KR101907400B1 - Compound inducing intra-mitochondrial biomineralization and pharmacological composition for the prevention and treatment of cancer containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a compound in which trialkoxysilane, which is a biomineralization-inducible moiety and triphenylphosphonium (TPP), which is a mitochondria-penetrating moiety, are bonded. More specifically, provided is a use of the compound to be used for cancer treatment method through biomineralization in mitochondria in cancer cells.

Description

TECHNICAL FIELD The present invention relates to a biocompatible biomineralization and pharmacological composition for the prevention and treatment of cancer, and a pharmaceutical composition for preventing or treating cancer,

The present invention relates to a compound to which a mitochondrial penetrating moiety, triphenylphosphonium (TPP) and a biomineralization-inducing moiety, trialkoxysilane, are bonded, Provides a use in which the compound can be used in a method for treating cancer through biochemicals in cancer cell mitochondria.

Biomineralization is an important physiological response, known as a reaction using an inorganic body in an organism cell (Non-Patent Document 1). Mineralization is a homeostasis that causes bone and joint tissues to have appropriate mechanical functions; And internal material support through deposition and reabsorption of inorganic materials by cells. Biomineralization within the cell may be involved in allowing final differentiated chondrocytes to undergo programmed cell death to maintain homeostasis of the musculoskeletal tissue. In addition, the isolation and separation of precipitates of intracellular minerals using amorphous calcium phosphate can control intracellular ion homeostasis, fate and signal transduction (Non-Patent Document 1, Non-Patent Document 1 Patent Document 2). These biochemical processes can be controlled through genetic control pathways and can also be controlled through physiological responses between inorganic and intracellular organic materials. Thus, it is noted that the addition of physiological substances to regulate mineralization may provide a new way to control cellular function and apply it as an additional therapeutic method.

Recently, studies have been reported related to the use of extracellular biomaterials such as calciumation and sialylation in vivo and in vitro, and it has been reported that such biomineralization can be applied to cancer treatment in cells (Non-Patent Document 3 and Non-Patent Document 4). However, the abnormal accumulation of minerals outside the cell can cause cell damage near the location of mineral row formation, creating barriers to diffusion of biomolecules, and the cell can lose sensitivity to environmental changes. For this reason, it is expected that a strategy of inducing biomaterialization to an appropriate position in a cell is required, which can be usefully used in that it can improve target transferability and reduce side effects for desired treatment Patent Document 5). Such an expectation has been reported for the purpose of inducing bioconjugation in many intracellular organelles, such as endosomes, endoplasmic reticulum, Golgi bodies, mitochondria and nuclei, which are divided into membranes (Non-Patent Document 6) Studies have been carried out on substances that specifically target organelles and exhibit a significant level of cancer cell killing effect.

Mitochondria, one of the typical intracellular organelles, play a role in generating intracellular energy. Mitochondria are known to overcome resistance to drugs and reduce side effects of toxic reactions, thereby improving the effect of cancer treatment using anticancer drugs (Non-Patent Document 7). Specifically, the mitochondrial membrane potential of cancer cells is ~220 mV, which is negative compared to the mitochondrial membrane potential of normal cells at ~ -160 mV level.

Accordingly, it is expected that a compound having a lipophilic cation will specifically target the mitochondria of cancer cells. It has been reported that triphenylphosphonium (TPP) can be used as one of the compounds having lipophilic cations (Non-Patent Document 8, Non-Patent Document 9, Patent Document 1). According to the above report, the accumulation efficiency of the cancer cell mitochondria is higher than that of the normal cell mitochondria by more than 10 times as high as that of the TPP-conjugated compound. Therefore, it can be expected that when the TPP is conjugated with a biologically active molecule such as a small molecule and a peptide, the cytotoxic effect of the mitochondrial target can be enhanced. However, biologically active molecules conjugated to TPP can be degraded by various intracellular enzymes, and thus there is a limit to the effect of treating cancer as an anticancer drug (Non-Patent Document 10).

Thus, while trying to develop an effective cancer treatment agent, the present inventors synthesized a compound in which trialkoxysilane and TPP were conjugated with each other, in anticipation of inducing the mineralization of the mitochondrial target. It was confirmed that the compound could be accumulated in the mitochondria of cancer cells by TPP, and thus the silica particles were formed by the mineralization of the trialkoxysilane, leading to the induction of apoptosis pathway, Thereby completing the invention.

KR 10-2015-0109540E (2015.10.02)

 Reznikov, N .; Steele, J. A. M .; Fratzl, P .; Stevens, M. M., Nature Reviews Materials 2016, 1 (8), 16041.  Mahamid, J .; Sharir, A .; Gur, D .; Zelzer, E .; Addadi, L .; Weiner, S., J. Struct Biol 2011, 174 (3), 527-35.  Zhao, R .; Wang, B .; Yang, X .; Xiao, Y .; Wang, X .; Shao, C .; Tang, R., Angew Chem Int Ed Engl 2016, 55 (17), 5225-9.  Wei, Y .; Yin, G. F .; Ma, C. Y .; Liao, X. M .; Chen, X. C .; Huang, Z. B .; Yao, Y. D.,. Med Hypotheses 2013, 81 (2), 169-171.  Rajendran, L .; Knolker, H. J .; Simons, K., Nat Rev Drug Discov 2010, 9 (1), 29-42.  Xu, W .; Zeng, Z .; Jiang, J. H .; Chang, Y. T .; Yuan, L., Angew Chem Int Ed Engl 2016, 55 (44), 13658-13699.  Smith, R. A .; Hartley, R. C .; Cocheme, H. M .; Murphy, M. P., Trends Pharmacol Sci 2012, 33 (6), 341-52.  Yanmada, Y .; . Harashima, H., Adv. Drug Deliv. Rev 2008, 60, 1439-1462.  Smith, R. A .; Porteous, C. M.; Gane, A. M .; Murphy, M. P., Delivery of bioactive molecules to mitochondria in vivo. Adv. Drug Deliv. Rev 2003, 100 (9), 5407-5412.  Wang, H .; Feng, Z .; Wang, Y .; Zhou, R .; Yang, Z .; Xu, B., J Am Chem Soc 2016, 138 (49), 16046-16055.  Kuno, T .; Nonoyama, T .; Hirao, K .; Kato, K., Langmuir, 2011, 27, 13154-13158.

