derivative thereof is preferably represented by the following formula (3).

[Formula 3]

In the above formula

A is a bond or a straight or branched hydrocarbon group having 1 to 7 carbon atoms which may have a single bond or a double bond.

Bis (4-pyridyl) is more preferably 4,4'-bipyridine (4,4'-bipyridine, bpy), 1,2-bis (4-pyridyl) ethane (1,2-bis (4 -pyridyl)ethane, bpa), 1,2-bis(4-pyridyl)ethene (1,2-bis(4-pyridyl)ethene, bpe) or 1,3-bis(4-pyridyl)propane (1 ,3-bis(4-pyridyl)propane, bpp).

The present invention provides a porous metal-organic framework.

The metal-organic framework compounds of the present invention are excellent in anticancer activity, antibacterial properties, and the like. In particular, the metal-organic framework of the present invention was designed in consideration of the unique properties of metals and organic ligands, such as oxidation number, counter ion, coordination mode, ligand size and crosslinking properties.

The present invention provides a metal-organic framework compound of Formula 1 below.

[Formula 1]

[M ₂ (L1) ₂ (μ-L2)]·x(H ₂ O)

In the above formula, M is Co,

L1 is a hydrocarbon group having two carboxylate groups,

L2 is a bis(4-pyridyl) compound or a derivative thereof

x is an integer from 1 to 10.

L1 of the present invention is a hydrocarbon group containing two carboxylate groups. The L1 is preferably the same as the following formula (2).

[Formula 2]

^- OOC-R-COO ^-

In the above formula, R is a bond, or a straight or branched hydrocarbon group having 1 to 7 carbon atoms which may have a single bond or a double bond.

L1 is more preferably malonat, succinate, fumarate, glutarate, adipate or muconate.

The metal of the metal-organic framework compound of the present invention is an L2 ligand to which bis(4-pyridyl) or a derivative thereof is bound. The bis(4-pyridyl) or a derivative thereof is preferably represented by the following formula (3).

[Formula 3]

In the above formula

A is a bond, or a straight or branched hydrocarbon group having 1 to 7 carbon atoms which may have a single bond or a double bond.

Bis (4-pyridyl) is more preferably 4,4'-bipyridine (4,4'-bipyridine, bpy), 1,2-bis (4-pyridyl) ethane (1,2-bis (4 -pyridyl)ethane, bpa), 1,2-bis(4-pyridyl)ethene (1,2-bis(4-pyridyl)ethene, bpe) or 1,3-bis(4-pyridyl)propane (1 ,3-bis(4-pyridyl)propane, bpp).

Hereinafter, the structure of the compound of the present invention will be described using a Cu-organic framework compound as an example. However, the present invention is not limited to the following compounds.

All of the Cu-glutarate metal-organic frameworks of the present invention were crystallized in a monoclinic C2/c space group. As a result of a single crystal X-ray study, it was found that all of the metal-organic frameworks of the present invention comprise a two-dimensional (2D) sheet shape including a paddle-wheel Cu ₂ heteronuclear unit connected by glutarate. I can. The two-dimensional sheet is connected by a bipyridyl ligand (L2) to form a three-dimensional (3D) framework (see FIGS. 1 and 2). In FIG. 2, the 3D framework when L2 is bpy in the [Cu ₂ (Glu) ₂ (μ-L2)]x(H ₂ O) compound is shown in (a) and the 3D framework in the case of bpa (b) Here, the 3D framework in the case of bpe is shown in (c), and the 3D framework in the case of bpp is shown in (d). The number of water molecules as a solvent was calculated from elemental analysis and the like. In the four metal-organic framework compounds, the coordination structure of each Cu(II) ion is in the form of a square pyramid consisting of four equatorial carboxylate O atoms and axial pyridyl N atoms.

