KR20120101798A - Novel hexanuclear arene-ruthenium nano prismatic cage compound, preparation method thereof and pharmaceutical composition for preventing and treating cancer as active ingredient - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing hexanuclear arene-ruthenium nano prismatic cage compound is provided to suppress the proliferation of human SK-hep-1(liver cancer), HeLa(ovarian cancer), HCT-15(colorectal cancer), A549(lung cancer), and MDA-MB-231(breast cancer) cells and to ensure excellent anticancer effect. CONSTITUTION: A novel hexanuclear nanoprismatic cage compound is denoted by chemical formula 1. A method for preparing the compound of chemical formula 1 comprises: a step of reacting half sandwich arene ruthenium metal receptors(3 or 4) and tri(pyridylethynyl)benzene(2) under the presence of a reaction solvent; and a step of adding diethyl ether to a reaction mixture to prepare a self-assembly compound of chemical formula 1. The reaction solvent is a methanol-dichloromethane solution. A pharmaceutical composition for preventing and treating cancer contains the compound of chemical formula 1 or pharmaceutically acceptable salt thereof as an active ingredient.

Description

Novel hexanuclear Arene-Ruthenium nano prismatic cage compound, preparation method etc. and pharmaceutical composition for preventing and treating cancer as active ingredient}

The present invention relates to a novel six-nuclear arene-ruthenium nano-prism cage compound or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing and treating cancer containing the same as an active ingredient.

The field of metal pharmacy has emerged as an important new field of medicinal chemistry because of the therapeutic application of metal-based drugs ((a) M. Mascini, G. Bagni, MLD Pietro, M. Ravera, S. Baracco and D. Osella, Bio Metals , 2006, 19, 409; (b) TW Hambley, Dalton Trans., 2007, 4929). Rearrangement of the organic ligands in a three-dimensional space from a wide range of coordination numbers and the accessible redox state of the controllable metal centers provide a broad spectrum of reactivity that can be used for medical purposes (U. Schatzschneider and N.Metzler-). Nolte, Angew. Chem., Int. Ed., 2006, 45, 1504.). Platinum complexes, particularly cisplatin, carboplatin, and oxoplatin, despite their high toxicity and unnecessary neuronal, liver, and kidney toxicity side effects ((a) Y. Jung and SJ Lippard, Chem. Rev., 2007, (B) C. Gianomenico and MUS Christen, Patent 6413953, 2000), which are currently used as the most effective chemotherapeutic agents ((a) L. Kelland, Nat. Rev. Cancer, 2007, 7, 573; (b J. Reedijk, Eur. J. Inorg. Chem., 2009, 1303. However, the high systemic toxicity and resistance issues associated with platinum-based drugs include alternative metal-based antitumor agents ((a) CHA Goss, W. Henderson, AL Wilkins and CJ Evans, J. Organomet. Chem. 2003, 679, 194; (b ) AG Quiroga and CN Ranninger, Coord. Chem. Rev. 2004, 248, 119; (c) W. Henderson, BK Nicholson and ERT Tiekink, Inorg. Chim. Acta, 2006, 359, 2046) and more secure and more effective A new era has opened with interest in the design and pharmacological development of therapeutics. In particular, ruthenium complexes represent a new class of promising metal-based drugs with low toxicity and high activity in tumors that do not respond well to platinum-based drugs ((a) CG Hartinger, S. Zorbas-Selfried, MA Jakupee, B. Kynast, H. Zorbas and BK Keppler, J. Inorg.Biochem. 2006, 100, 891; (b) YK Yan, M. Melchart, A. Habte mariam and PJ Sadler Chem. Commun., 2005, 4764). Two ruthenium complexes, ImH [trans RuCl ₄ (DMSO) Im]] (NAMI-A) and KO1019, were the first mononuclear ruthenium-based anticancer drugs that successfully passed Phase I clinical trials ((a) JM Rademaker-Lakhai, D. Van Den Bongard, D. Pluim, JH Beijnen and JHM Schellens, Clin. Cancer Res., 2004, 10, 3717; (b) M. Groessl, CG Hartinger, K. Polec-Pawlak, M. Jarosz, PJ Dyson and BK Keppler, Chem. Biodiversity, 2008, 5, 1609.).