Accordingly, the present inventors have found that a compound in which trialkoxysilane, which is a triphenylphosphonium (TPP) and biomineralization-inducing moiety, is bonded to a silica particle through biocatalytic activity in cancer cell mitochondria The present invention has been completed based on this finding.

Accordingly, it is an object of the present invention to provide a biochemical inducing compound of a cancer cell mitochondrial target.

It is still another object of the present invention to provide a therapeutic agent for cancer comprising the above compound as an active ingredient.

In order to accomplish the above object, the present invention provides a mitochondrial penetrating moiety, triphenylphosphonium (TPP); And a trialkoxysilane moiety that is a biomineralization inducing moiety; or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method for producing a mitochondrial targeting moiety comprising the step of linking a mitochondrial penetrating moiety, triphenylphosphonium, to a trialkoxysilane, which is a biomineralization inducing moiety, by a linking moiety or without a linking moiety ≪ / RTI >

In a preferred embodiment of the present invention, the trialkoxysilane may be triethoxysilane.

In a preferred embodiment of the present invention, the TPP and trialkoxysilane are connected by a connecting moiety, and the connecting moiety may be a peptide linker.

In a preferred embodiment of the present invention, the compound may be triethoxypropylsilane-triphenylphosphonium having the structure of Formula 1:

[Chemical Formula 1]

.

.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises the mitochondria-targeted compound as an active ingredient.

In addition, the present invention provides a health functional food for cancer prevention or improvement, which contains the mitochondria-targeted compound as an active ingredient.

According to a preferred embodiment of the present invention, the compound can form silica particles through biomassification in the range of pH 7.0 to pH 10.0.

In a preferred embodiment of the present invention, the compound may be contained at a concentration of 1 to 50 mM.

In one preferred embodiment of the present invention, the cancer may be at least one selected from the group consisting of prostate, cervical cancer, breast cancer, liver cancer, gastric cancer, esophageal cancer, nasopharyngeal cancer, skin cancer and lung cancer.

Accordingly, the present invention relates to a mitochondrial penetrating moiety, triphenylphosphonium (TPP); And trialkoxysilane, which is a biomineralization-inducing moiety, to provide a mitochondrial targeted compound.

The mitochondria-targeted compound of the present invention can enter and accumulate in the mitochondria of cancer cells by TPP, which is a mitochondrial penetration-enhancing moiety. Thus, silica particles are formed by the mineralization of trialkoxysilane, And the cancer cell death effect can be shown. Since the mitochondria of cancer cells show basic conditions and the compounds of the present invention can effectively form silica particles, the accumulation and mineralization of the compounds of the present invention in the mitochondria of the present invention are not significantly induced in normal cells, Can be usefully used.