In the metal-organic framework compounds of the present invention, solvated water molecules are trapped in one-dimensional (1D) channels. The metal-organic framework of the present invention has a pore volume of 10 to 40 vol%, preferably 15 to 35 vol%, respectively, based on PLATON analysis. All of the metal-organic framework compounds of the present invention contain well-defined 1D channels and have very similar pore shapes with appropriate pore sizes and pore volumes. These pores and void volumes are thought to have an effect on anticancer activity.

The anticancer agent comprising the metal-organic framework of the present invention is one that exhibits anticancer activity against any one or more cancers selected from lung cancer, breast cancer, cervical cancer, brain cancer, colon cancer, prostate cancer, liver cancer, ovarian cancer, rectal cancer and osteosarcoma. However, the types of cancer that can be treated are not necessarily limited thereto.

The anticancer agent of the present invention may contain a metal-organic framework in an amount of 0.01 to 50% by weight based on the total weight of the anticancer agent.

The anticancer agent of the present invention may additionally contain a pharmaceutically acceptable additive. At this time, pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, syrup, arabic rubber, pregelatinized powder starch, corn starch, powder cellulose, Hydroxypropyl cellulose, sodium starch glycolate, carnaubanap, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, sucrose, dextrose, sorbitol and talc may be used, but are not necessarily limited thereto. These additives may be included in 50 to 99.99% by weight of the anticancer agent.

The anticancer agent of the present invention can be administered in various oral and parenteral dosage forms at the time of clinical administration.When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants are used. Can be prepared.

Solid or liquid formulations may be used for oral administration. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient for anticancer drugs, such as starch, calcium carbonate, sucrose, lactose, or gelatin. It can be prepared by mixing. Liquid formulations for oral administration include suspensions, liquid formulations, emulsions and syrups, and such liquid formulations include water, liquid paraffin and various excipients, which are commonly used simple diluents, such as wetting agents, sweetening agents, and fragrances. , Preservatives, etc. may be included.

Formulations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, suppositories, etc., and non-aqueous solvents and suspensions include vegetable oils such as propylene glycol, polyethylene glycol, and olive oil, Injectable esters such as ethyl oleate may be used. Meanwhile, as a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

The anticancer agent of the present invention can be administered orally or parenterally according to a desired method. In parenteral administration, external use of the skin or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection and You can choose the same injection method.

The dosage of the anticancer agent according to the present invention can be appropriately determined in consideration of the target patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease, and, for example, daily administration The amount may be 0.01 to 100 mg/kg based on the anticancer agent of the present invention, and the number of administrations per day may be about 1 to 6 times.

The metal-organic framework compound of the following formula 1 of the present invention is not limited, but is preferably prepared by the following method.

[Formula 1]

[Cu2(L1)2(μ-L2)]·x(H ₂ O)

In the above formula, M is Cu, Zn or Co,

L1 is a hydrocarbon group having two carboxylate groups,

L2 is a bis(4-pyridyl) compound or a derivative thereof

x is a number from 1 to 10.

In the present invention, a metal (II) salt compound, a hydrocarbon compound having two carboxylate groups, and a pyridyl compound are mixed in water and then dissolved. After that, it is reacted for 12 hours to 10 days at 25 to 100 ℃ in a high pressure container. After cooling the reaction solution, the generated crystals are recovered.

The metal (II) salt compound may be a metal nitrate, sulfate, carbonate, or chloride salt.

The hydrocarbon compound having the two carboxylate groups is preferably HOOCRCOOH (R is a bond, a linear or branched hydrocarbon group having 1 to 7 carbon atoms that may have a single bond or a double bond) or a sodium salt, calcium salt thereof, or It is a potassium salt.

When mixing with water, ultrasound can be used to increase solubility, and NaOH aqueous solution can be added if necessary.

Hereinafter, the present invention will be described in detail through an embodiment. However, the present invention is not limited to the following examples.