Multinuclear drugs are also designed to increase the range of treatable tumors. Many polymeric platinum compounds ((a) Z. Yang, X. Wang, H. Diao, J. Zhang, H. Li, H. Sung and Z. Guo, Chem. Commun., 2007, 3453; (b) NJ Wheate , AI Day, RJ Blanch, AP Arnold, C. Cullinane and JG Collins, Chem. Commun., 2004, 1424), for example polymer linked diaminocyclohexyl metal chemotherapeutic (AP5346) and pt-coordinated higher orders Branched polyglycerol polymers provide selective permeation, retention effect (EPR) (Y. Matsumura and H. Maeda, Cancer. Res., 1986, 46, 6387.) and long-range and intrastrand DNA crosslinking. Because of their unique extracellular environment that allows drugs to selectively accumulate in cancer cells, they could potentially be used for target specific tumor cells. Therefore, research on multinuclear metal-polymer complex compounds is being actively conducted.

The prior art related to the ruthenium complex is as follows, US 2008-0096846 discloses a ruthenium (II) compound of the formula, a solvate or prodrug thereof, and a method of preparing the same as a drug for treating cancer, which shows anticancer activity for a long time. have.

Where p is 0 or 1, r is 1 when p is 0, r is 2 when p is 1, and when p is 1, ligand A is different so that the compound contains two ruthenium atoms Bound to ligand A, the complex is called a dinuclear complex)

EP 1950217 is a novel organometallic compound for the treatment of various diseases such as cancer, inflammatory or immune disorders, comprising a central porphyrin or phthalocyanine backbone to which ligands coordinated to at least one or more transition metals bind. Also disclosed are tetranuclear ruthenium (+ II) complexes of the formula wherein eta-5 or eta-6 aromatic hydrocarbons are bonded to the transition metal.

EP 2019109 also discloses trinuclear ruthenium-arene clusters that can be used for the treatment of cancer.

The inventors of the present invention prepared a novel 6-nuclear Arene-ruthenium nano-prism cage compound, and found that the compound exhibited a micromolar concentration And thus the present invention has been completed.

It is an object of the present invention to provide a novel six-nuclear arene-ruthenium nano-prism cage compound or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the novel six-nuclear arene-ruthenium nano-prism cage compound.

Another object of the present invention to provide a pharmaceutical composition for the prevention and treatment of cancer containing the novel six-core arene-ruthenium nano-prism cage compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a novel six-nuclear arene-ruthenium nano-prism cage compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In the formula 1,

는

이고,

The

ego,

은

또는

이다)

silver

or

to be)

In addition, the present invention as shown in Scheme 1,

Reacting the half-sandwich arene ruthenium metal receptor (3 or 4) with tri (pyridylethynyl) benzene (2) in a ratio of 3: 2 under a reaction solvent (step 1); And

A method for preparing the novel six-nuclear arene-ruthenium nanoprism cage compound comprising the step of adding diethyl ether to the concentrated reaction mixture to produce self-assembled compound of formula (Step 2).

[Reaction Scheme 1]

및

은 상기 화학식 1에서 정의한 바와 같다)(In Scheme 1 above

And

Is as defined in Formula 1)

Furthermore, the present invention provides a pharmaceutical composition for preventing and treating cancer containing the novel 6-nuclear arene-ruthenium nano-prism cage compound or a pharmaceutically acceptable salt thereof as an active ingredient.

 The novel six-nuclear arene-ruthenium nano-prism cage compounds according to the invention are human SK-hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 (lung cancer), and MDA-MB-231 ( Breast cancer) It inhibits the proliferation of cells at low micromolar concentrations and shows excellent anticancer activity by inhibiting the activity of cancer cells through apoptosis that regulates the cell growth cycle, such as liver cancer, ovarian cancer, rectal cancer, lung cancer, breast cancer, etc. It can be usefully used for the prevention and treatment of cancer.