1 is a schematic diagram showing a process in which a compound of the present invention accumulates in the cancer cell mitochondria and exhibits a cancer cell killing effect through bioconversion.
Figure 2 shows the preparation of cancer cell-specific biochemical inducing compounds:
2A is a diagram showing a process of synthesizing trialkoxypropyl silane-TPP; And
2B is a diagram showing the structures of the compounds 1 and 2 of the present invention.
Figure 3 shows the structural analysis of triethoxypropane-triphenylphosphonium (Compound 1): < RTI ID = 0.0 >
Figure 3a is a ¹ H NMR spectrum of compound 1; Figure 3b is a ¹³ C NMR spectrum of compound 1; And Fig. 3C are ESI-MS results for confirming the molecular weight of Compound 1. Fig.
Figure 4 shows the structural analysis of trimethylpropyl-triphenylphosphonium (compound 2): < RTI ID = 0.0 >
4A is a ¹ H NMR spectrum of compound 2; Figure 4b is a ¹³ C NMR spectrum of compound 2; And FIG. 4C are MALDI-TOF results for confirming the molecular weight of the compound 2. FIG.
Figure 5 shows confirmation of the silification conditions of the compounds that induce mineralization:
Figure 5a shows the effect of silica particles formation of Compound 1 and Compound 2 on various pH conditions and various concentrations;
FIG. 5B is a TEM analysis result showing formation of silica particles in a medium containing 40 mM Compound 1; FIG. And
FIG. 5C is a TEM analysis showing the formation of silica particles in a medium containing 1 mM Compound 1. FIG.
6 shows the results of confirming the degree of depolarization of cancer cell mitochondria by triethoxypropylsilane-TPP:
6A is the result of TMRM analysis of Hek293T cells as normal cells; FIG. 6B shows the results of TMRM analysis of cancer cell host SCC7 cells; FIG. 6C shows the results of TMRM analysis of Hek293T cells after treating 40 μM Compound 1 for 5 hours; FIG. Figure 6d shows the results of TMRM analysis of SCC7 cells after treating 40 μM Compound 1 for 5 hours; And FIG. 6E are the results of TMRM analysis according to time after treatment of 40 μM compound 1 with SCC7 cells.
FIG. 7 shows the result of confirming the effect of mitochondrial depolarization reduction in HeLa cells at 75 μM compound 1.
Fig. 8 shows the results of confirming ROS production in SCC7 cell mitochondria by triethoxypropylsilane-TPP. Fig.
8A is a result of confirming ROS generation using a Mito-sox kit; And FIG. 8B are results of confirming ROS generation using TMSP.
9 shows the results of confirming the production of ROS in HeLa cell mitochondria by triethoxypropylsilane-TPP:
Figure 9a is a fluorescence microscopy result to confirm ROS production in mitochondria; And Fig. 9B is an enlarged image of the results of the fluorescence microscope.
Figure 10 shows the confirmation of the effect of triethoxypropylsilane-TPP on the production of silica particles in cancer cell mitochondria:
FIG. 10A is a TEM image showing the silica particles produced in the mitochondria of Hek293T cells treated with 10 μM Compound 1; FIG. FIG. 10B is a magnified view of FIG. 10A; FIG.
FIG. 10C is a TEM image showing the silica particles produced inside the mitochondria of SCC7 cells treated with 10 μM Compound 1; FIG. FIG. 10D is a result of enlarging the FIG. 10C;
Figure 10E is a TEM image of SCC7 cells without Compound 1 treatment; And Fig. 10F are ICP-OES results for the quantitative analysis of silica particles produced in Hek293T cells and SCC7 cells treated with 25 [mu] M Compound 1 for 48 hours.
FIGS. 11 and 12 show the cell viability of the compound 1 in the mitochondrial biomineralization reaction in various cancer cell lines:
Figure 11a shows cell viability for SCC7 cells; Figure 11b shows cell viability for MDA-MB-468 cells; Figure 11C shows cell viability for HeLa cells; Figure 11d shows cell viability for KB cells; Figure 11E shows cell viability for PC3 cells; Figure 11f shows cell viability for SNU-620-ADR cells; Figure 11g shows cell viability for MCF7 / ADR cells; Figure 11h shows cell viability for Hek293T cells; And Fig. 11i show cell viability for NH-3T3 cells.
Figure 12a shows cell viability for MDA-MB-231 cells; Figure 12b shows cell viability for SKBR3 cells; And Fig. 12C shows cell viability for KB cells.
Figure 13 shows the cell viability by biomineralization in mitochondria of Compound 2 in various cancer cell lines:
Figure 13a shows cell viability for SCC7 cells; Figure 13b shows cell viability for HeLa cells; And Fig. 13C shows cell viability for Hek293T cells.
14 and 15 show confirmation of apoptosis by mitochondrial biochemical reaction:
14A is a fluorescence microscope image of HeLa cells treated with Compound 1 and stained with Annexin-V-FITC / PI for 24 hours;
14B is a fluorescence microscope photograph of Hek293T cells treated with Compound 1 and stained with Annexin-V-FITC / PI for 24 hours.
15A is the result of flow cytometry analysis of SCC7 cells not treated with compound;
FIG. 15B shows the result of flow cytometry of SCC7 cells treated with Compound 1 and cultured for 24 hours; And Fig. 15C are results of flow cytometry analysis of SCC7 cells treated with Compound 1 and incubated for 48 hours.
16 shows the confirmation of the tumor growth inhibitory effect by the biomineralization reaction in vivo:
16A shows the results of comparing tumor tissue size changes when Compound 1 or Compound 2 was administered to a tumor model mouse; And
FIG. 16B shows the result of confirming weight change in the tumor model mouse group.

Hereinafter, the present invention will be described in detail.

As described above, studies for applying bioconversion to cancer treatment continue, but there are limitations in effectively inducing bioconversion in order to reduce side effects at specific sites, and research on this has continued.

The mitochondria-targeted compound of the present invention can enter and accumulate in the mitochondria of cancer cells by TPP, which is a mitochondrial penetration-enhancing moiety. Thus, silica particles are formed by the mineralization of trialkoxysilane, And the cancer cell death effect can be shown. Since the mitochondria of cancer cells show basic conditions and the compounds of the present invention can effectively form silica particles, the accumulation and mineralization of the compounds of the present invention in the mitochondria of the present invention are not significantly induced in normal cells, Can be usefully used.

Accordingly, the present invention relates to a mitochondrial penetrating moiety, triphenylphosphonium (TPP); And a trialkoxysilane moiety that is a biomineralization inducing moiety; or a pharmaceutically acceptable salt thereof.

In the mitochondria-targeted compound of the present invention, "mitochondria penetrating moiety" "triphenylphosphonium (TPP)" has a lipophilic property due to three phenyl groups and is a cationic compound, And that it can be targeted.

In the mitochondria-targeted compounds of the present invention, the "mineralization inducing moiety" trialkoxysilane "forms a silsesquioxane, which is a silicon compound of an organic substance, through hydrolysis and condensation under basic or acidic conditions . The alkoxy group in the trialkoxysilane is preferably C1 to C10, and may be C1 to C3. More specifically, C2 is triethoxysilane, but it is not limited thereto. However, if the alkoxy group becomes too long, the reaction may not proceed effectively in the step of entering the mitochondria or forming the silica particles through the biomassification.

In the mitochondria targeted compounds of the present invention, "triphenylphosphonium (TPP)" and "trialkoxysilane" may be connected by a linking moiety. In this case, the linking moiety may be a structure that can be selected by a person skilled in the art such as a peptide linker or a carbon chain, but it is more preferably a peptide linker.