Manufacturing example. [M ₂ (L1) ₂ (μ-L2)]·x(H ₂ O) preparation

1. [Cu ₂ (Glu) ₂ (bpy)]·3(H ₂ O)

20 mL solution of distilled water containing Cu(NO ₃ ) ₂ · 3H ₂ O (0.193 g, 0.8 mmol), glutaric acid (0.317 g, 2.4 mmol) and 4,4'-bipyridine (0.374 g, 2.4 mmol) Was subjected to ultrasonic treatment and placed in a high-pressure container lined with Teflon. The container was placed in an oven at 80° C. for 48 hours. After cooling to room temperature, the turquoise block crystal was recovered by filtration, washed with distilled water, and dried in air overnight. The yield was 0.028 g. [Cu ₂ (C ₅ H ₆ O ₄ ) ₂ (C ₁₀ H ₈ N ₂ )] · 3(H ₂ O) (MW=597.5)

2. [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O)

Cu(NO ₃ ) ₂ · 3H ₂ O (0.48 g, 2.0 mmol), glutaric acid (0.26 g, 2.0 mmol) and 1,2-bis in distilled water (200 mL) containing 1.0 M NaOH (2 mL) (4-pyridyl)ethane (0.18 g, 1.0 mmol) was added and placed in a high-pressure container lined with Teflon. The container was placed in an oven at 80° C. for 48 hours. After cooling to room temperature, a blue-green crystal needle was obtained. This was recovered by filtration, washed with distilled water, and dried in air overnight. The yield was 0.40 g. [Cu ₂ (C ₅ H ₆ O ₄ ) ₂ (C ₁₂ H ₁₂ N ₂ )] · 3(H ₂ O) (MW=625.6)

3. [Cu ₂ (Glu) ₂ (bpe)]·6(H ₂ O)

In distilled water (200 mL) containing 1.0 M NaOH (2 mL), Cu(NO ₃ ) ₂ · 3H ₂ O (0.48g, 2.0mmol), glutaric acid (0.26g, 2.0mmol) and 1,2-bis (4-pyridyl)ethylene (0.18g, 1.0mmol) was added and placed in a high pressure container lined with Teflon. The container was placed in an oven at 80° C. for 48 hours. After cooling to room temperature, the cyan crystal needles were recovered by filtration, washed with distilled water, and dried in air overnight. The yield was 0.46 g. _{[[Cu 2 (C 5 H} 6 O 4) 2 (C 12 H 10 N 2)] · 6 (H 2 O) (MW = 677.7)

4. [Cu ₂ (Glu) ₂ (bpp)]·6(H ₂ O)

Cu(NO ₃ ) ₂ · 3H ₂ O (0.060g, 0.25mmol), glutaric acid (0.033g, 0.25mmol), 1,3-bis(4-pyridyl)propane (0.046g, 0.25mmol) and urea 0.052 g, 0.87 mmol) solution was left at room temperature for 7 days. Turquoise crystals were recovered by filtration, washed with distilled water, and dried in air overnight. The yield was 0.033 g. _{[Cu 2 (C 5 H 6} O 4) 2 (C 13 H 14 N 2)] · 6 (H 2 O) (MW = 693.7)

The results of structural analysis of the compound are shown in Table 1 below.

One 2 3 4 Empirical formula C ₂₀ H ₂₆ Cu ₂ N ₂ O ₁₁ C ₂₂ H ₃₀ Cu ₂ N ₂ O ₁₁ C ₂₂ H ₃₄ Cu ₂ N ₂ O ₁₄ C ₂₃ H ₃₈ Cu ₂ N ₂ O ₁₄ Formula weight 597.5 625.6 677.7 693.7 Temperature (K) 296(2) 223(2) 296(2) 296(2) Wavelength (Å) 0.71073 Å 0.71073 Å 0.71073 Å 0.71073 Å Space group C 2/c C 2/c C 2/c C 2/c

5. [Co ₂ (Glu) ₂ (bpa)]