1 is an NMR spectrum of the nanoprism cage compounds of Examples 1 and 2 of the present invention ((a) Example 1, (b) Example 2).
2 is an ESI mass spectrometry spectrum of the nanoprism cage compounds of Examples 1 and 2 of the present invention ((a) Example 1, (b) Example 2, red: theory, blue: experimental value).
3 shows the X-ray structure of the nanoprism cage compound of Example 1 of the present invention (dark red = Ru; red = O; blue = N; H atoms, corresponding anions and solvent molecules have been omitted for clarity).
4 is a graph showing the anticancer effect of the nanoprism cage compound and the reaction compound of Example 1 of the present invention in the A549 cell line.
5 is a graph showing the apoptosis effect in the A549 cell line of the nanoprism cage compound of Example 1 of the present invention.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention provides a novel six-nuclear nano-prism cage compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(In the formula 1,

는

이고,

The

ego,

은

또는

이다)

silver

or

to be)

The novel six-nucleus nano-prism cage compound of the present invention represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and the salt may be an acid addition salt formed by a pharmaceutically acceptable free acid. useful. The inorganic acid and organic acid may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, and methanesulfonic acid may be used as the organic acid. , Acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, and the like can be used. Preferably, hydrochloric acid may be used as the inorganic acid, and methanesulfonic acid may be used as the organic acid.

In addition, the novel six-nuclear nano-prism cage compound represented by the formula (1) of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.

The present invention also provides a method for producing a novel six-nucleus nano-prism cage compound represented by the following formula (1).

The preparation method according to the present invention is as shown in Scheme 1 below,

Reacting the half-sandwich arene ruthenium metal receptor (3 or 4) with tri (pyridylethynyl) benzene (2) in a ratio of 3: 2 under a reaction solvent (step 1); And

Adding diethyl ether to the concentrated reaction mixture to produce self-assembled compound of formula 1 (step 2).

[Reaction Scheme 1]

및

은 상기 화학식 1에서 정의한 바와 같다)
(In Scheme 1 above

And

Is as defined in Formula 1)

Specifically, the novel six-nuclear nanoprism cage compound according to the present invention is a half-sandwich arene ruthenium metal receptor (3 or 4) in methanol-dichloromethane solution of tri (pyridylethynyl) benzene (2) and 3: 2. It can be easily prepared by reacting in ratio, and the addition of diethyl ether to the concentrated reaction mixture separates the pure self-assembled product (1) as sea green and green solid, respectively.

As described above, the novel 6-nucleus nano-prism cage compound prepared according to the present invention is prepared after infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement and representative compounds. The molecular structure can be confirmed by comparing elemental analysis calculations with actual measurements.

In particular, as a result of measuring the prepared novel 6-nucleus nano-prism cage compound according to the X-ray structure determination method, it can be seen that formed in the shape of a triangular prism as shown in FIG.

In addition, the present invention provides a pharmaceutical composition for the prevention and treatment of cancer using the novel six-nucleus nano-prism cage compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Compounds of formula (1) according to the invention and their pharmaceutically acceptable salts are SK-hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 (lung cancer), and MDA-MB-231 Breast cancer cells exhibit an IC ₅₀ value of 3.4-9.2 μM, exhibiting anticancer effects equivalent to or greater than cisplatin used as a conventional anticancer agent (see Table 1). Flow cytometry assays regulate cell growth cycle. It has been shown to inhibit the activity of cancer cells through apoptosis (see FIG. 5).

Therefore, the novel six-nuclear arene-ruthenium nano-prism cage compound according to the present invention exhibits excellent anticancer activity and can be usefully used for the prevention and treatment of cancers such as liver cancer, ovarian cancer, rectal cancer, lung cancer and breast cancer.

When the composition of the present invention is used as a medicine, the pharmaceutical composition containing the compound of Formula 1 as an active ingredient may be formulated and administered in various oral or parenteral dosage forms as described below, but is not limited thereto. It is not.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like. Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

Pharmaceutical compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, in order to formulate the composition for parenteral administration, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which is then formulated into an ampule or vial unit dosage form can do. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

In addition, the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the Examples.