The most preferred structure of the mitochondria-targeted compounds of the present invention is triethoxypropylsilane-TPP, which is a structure of the following Formula 1:

[Chemical Formula 1]

.

.

Also provided is a method for producing a mitochondrial targeted compound comprising the step of linking a mitochondrial penetrating moiety, triphenylphosphonium, to a trialkoxysilane, a biomineralization inducing moiety, by a linking moiety or linking moiety And a manufacturing method thereof.

More specifically, as a representative example of the above-mentioned " linking by a linking moiety ", it can be synthesized through a dicyclohexylcarbodiimide (DCC) reaction. According to this, it is most preferred that the method for producing the mitochondria-targeted compound of the present invention comprises the steps of a) to c) below:

a) (4-carboxybutyl) triphenylphosphonium bromide, dicyclohexylcarbodiimide and 4-dimethylaminopyridine were dissolved in 20 ml of DCM to prepare a mixed solution. ;

b) adding 3-aminopropyltrialkoxysilane to the mixed solution and stirring to react;

c) removing the residue from the reacted reaction solution and obtaining the compound via chromatographic purification.

In a specific embodiment of the present invention, the present inventors intend to prepare a compound capable of inducing biocatalysis while being capable of targeting mitochondria, including TPP as a mitochondrial target moiety and tripeptide Triethoxypropylsilane-triphenylphosphonium (Compound 1) containing methoxypropylsilane was designed and synthesized (Figs. 1 to 4).

As a result of confirming that the synthesized Compound 1 can form silica particles by the mineralization, it was confirmed that Compound 1 of the present invention can form silica particles in a concentration-dependent manner in an aqueous solution under basic conditions ).

The inventors of the present invention confirmed that the compound 1 synthesized was able to target the cancer cell mitochondria significantly, and as a result, the compound 1 of the present invention was significantly accumulated in the mitochondria of the cancer cells. Thus, the silica particles produced in the mitochondria, (FIG. 6 and FIG. 7), inducing ROS production inside the mitochondria and inducing an increase in mitochondrial stress (FIGS. 8 and 9).

In addition, the present inventors confirmed that Compound 1 synthesized can form silica particles intracellularly, and as a result, it was confirmed through TEM image analysis that Compound 1 could accumulate in mitochondria of cancer cells to form silica particles ( 10).

In addition, the inventors of the present invention confirmed that the compound 1 synthesized can induce cancer cell death by inducing the formation of silica particles in the mitochondria to increase the stress, and as a result, the cell survival rate (Figs. 11 and 12). In contrast, it was confirmed that trimethylpropylsilane-TPP (Compound 2, Comparative Example) synthesized to have a methyl group other than an ethoxy group did not exhibit significant cytotoxic effects in cancer cells and normal cells (FIG. 13).

Furthermore, the present inventors have confirmed that Compound 1, which has been synthesized, decreases the cell survival rate of cancer cells. As a result, when compound 1 is treated, apoptosis of cancer cells can be induced, (Fig. 14 and Fig. 15).

In addition, the inventors of the present invention have confirmed that when the compound 1 is administered, the compound 1 can inhibit tumor growth significantly in vivo. As a result, when the compound 1 is treated, the tumor size of the tumor mouse model does not grow, (Fig. 16).

Accordingly, the present invention relates to a mitochondrial penetrating moiety, triphenylphosphonium (TPP); And trialkoxysilane, which is a biomineralization-inducing moiety, to provide a mitochondrial targeted compound.

The mitochondria-targeted compound of the present invention can enter and accumulate in the mitochondria of cancer cells by TPP, which is a mitochondrial penetration-enhancing moiety. Thus, silica particles are formed by the mineralization of trialkoxysilane, And the cancer cell death effect can be shown. Since the mitochondria of cancer cells show basic conditions and the compounds of the present invention can effectively form silica particles, the accumulation and mineralization of the compounds of the present invention in the mitochondria of the present invention are not significantly induced in normal cells, Can be usefully used.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises the mitochondria-targeted compound as an active ingredient.

The above compound can form silica particles through biomassification in the range of pH 7.0 to pH 10.0, and it is possible to form significant silica particles in a basic environment having a pH range of 8.0 or more. In addition, it is preferably contained at a concentration of 1 to 50 mM, more preferably at a concentration of 10 to 50 mM, but is not limited thereto.

In the pharmaceutical composition for preventing or treating cancer according to the present invention, it is preferable that the cancer is any one or more selected from the group consisting of prostate, cervical cancer, breast cancer, liver cancer, gastric cancer, esophageal cancer, And is not limited, and any cancer that can be treated with an anticancer agent can be applied without limitation.

The compound of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the invention can be prepared by a conventional method, for example by dissolving the mitochondria-targeted compound of the present invention in an excess of an aqueous acid solution and treating the salt in a water-miscible organic solvent such as methanol, ethanol, Followed by precipitation using nitrile. It is also possible to prepare an equal amount of mitochondria-targeted compound and an acid or alcohol in water by heating, followed by evaporating the mixture to dryness or by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In addition, the mitochondria-targeted compounds of the present invention include all salts, hydrates and solvates which can be prepared by conventional methods, as well as pharmaceutically acceptable salts.

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

When the composition of the present invention is used as a medicine, the pharmaceutical composition comprising the compound of the present invention may be formulated into various oral or parenteral dosage forms at the time of clinical administration, but the present invention is not limited thereto.

Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and elixirs. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, (E.g., silica, talc, stearic acid and magnesium or calcium salts thereof and / or polyethylene glycols), such as, for example, water, rosin, sucrose, mannitol, sorbitol, cellulose and / or glycine. The 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.

The pharmaceutical composition containing the compound of the present invention of the present invention can be administered parenterally, and parenteral administration is by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this case, the compound of the present invention may be prepared into a solution or suspension by mixing the compound of the present invention together with a stabilizer or a buffer in water to formulate the composition for parenteral administration, and may be prepared into an ampule or vial unit dosage form. The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

The dose of the compound of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity. In general, when referring to an adult patient weighing 60 kg, And may be 0.01 to 500 mg / day, preferably 0.01 to 500 mg / day, and may be administered once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.

In addition, the present invention provides a health functional food for cancer prevention or improvement, which contains the mitochondria-targeted compound as an active ingredient.

The above compound can form silica particles through biomassification in the range of pH 7.0 to pH 10.0, and it is possible to form significant silica particles in a basic environment having a pH range of 8.0 or more. In addition, it is preferably contained at a concentration of 1 to 50 mM, more preferably at a concentration of 10 to 50 mM, but is not limited thereto.

In the pharmaceutical composition for preventing or treating cancer according to the present invention, it is preferable that the cancer is any one or more selected from the group consisting of prostate, cervical cancer, breast cancer, liver cancer, gastric cancer, esophageal cancer, And is not limited, and any cancer that can be treated with an anticancer agent can be applied without limitation.

The food composition according to the present invention can be prepared in various forms according to a conventional method known in the art. Common foods include but are not limited to beverages (including alcoholic beverages), fruits and processed foods (eg, canned fruits, jam, maamalade, etc.), fish, meat and processed foods (Eg butter, chewing), edible vegetable oil, margarine (such as corn oil, etc.), breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), juice, various drinks, cookies, , Vegetable protein, retort food, frozen food, various kinds of seasoning (e.g., miso, soy sauce, sauce, etc.). The nutritional supplement may be prepared by adding the compound of the present invention to capsules, tablets, rings and the like. The health functional food is not limited thereto. For example, the compound of the present invention itself may be prepared in the form of tea, juice, and drink to be liquefied, granulated, encapsulated, can do. In order to use the compound of the present invention in the form of a food additive, it may be prepared in the form of powder or concentrate. In addition, the compound of the present invention may be mixed with a known active ingredient known to have an anticancer effect to prepare a composition.

When the compound of the present invention is used as a health drink, the health beverage composition may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose; Polysaccharides such as dextrin, cyclodextrin; Xylitol, sorbitol, erythritol, and the like. Sweeteners include natural sweeteners such as tau Martin and stevia extract; Synthetic sweetening agents such as saccharin and aspartame, and the like can be used. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 mL of the composition of the present invention.

In addition, the compound of the present invention may be contained as an active ingredient of a food composition for cancer prevention and improvement, and the amount thereof is not particularly limited, but is preferably 0.01 To 100% by weight. The food composition of the present invention can be prepared by mixing together with other active ingredients known to be effective in compositions for preventing and improving cancer.

In addition to the above, the health food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acid, protective colloid thickener, pH adjusting agent, Glycerin, an alcohol or a carbonating agent, and the like. In addition, the health food of the present invention may contain natural fruit juice, fruit juice drink, or pulp for the production of vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

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.

Production of compounds that induce cancer cell-specific biochemicalization

<1-1> Compound 1: Synthesis of triethoxypropylsilane-triphenylphosphonium (TPP)

The cancer cell-specific biochemical induction compound of the present invention was synthesized through dicyclohexylcarbodiimide (DCC) reaction as shown in FIG. 2A.

Specifically, (4-carboxybutyl) triphenylphosphonium bromide (1.00 g, 2.26 mmol), dicyclohexylcarbodiimide (0.560 g, 2.71 mmol) and 4-dimethylaminopyridine (4-Dimethylaminopyridine) (0.055 g, 0.450 mmol) was dissolved in 20 mL of DCM. Then, 3-aminopropyltriethoxysilane (0.5 g, 2.26 mmol) was added to the mixture. The mixture was stirred at room temperature for 5 hours, and the mixture was mixed. After filtration, the residue was removed and purified using size exclusion chromatography. The compound obtained after purification was referred to as Compound 1 as triethoxypropylsilane-TPP. The compound 1 was a yellow oily phase and the yield was 0.703 g (55%). The obtained Compound 1 was subjected to H 1 NMR, C 13 NMR and ESI-MS analyzes to analyze the molecular weight and the molecular structure (FIGS. 3A to 3 C). As a result, it was confirmed that the compound was a compound having the structure of the following formula :

[Chemical Formula 1]

.

.