DMF (20 mL) in _{Co (NO 3) 2 · 6H} 2 O (0.232 g, 0.8 mmol), glutaric acid (0.317 g, 2.4 mmol) and 1,2-bis (4-pyridyl) ethane (0.442 g, 2.4 mmol) sonicated and placed in a high pressure vessel lined with Teflon. The container was placed in an oven at 130° C. for 48 hours. After cooling to room temperature, the crystals were recovered by filtration, washed with DMF and dried in air overnight. The yield was 0.028 g. [Co ₂ (C ₅ H ₆ O ₄ ) ₂ (C ₁₂ H ₁₂ N ₂ )] (MW=562.3)

6. [Co ₂ (Glu) ₂ (bpe)]

DMF (20 mL) in _{Co (NO 3) 2 · 6H} 2 O (0.232 g, 0.8 mmol), glutaric acid (0.317 g, 2.4 mmol) and 1,2-bis (4-pyridyl) ethylene (1, A solution containing 2-bis(4-pyridyl)ethylene, 0.437 g, 2.4 mmol) was sonicated and placed in a high-pressure container lined with Teflon. The container was placed in an oven at 130° C. for 48 hours. After cooling to room temperature, the crystals were recovered by filtration, washed with DMF and dried in air overnight. The yield was 0.028 g. [Co ₂ (C ₅ H ₆ O ₄ ) ₂ (C ₁₂ H ₁₀ N ₂ )] (MW=560.3)

7. [Zn ₂ (Glu)(bpe)]·2(H ₂ O) preparation

_{Zn (NO 3) 2 · 6H} 2 O (0.0304g, 0.1mmol) and glutaric acid (0.0133g, 0.1mmol) of 1,2-bis (4-pyridyl) above were dissolved in 4mL H ₂ O ethylene (0.0376 g, 0.2mmol) 4mL acetonitrile solution is carefully added. A crystal can be obtained after leaving it for two weeks. The yield is 0.0287 g. [Zn ₂ (C ₅ H ₆ O ₄ ) ₂ (C ₁₂ H ₁₀ N ₂ )] · 2(H ₂ O) (MW=609.3)

[Test Methods]

Cell culture

Brain tumor cells (U87 and LN229) and ovarian cancer cells (SKOV3) were purchased from ATCC (American Type Culture Collection, Manassas, VA), and normal astrocytes (astrocyte) were purchased from Lonza (Alpharetta, GA). All cells were cultured in Dulbecco's Modified Eagle Medium (DMEM, Weljin, Daegu, Korea) containing 10% fetal bovine serum (FBS; Life Technologies, Carlsbad, CA) and 1x antibiotic-antimycotic (Thermo Fisher Scientific, Waltham, Ma). I did. Cells were cultured in an incubator at 37° C. in 5% CO ₂ atmosphere.

Cell viability analysis

In order to confirm the survival rate by the MOF compound treatment, 1 x 10 ⁴ ovarian cancer cells were placed in 96-well plates and cultured for 24 hours, and then a specific concentration of the MOF compound was dissolved in a serum-free medium and then treated on the cells. Serum-free medium without MOF was used as a control. After 24 hours of MOF treatment, cell viability was measured using an EZ-cytox kit (Dae-Il Research Service, Seoul, Korea).

In order to confirm the effect of the MOF compound on the cells, 4 x 10 ³ brain tumors, ovarian cancer and astrocytes were placed in 96-well plates, respectively. After incubation for 24 hours, various concentrations of MOF were dissolved in a serum-free medium, and then the cells were treated. Serum-free medium without MOF was used as a control. After 24 hours of MOF treatment, cell viability was measured using an EZ-cytox kit (Dae-Il Research Service, Seoul, Korea).