< Example  1>

Hexagonal Nano Prism Cage  Preparation of Compounds 1

Donor compounds (T. Kikuchi, T. Murase, S. Sato and M. Fujita, Supramolecular. Chem., 2008, 20, 81) and areren-ruthenium receptors (NPE Barry and Bruno Therrien, Eur. J. Inorg. Chem. , 2009, 4695) were prepared according to conventional methods. Deuterated solvents were purchased from Cambridge Isotope Laboratory (Andover, Mass.). NMR spectra were recorded on a Bruker 300 MHz spectrometer. ¹ H NMR chemical shifts were recorded relative to residual solvent signal. Mass spectra for self-assembly were recorded on a Micromass Quattro II triple-quadrupole mass spectrometer using electron spray ionization with the MassLynx operating system (H.-B. Yang, AM Hawkridge, SD Huang, N. Das, SD Bunge, DC Muddiman, and PJ Stang, J. Am. Chem. Soc., 2007, 129, 2120.). Diffraction data from single crystals of the prepared compounds were collected on ADSC proton 210 CCD diffractometer using synchrotron radiation (λ = 0.90000 Hz) at 100 K in macromolecular crystallography beam line 6B1, Pohang Accelerator Laboratory (PAL). Initial data was processed and reduced using the program HKL2000. The structure was identified by direct method and refined to full-matrix least-squares refinement on F2 using appropriate software in the SHELXTL program package.

A solution (0.5 mL) of triangular donor compound (2) (1.50 mg, 0.004 mmol) in CH ₂ Cl ₂ was dissolved in ruthenium triflate receptor (3) (5.15 mg, 0.006 mmol) in CH ₃ OH. To the solution (0.5 mL) was added dropwise. Thereafter, the reaction mixture was stirred at room temperature for 4 hours and then diethyl ether was added to give a greenish green crystalline powder (yield: 91%)

¹ H NMR (300 MHz, CD ₃ COCD ₃ ): δ = 8.61 (d, 3JH, H = 6.6 Hz, 12H, Hα), 7.77 (s, 6H; Hbz), 7.57 (d, 3JH, H = 6.6 Hz , 12H, Hβ), 7.31 (s, 12H, Hq), 6.00 (d, 3JH, H = 6.0Hz, 12H, Hcym), 5.81 (d, 3JH, H = 6.0Hz, 12H, Hcym), 2.96 [sept , 3JH, H = 6.9 Hz, 6H, CH (CH ₃ ) ₂ ], 2.19 (s, 18H, CH ₃ ), 1.33 [d, 3JH, H = 6.9 Hz, 36H, CH (CH ₃ ) ₂ ] ppm ( (A) of FIG. 1).

¹³ C {1H} NMR (75 MHz, CD ₃ COCD ₃ ): δ = 171.8 (CO), 170.7 (CBz), 154.3 (CHα), 145.2 (CBz), 138.4 (CHq), 125.0 (CHβ), 112.5 ( Cq), 104.9 (Ccym), 100.5 (Ccym), 85.2 (CHcym), 84.2 (CHcym), 31.5 [CH (CH ₃ ) ₂ ], 23.1 [CH (CH ₃ ) ₂ ], 22.3 [CH (CH ₃ ) ₂ ], 17.3 (CH 3) ppm.

MS (ESI) (C ₁₅ 0H ₁₂₆ F ₁₈ N ₆ O ₃₀ Ru ₆ S ₆ : 1667.2 [M-2OTf] ²⁺ ; 1062.2 [M-3OTf] ³⁺ (see FIG. 2 (a), red: theoretical, Blue: experimental value).

X-ray crystal structure (see FIG. 3): triangular prism shape with six ruthenium atoms.

< Example  2>

Hex Nucleus Prism Cage  Preparation of Compound 2

A green crystalline solid was carried out in the same manner as in Example 1 except for using triangular donor compound (2) (2.63 mg, 0.007 mmol) and acceptor compound (4) (9.37 mg, 0.010 mmol) as reactants. Was obtained (Yield: 87%).