NMR analysis results are as ^{follows: 1 H NMR (400 MHz,} CDCl 3): δ0.6 (t, 2H), 1.22 (t, 9H), 1.26 (m, 2H), 1.56-1.71 (m, 4H) (M, 2H), 1.94 (m, 2H), 2.71 (t, 2H), 3.17 (q, 2H), 3.70 (t, 2H), 3.81 ) ¹³ C NMR (400 MHz, CDCl ₃ ):? 7.94, 18.34, 22.91, 26.06, 34.11, 42.24, 58.34, 117.75, 118.60, 130.41, 133.62, 135.05, 172.72. ESI-MS: 567.12 [M] &lt;

<1-2> Compound 2: Synthesis of trimethylpropylsilane-triphenylphosphonium (TPP)

Compound 2 was synthesized for use as Compound 1 and as a control. (4-carboxybutyl) triphenylphosphonium bromide (1.01 g, 2.28 mmol), dicyclohexylcarbodiimide (0.565 g, 2.74 mmol) and 4-dimethylaminopyridine (4-carboxybutyl) triphenylphosphonium bromide -Dimethylaminopyridine (0.055 g, 0.450 mmol) was dissolved in 20 mL of DCM. Then, 3-aminopropyltriethoxysilane (0.3 g, 2.28 mmol) was added to the mixture. After the mixture was stirred at room temperature overnight, the mixture was mixed and then filtered to remove the residue and purified using size exclusion chromatography. The compound obtained after purification was referred to as Compound 2 as trimethylpropylsilane-TPP. H1 NMR, C13 NMR, and MALDI-TOF analyzes were performed on the obtained compound 2 to analyze molecular weight and molecular structure (FIGS. 4A to 4C).

Compound 2 was a yellow oily phase and the yield was 0.739 g (68%). The results of NMR analysis are as follows: (400 MHz, CDCl ₃ ):? 0.01 (s, 9H) 0.45 (t, 2H), 1.25 (m, 2H), 1.56-1.71 2H), 2.56 (t, 2H ), 3.65 (q, 2H), 7.67-7.81 (m, 15H), 8.22 (t, 1H) 13 C NMR (400MHz, CDCl 3): δ 0.13, 15.86, 24.72, 27.67 , 35.01, 53.20, 119.21, 120.18, 132.31, 135.34, 136.83, 174.64. MALDI-TOF: 476.29 [M].

<1-3> Induction of silicification reaction of a compound inducing mineralization

The present inventors have anticipated that among the synthesized compounds, the trialkoxysilane component can form silsesquioxane, which is a silicon compound of an organic matter, through hydrolysis and condensation reaction in an aqueous solution. Thus, the trialkoxysilane- The TPP compound induced the silylation reaction with silica particles.

Specifically, Compound 1 or Compound 2 synthesized in Examples <1-1> and <1-2> was dissolved in ammonium buffer solution of pH 8.0 at a concentration of 1 mM, 10 mM or 40 mM, For 72 hours to induce a silylation reaction. In order to confirm the difference in the degree of silicification reaction depending on the pH of the surrounding environment, the silicification reaction was also induced in the same manner as in the ammonium buffer solution of pH 7.4. The degree of silica particles generated by the silicidation reaction was confirmed by measuring the light scattering intensity by performing dynamic light scattering (DLS).

As a result, as shown in FIG. 5A, compound 1 (triethoxypropylsilane-TPP) significantly increased light scattering intensity over time at concentrations of 10 mM and 40 mM and stored in buffer solution for 72 hours , Respectively, indicating light scattering signals of 180 kcps and 200 kcps, respectively. In addition, it was confirmed that the light scattering signal was not significantly increased at 1 mM concentration, and it was only a signal of 2 kcps even when stored in the buffer solution for 72 hours. Thus, in order for the compound of the present invention to form silica particles Dependent response.

In contrast, Compound 2 (trimethylpropylsilane-TPP) did not significantly increase the light scattering intensity even at a concentration of 40 mM, confirming that silica particles were not formed significantly when no alkoxy groups were present in the compound (Fig. 5A).

When the silicate reaction was induced in the buffer solution of pH 7.4 in order to check whether there was a difference in the formation of the silica particles according to the pH change, it was confirmed that the scattering light intensity was lower in the buffer solution of pH 7.4 than the buffer solution of pH 8.0, It was confirmed that dehydration condensation can be promoted under basic conditions (Fig. 5A). This difference is confirmed by the fact that the trialkoxysilane maintains a stable structure under conditions of low neutral and ionic concentrations while silica particles are formed due to the catalytic dehydration condensation under acidic or basic conditions, The mitochondrial matrix of the cancer cells showed basic conditions of about pH 8.0, and it was confirmed that the compounds of the present invention can induce the biochemical reaction significantly when introduced into the cancer cell mitochondria.

&Lt; 1-4 > Observation of the silica particles formed by the silylation-induced compound 1

When Compound 1 formed silica particles, TEM imaging analysis was performed to observe the size and morphological characteristics of the formed silica particles.

To form the silica particles under the conditions as described in Example 1-3, 40 mM of Compound 1 was dissolved in pH 8.0 ammonium buffer solution and stored at 37 DEG C for 72 hours. Then, one drop of the buffer solution was added to 300- Moisture was evaporated by dripping on a mesh coated formvar / carbon coated copper plate and drying at atmospheric conditions. The samples were observed using JEM-1400 at 120 kV. The TEM results were analyzed using the Gatan Digital Micrograph program.

As a result, it was confirmed that silica particles having an average diameter of 800 nm could be produced in the buffer solution in which Compound 1 was dissolved at a concentration of 40 mM as shown in Figs. 5B and 5C (Fig. 5B). In contrast, it was confirmed that particles having a diameter of 200 nm were rarely formed in the buffer solution in which Compound 1 was dissolved at a concentration of 1 mM (FIG. 5C).

Triethoxypropylsilane - TPP  Of Cancer Cells by Mitochondria

<2-1> Triethoxypropylsilane - TPP  Of Cancer Cells by Mitochondria depolarization  Check the degree

When depolarization is induced in the mitochondrial inner membrane, apoptosis is induced and the cell can be killed. The present inventors predicted that when triethoxypropylsilane-TPP is targeted to cancer cell mitochondria and then formed silica particles through the biomineralization reaction, depolarization is induced in mitochondria and cancer cells can be killed. In order to confirm this, the present inventors have identified compound 1 accumulated in the mitochondria using tetramethylrhodamine methyl ester (TMRM) in which red fluorescence is controlled by depolarization of the mitochondrial membrane.