Cell death assay

2 x 10 ⁶ brain tumor cells and ovarian cancer cells were cultured in a 100 mm culture dish for 24 hours. Brain tumor cells were exposed to MOF at a concentration of 100 μg/ml and ovarian cancer cells at a concentration of 12.3 μg/ml for 24 hours. For apoptosis analysis, annexin V-FITC Apoptosis Detection Kit (BD PharMingen, San Diego, California, USA) was used to perform the method described in the manufacturer's instructions. Cells were washed twice with PBS and resuspended in buffer solution (1 x 10 ⁶ cells/ml). Cells stained with annexin V-FITC and PI were analyzed by flow cytometry (BD, FACSAria™) within 1 hour of staining.

statistics

All experimental results were calculated as standard deviation (± SD) from at least three or more independent experiments or expressed as a percentage of the control group. Differences between the two groups were analyzed by Student's t-test, and differences between the different groups were evaluated using analysis of variance (ANOVA) with post-hoc. A p value of 0.05 or less was considered statistically significant.

Example 1. Anti-cancer effect on ovarian carcinoma SKOV3

Prepare the concentration of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) at 1.6, 12.5, 25, 50, 100 μg/ml An anticancer test was performed on ovarian cancer and the results are shown in Table 2 below. In addition, the anticancer effect results are shown in FIG. 3. In the case of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) of the present invention, it can be seen that the cell viability is greatly reduced even at a relatively low concentration (1.6 μg/ml).

sample cell viability(%) NC 100±6.79 Cu ₂ (Glu) ₂ (bpa) 1.6μg/ml 85.6±4.90 12.5μg/ml 49.41±2.6 25μg/ml 19.6±2.13 50μg/ml 7.28±0.37 100μg/ml 7.14±0.34

NC: non-treated control, media

Example 2. Anticancer effect on Glioblastoma U87 MG

Prepare the concentration of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) at 10, 100 μg/ml Cell viability for brain cancer was measured and the results are shown in Table 3 below. In addition, Figure 4 shows the results of the anticancer effect of brain cancer.

sample cell viability(%) NC 100±2.56 Cu ₂ (Glu) ₂ (bpa) 10μg/ml 103.9±5.85 100μg/ml 61.3±25.75

NC: non-treated control, media

Example 3. Anticancer effect on LN229 of brain cancer (Glioblastoma)

Prepare the concentration of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) at 10, 100 μg/ml An anticancer test was performed on brain cancer and the results are shown in Table 4 below. In addition, Figure 5 shows the results of the anticancer effect of brain cancer.

sample cell viability(%) NC 100±2.56 Cu ₂ (Glu) ₂ (bpa) 10μg/ml 101.3±16.34 100μg/ml 37.5±6.50

NC: non-treated control, media

Example 4. Effects on astrocytes

Prepare the concentration of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) at 10, 100 μg/ml Cell viability was performed on astrocytes and the results are shown in Tables 5 and 6 below.

sample cell viability(%) NC 100±2.56 Cu ₂ (Glu) ₂ (bpa) 10μg/ml 178.6±15.06 100μg/ml 18.23±17.3

NC: non-treated control, media

[Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) When comparing the cell viability after treatment with 100 μg/ml of the compound on brain tumor cells, U87 is 61.3±25.75%, LN229 is 37.5±6.50%, and astrocyte is 18.23 It was observed that the cell viability decreased to 7.14±0.34% in the case of ovarian cancer. It can be seen that the compound of the present invention has an anticancer effect, and in particular, has selectivity for ovarian cancer.

Example 5. Cell death assay

Apoptosis by [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) against brain cancer (Glioblastoma) U87 MG cells, brain cancer (Glioblastoma) LN229 cells, and ovarian carcinoma SKOV3 cells The experiment was conducted and the results are shown in FIG. 7. The case not treated with MOF was shown together as a control. The concentrations of [Cu ₂ (Glu) ₂ (bpa)]·3(H ₂ O) for U87 MG cells, LN229 cells and SKOV3 cells were 100 μg/ml, 100 μg/ml and 12.3 μg/ml, respectively.

According to FIG. 7, it can be seen that, unlike the control, when the MOF compound of the present invention is treated, total apoptosis (early and late apoptosis) is increased. %).