1 H NMR (300 MHz, CD ₃ COCD ₃ ): δ = 8.85 (br., 12H, Hbq), 8.77 (d, 3JH, H = 6.6 Hz, 12H, Hα), 7.99 (br., 12H, Hcq), 7.97 (s, 6H; Hbz), 7.44 (d, 3JH, H = 6.6 Hz, 12H, Hβ), 6.20 (d, 3JH, H = 6.3 Hz, 12H, Hcym), 5.98 (d, 12H, Hcym), 3.08 [sept, 3JH, H = 6.9 Hz, 6H, CH (CH ₃ ) ₂ ], 2.26 (s, 18H, CH ₃ ), 1.37 [d, 3JH, H = 6.9 Hz, 36H, CH (CH ₃ ) ₂ ppm (see FIG. 1 (b)).

¹³ C {1H} NMR (75 MHz, CD ₃ COCD ₃ )): δ = 170.5 (Ctpt), 170.0 (CO), 154.1 (CHα), 145.0 (Ctpt), 134.6 (Cq), 134.1 (CHcq), 128.2 (CHbq), 124.9 (CHβ), 108.1 (Cq), 104.9 (Ccym), 100.7 (Ccym), 85.1 (CHcym), 83.6 (CHcym), 31.5 [CH (CH ₃ ) 2], 22.5 [CH (CH ₃₎ 2], 17.8 (CH ₃ ) ppm.

MS (ESI) (C ₁₇₄ H ₁₃₈ F ₁₈ N ₆ O ₃₀ Ru ₆ S ₆ ): 1817.6 [M-2OTf] ²⁺ , 1162.3 [M-3OTf] ³⁺ (see FIG. 2B, red: theoretical , Blue: experimental value).

< Experimental Example  1>

Cancer cell growth inhibition assay MTT  analysis)

Growth inhibition assays for SK-hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 (lung cancer), and MDA-MB-231 (breast cancer) cells of the compounds of the present invention are performed It was.

Specifically, the cancer cells described above were cultured at 37 ° C. and 5% CO ₂ in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% heat inactivated fetal bovine serum (FBS) and 1% penicillin streptomycin. Suspensions of different cells were seeded in 96-well plates at a concentration of 5 × 10 ⁴ cell counts / well (90 μL / well and 10 μL samples). MTT was then dissolved in phosphate buffer (PBS, pH 7.2) and filtered to prepare 5 mg / ml of stock solution. 10 μL of MTT solution was added to each well after no treatment as a control, compound treatment of Example 1 and cisplatin treatment as a conventional anticancer agent as a comparative group. After incubation for 4 hours at 37 ° C. and 5% CO ₂ , 100 μL of DMSO (dimethylsulfoxide) was added to each well. The 96-well plate was then read by absorbance at 570 nm with an enzyme-linked immunosorbent assay (ELISA) reader to determine cell viability and viability from the ratio of the absorbance of cells treated with the compound of Example 1 and untreated cells. The percentage of was measured.

IC ₅₀ values for cell growth inhibition were determined by fitting a plot of log percentages of viable cells to the log of drug concentration using a linear regression function.

The measurement results are shown in Table 1.

Cancer cells
IC ₅₀ value (μM) Example 1 The comparative group (cisplatin) SK-hep-1 3.8 6.3 HeLa 9.2 10.5 HCT-15 4.1 5.6 A549 3.4 2.4 MDA-MB-231 7.6 2.7

As shown in Table 1, the novel six-nuclear arene-ruthenium nano-prism cage compound according to the present invention is SK-hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 (lung cancer), And by showing an IC ₅₀ value of 3.4 ~ 9.2 μM for MDA-MB-231 (breast cancer) cells showed an anticancer effect equivalent to or more than cisplatin used as a conventional anticancer agent. Therefore, the novel six-nuclear arene-ruthenium nano-prism cage compound according to the present invention can be usefully used for the prevention and treatment of cancers such as liver cancer, ovarian cancer, rectal cancer, lung cancer, breast cancer and the like.

In addition, a 96-well plate as described above was treated with a donor compound (2) and a ruthenium triflate receptor (3), which are reactants, to the A549 cell line having the lowest IC ₅₀ value. By measuring the absorbance at 570 nm with a linked immunosorbent assay (ELISA) reader, cell viability was measured from the ratio of the absorbance of the cells treated with the compounds of Example 1, the compounds of Formulas 2 and 3 and the untreated cells. 4 is shown.