Specifically, mouse squamous cell carcinoma cell SCC 7 cells or normal cells, control cells, were inoculated with fibroblast HEK 293T cells into a Lab Tek II four well slide chamber and cultured to a cell saturation of 60-80%. At this time, the culture medium was RPMI or RPMI medium supplemented with 10% fetal bovine serum (FBS; Life Technologies) and 1% penicillin / streptomycin (Life Technologies) and cultured in a 5% CO ₂ incubator at 37 ° C. When the degree of cell saturation reached 60 to 80%, 200 nM TMRM was added to label the cells, and 40 [mu] M of Compound 1 or Compound 2 was added and incubated for 5 hours. As a solvent control, DMSO was added instead of the compound. It was then analyzed over time with an FV1000 laser confocal microscope. As a negative control, only PBS without compound 1 was treated.

As a result, as shown in FIGS. 6a to 6e and 7, it was confirmed that red fluorescence was significantly exhibited in SCC7 cells treated with PBS alone, and it was confirmed that depolarization was not observed in the mitochondrial inner membrane (FIG. 6b) In the cells treated for 5 hours, depolarization was observed and it was confirmed that the red fluorescence completely disappeared (Fig. 6d). However, Hek293T cells labeled with TMRM were found to produce similar fluorescence in all cases, with or without treatment of Compound 1 (Fig. 6A and Fig. 6C), and Compound 1 could accumulate selectively only within the mitochondria of cancer cells Respectively. In addition, HeLa cells were treated with 75 μM of Compound 1 instead of SCC7 cells. As a result, depolarization of the mitochondrial inner membrane was observed over time (FIG. 7).

When Compound 2 was added, it was confirmed that red fluorescence appeared bright even when 40 μM Compound 2 was treated for 5 hours in SCC7 cells. Therefore, only in the case of Compound 1 having alkoxy group, significant mineralization was induced And it is possible to induce depolarization inside the mitochondria.

< 2-2> Triethoxypropylsilane - TPP  Cancer cells by mitochondria ROS  Verification of generation

Overexpression of ROS in the cells may cause mitochondrial membrane damage, DNA damage and protein breakdown. The present inventors have confirmed the degree to which ROS is generated in the mitochondria as Compound 1 of the present invention forms silica particles inside the mitochondria.

Specifically, SCC7 and HeK293T cells were inoculated and cultured in RPMI and DMEM medium supplemented with 10% FBS and 1% penicillin / streptomycin to a 90% saturation concentration in a Lab Tek II two well chamber cover glass. The medium was treated with 40 μM of Compound 1 or Compound 2 and cultured, and viable cells were identified according to the protocol provided by the manufacturer (Mito-SOX kit, M36008). Then, the cell culture medium was added with 1 to 2 ml of the Mito-SOX reagent so that the final concentration would be 5 [mu] M. The cells were incubated in a dark room at 37 ° C for 10 minutes, then the medium was removed, washed, and analyzed by FV1000 laser confocal microscopy. In addition, dihydroethidium (DHE) analysis was performed to determine the cytotoxicity associated with ROS (Santa Cruz, SC-204724A). DHE was analyzed by FV1000 laser confocal microscopy.

Confocal image analysis using DHE analysis revealed that red fluorescence was strongly emitted when Compound 1 was treated and cultured for 30 minutes as shown in FIG. 8A, in the presence of ROS. In addition, when the production level of ROS was confirmed using Mito-sox, it was confirmed that red fluorescence was brightened when Compound 1 was treated to produce ROS (Fig. 8A). When ROS production level was confirmed using TMSP in addition to Mito-sox, it was confirmed that ROS was produced when 40 μM of Compound 1 was treated (or 8b). In addition, the HeLa cell line was treated with 25 μM of Compound 1 and cultured for 38 hours, followed by Mito-sox staining. As a result, it was confirmed that ROS was generated inside the mitochondria (FIGS. 9A and 9B).

In contrast, when Compound 2 was treated under the same conditions, it was confirmed that ROS production and mitochondrial damage caused by ROS were not significantly exhibited. Thus, it was confirmed that Compound 1 forms silica particles in the mitochondria of cancer cells, inducing the production of ROS, thereby inducing mitochondrial damage.

Triethoxypropylsilane - TPP  Identification of the effect of silica particle formation in cancer cell mitochondria

It was confirmed that Compound 1 of the present invention can induce mitochondrial damage significantly in the mitochondria of cancer cells, and it was confirmed whether or not silica particle formation due to biomassification occurs inside the mitochondria.