According to the anticancer test results, it can be seen that the compound of the present invention has excellent anticancer effects against various cancers.

Claims (14)

Anticancer agent comprising a metal-organic framework of the following formula (1)
[Formula 1]
[M ₂ (L1) ₂ (μ-L2)]·x(H ₂ O)
In the above formula, M is Cu, Zn or Co,
L1 is a hydrocarbon group having two carboxylate groups,
L2 is bis(4-pyridyl) or a derivative thereof
x is a number from 1 to 10. The anticancer agent according to claim 1, wherein L1 is a group represented by the following formula (2)
[Formula 2]
^- OOC-R-COO ^-
In the above formula, R is a bond, or a straight or branched hydrocarbon group having 1 to 7 carbon atoms which may have a single bond or a double bond. The anticancer agent of claim 1, wherein L1 is malonat, succinate, fumarate, glutarate, adipate, or muconate. The anticancer agent according to claim 1, wherein L2 is a compound represented by Formula 3 below.
[Formula 3]

In the above formula
A is a bond, or a straight or branched hydrocarbon group having 1 to 7 carbon atoms which may have a single bond or a double bond. The method according to claim 1, wherein L2 is 4,4'-bipyridine (4,4'-bipyridine, bpy), 1,2-bis(4-pyridyl)ethene (1,2-bis(4-pyridyl)ethene, bpe), 1,2-bis(4-pyridyl)ethane (1,2-bis(4-pyridyl)ethane, bpa) or 1,3-bis(4-pyridyl)propane (1,2-bis( Anticancer agent, characterized in that 4-pyridyl)propane, bpp) The anticancer agent according to claim 1, wherein the cancer that can be treated with the anticancer agent is at least one selected from the group consisting of lung cancer, breast cancer, cervical cancer, brain cancer, colon cancer, prostate cancer, liver cancer, ovarian cancer, rectal cancer and osteosarcoma. The anticancer agent according to claim 1, wherein the anticancer agent comprises a metal-organic framework in an amount of 0.01 to 50% by weight based on the total weight of the anticancer agent. The anticancer agent according to claim 7, wherein the anticancer agent additionally contains 50 to 99.99% by weight of a pharmaceutically acceptable additive. The method according to claim 8, wherein the pharmaceutically acceptable additive is starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch , Powdered cellulose, hydroxypropyl cellulose, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, sucrose, dextrose, sorbitol, and talc. Anticancer agent characterized by Metal-organic framework of the following formula 1
[Formula 1]
[M ₂ (L1) ₂ (μ-L2)]·x(H ₂ O)
In the above formula, M is Co,
L1 is a hydrocarbon group having two carboxylate groups,
L2 is bis(4-pyridyl) or a derivative thereof
x is a number from 1 to 10. The metal-organic framework according to claim 10, wherein L1 is a group represented by the following formula (2).
[Formula 2]
^- OOC-R-COO ^-
In the above formula, R is a bond, or a straight or branched hydrocarbon group having 1 to 7 carbon atoms which may have a single bond or a double bond. The metal of claim 10, wherein L1 is malonate, succinate, fumarate, glutarate, adipate, or muconate. Organic Framework The metal-organic framework according to claim 10, wherein L2 is a compound represented by the following formula (3)
[Formula 3]

In the above formula
A is a bond, or a straight or branched hydrocarbon group having 1 to 7 carbon atoms which may have a single bond or a double bond. The method of claim 10, wherein L2 is 4,4'-bipyridine (4,4'-bipyridine, bpy), 1,2-bis(4-pyridyl)ethene (1,2-bis(4-pyridyl)ethene, bpe), 1,2-bis(4-pyridyl)ethane (1,2-bis(4-pyridyl)ethane, bpa) or 1,3-bis(4-pyridyl)propane (1,2-bis( Metal-organic framework, characterized in that 4-pyridyl)propane, bpp)

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