As shown in FIG. 4, the donor compound (2) alone did not show anticancer activity against the A549 cell line, and the ruthenium triflate receptor (3) also showed lower anticancer activity than the compound of the present invention. Therefore, the novel six-nuclear arene-ruthenium nano-prism cage compound according to the present invention shows excellent anticancer activity even when compared to the reactants alone, and thus can be usefully used for the prevention and treatment of cancer.

< Experimental Example  2>

Apoptosis ( Apotosis ) analysis

In order to elucidate the mechanism of the anticancer effect of the novel six-nuclear arene-ruthenium nano-prism cage compound according to the present invention, a flow cytometry assay on the A549 cell line was performed by cell-cycle assay.

Specifically, cells were trypsinized at the ends treated with the compound of Example 1, washed twice with 1 × PBS, and then pelleted by centrifugation. The pellet was placed in 70% ethanol and resuspended at 4 ° C. for 1 hour. The cells were then lysed with DNA-bound dry propidium iodine (PI) solution [0.1% sodium citrate (w / v), 0.1% triton × -100 (v / v), and 100 μg / ml PI in deionized water ] Was incubated at room temperature for 30 minutes. Finally, the cells were measured for apoptosis rate of the compound of Example 1 on A549 cells using a FACS Caliber Flow Cytometry (BD, San Jose, Calif.).

The measurement results are shown in Table 2 and FIG. 5.

Concentration of Example 1 (mM) Apoptosis rate 0.8 1.49 ± 0.73 4 4.88 ± 1.21 20 4.11 ± 0.86

As shown in Table 2 and Figure 5, the novel six-nuclear arene-ruthenium nano-prism cage compound according to the present invention showed about 2.5-fold apoptosis compared to the control at 4 mM. From this, the novel six-nuclear arene-ruthenium nano-prism cage compound according to the present invention inhibits the activity of cancer cells through apoptosis that regulates the cell growth cycle, and thus is useful for the treatment of cancer tumors that are difficult to treat with chemotherapy. Can be used.

On the other hand, the compound according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example  1>

Tablet (direct pressurization)

After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.

< Formulation example  2>

Tablets (Wet Assembly)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The fine particles were pressed to prepare tablets.

< Formulation example  3>

Powder and Capsule

5.0 mg of the active ingredient was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was extruded through a hard No. Capsules were prepared in 5 gelatin capsules.

< Formulation example  4>

Injection

100 mg of active ingredient, mannitol 180 mg, 26 mg of Na ₂ HPO ₄ 12H ₂ O and 2974 mg of distilled water were mixed. The mixed solution was filled into an ampoule of transparent glass, filled under dissolution by dissolving the glass, and autoclaved at 120 ° C. for at least 15 minutes to prepare an injection.

Claims (7)

The novel hex nucleus nano-prism cage compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,

The

ego,

silver

or

to be).
As shown in Scheme 1 below,
Reacting the half-sandwich arene ruthenium metal receptor (3 or 4) with tri (pyridylethynyl) benzene (2) under a reaction solvent (step 1); And
A process for preparing the novel six-nuclear arene-ruthenium nanoprism cage compound of claim 1 comprising the step of adding diethyl ether to the concentrated reaction mixture to produce self-assembled compound of formula 1 (step 2):
[Reaction Scheme 1]

(In Scheme 1 above

And

Is as defined in formula 1 of claim 1). The method of claim 2,
The reaction solvent is a methanol-dichloromethane solution, the method for producing a novel six-core arene-ruthenium nano-prism cage compound. The novel hex nucleus arene-ruthenium nano-prism cage compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, the pharmaceutical composition for preventing and treating cancer. The method of claim 4, wherein
The cancer is liver cancer, ovarian cancer, rectal cancer, lung cancer or breast cancer, characterized in that the pharmaceutical composition for the prevention and treatment of cancer. The method of claim 4, wherein
The composition is a pharmaceutical composition for preventing and treating cancer, characterized in that exhibits anticancer activity through apoptosis of cancer cells. The method of claim 4, wherein
The composition is a pharmaceutical composition for the prevention and treatment of cancer, characterized in that the formulation is administered in oral or parenteral dosage form.

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