Specifically, mouse squamous cell carcinoma cell SCC 7 cells or control cells, which are normal cells, were inoculated with the fibroblast HEK 293T cells inoculated on a 15 mm diameter Theramanox cover slip and cultured. The cultured cells were transferred to a 24-well plate at a cell concentration of 50,000 cells / ml and cultured for 24 hours. At this time, the culture medium was RPMI or RPMI medium supplemented with 10% fetal bovine serum (FBS; Life Technologies) and 1% penicillin / streptomycin (Life Technologies) and cultured in a 5% CO ₂ incubator at 37 ° C. After culturing for 24 hours, the medium was replaced with serum-containing medium supplemented with 10 μM of Compound 1 or Compound 2 and further incubated for 72 hours. After 72 hours of culture, the medium was removed and the cells were washed three times with 0.1 M sodium phosphate buffer (pH 7.0). The washed cells were immersed in 0.05 M sodium phosphate buffer (pH 7.0) containing 2% glutaraldehyde and 5% sucrose for 30 minutes to immobilize the cells, and the cells were treated with 0.05 M phosphoric acid containing 5% sucrose And washed three times with sodium buffer solution (pH 7.0) for 30 minutes or more. After washing, the cells were treated with a 0.05 M sodium phosphate buffer solution (pH 7.0) containing 1% Osmium Tetroxide and 5% sucrose for 1 hour to fix. It was then washed three times with distilled water, dehydrated using step diluted acetone, and embedded in epoxy resin. The resin was polymerized at 80 ° C for 12 hours. Ultrathin sections of 70 nm thickness were obtained with a CR-X ultramicrotome and imaged at 120 kV using JEM-1400. When the sample was dyed, 2% acetic acid uranium was added to the surface of the copper plate on which the sample was placed, and the mixture was colored for at least 1 minute. The stained cells were observed using JEM-1400 at 120 kV. The TEM results were analyzed using the Gatan Digital Micrograph program.

As a result, as shown in FIG. 9A and FIG. 9B, the formation of silica particles was not observed in the cells and mitochondria in the normal cell line Hek293T cells, and it was confirmed that the cells maintained their normal shape. On the other hand, it was confirmed that silica particles were formed in mitochondria in cancer cell host SCC7 cells, thus destroying mitochondrial membrane (FIGS. 9C, 9D and 9E). In addition, when the amount of silica particles produced in the cells was quantified, it was confirmed that the silica particles accumulated in SCC7 cells and Hek293T cells were 8.07 pg and 0.783 pg, respectively (Fig. 9f).

Mitochondria Mineralization  Determination of Cancer Cell Death by Reaction

<4-1> Various In Cancer Cells  Identification of cell viability by biochemical reaction in mitochondria

It was confirmed that Compound 1 of the present invention forms silica particles through biomass formation in mitochondria of cancer cells and induces malfunction of mitochondria. Since mitochondria play an important role in maintaining cell function, they are expected to show cytotoxicity against cancer cells by mitochondrial dysfunction due to biomassification.

Specifically, the target cells were PC3 cells, prostate-derived cancer cell hosts; Cervical cancer cell line HeLa cells; Breast cancer cell lines SK BR3, MDA MB 231, MCF7 / ADR and MDA MB 468; Liver cancer cell line SK HEP; SNU-620 ADR, a dox-resistant gastric cancer cell line; KB cell, a non-human cancer cell line; And mouse squamous cell carcinoma cell SCC 7 cells were used. As control cells, HEK 293T and NIH3T3 cells, which are fibroblast cells, were used. Each cell was selected from DMEM, L-15 or RPMI 1640 (Life Technologies) medium and used as a growth medium. The cells were inoculated on a 96-well Nunc plate at a density of 5 × 10 ³ cells per well and cultured in a 5% CO ₂ incubator at 37 ° C. for 24 hours. After incubation, each medium was treated with Compound 1 or Compound 2 at a concentration of 0.1, 2, 3, 5, 10, 15, 20, 25, 30, 35 or 40 μM / well and further incubated for a total of 72 hours. Cell viability was analyzed by Alamar blue assay at 24, 48 and 72 hours after initiation of culture. Fluorescence analysis was performed using a plate reader (Tecan Infinite Series, Germany) set at an excitation wavelength of 565 nm and an emission wavelength of 590 nm.

As a result, as shown in FIG. 11 and FIG. 12, it was confirmed that when the compound 1 was treated in the culture of various cancer cells, it could show significant toxicity. Comparing the cancer cell survival rate with time, it takes time until the compound 1 shows toxicity in the cancer cell line. When the compound 1 is cultured for 24 hours after the treatment, . However, after 72 hours, the cytotoxicity was remarkably increased, and it was confirmed that the IC ₅₀ concentration was 5 to 15 μM for SCC7 cells, MDA-MB-468 cells and HeLa cells (FIGS. 11 11c). These results indicate that Compound 1 of the present invention enters the mitochondria of cancer cells and takes time to form silica particles through biochemical reaction. Compounds 1 showed significant cytotoxicity against PC3 cells and SNU-620-ADR cells predominantly known to be cancer-resistant drug-resistant cancer cells and showed IC ₅₀ values of 10 to 20 μM (FIGS. 11 d to 11 f). However, it was confirmed that the normal cell line did not show cytotoxicity due to no mineralization in mitochondria for Compound 1, and thus it was confirmed that Compound 1 could be used as a target treatment for cancer cells in cancer treatment ( 11g and 11i).

Compared with the cancer cell killing effect of Compound 1, Compound 2 showed no significant cytotoxic effect on both cancer cell lines and normal cell lines, indicating that it did not show significant cancer cell toxicity (Fig. 13).

<4-2> In mitochondria Mineralization  Cell death by reaction ( apoptosis ) Confirm

It was confirmed that Compound 1 of the present invention specifically induced mitochondrial dysfunction by forming biodegradable silica particles in the mitochondria, thereby lowering the cell survival rate.

Specifically, SCC7 cells were inoculated into a Lab Tek II two-chamber chamber cover glass and cultured in RPMI and DMEM medium supplemented with 10% fetal bovine serum (FBS; Life Technologies) and 1% penicillin / streptomycin (Life Technologies) And cultured in a 5% CO ₂ incubator at 37 ° C. When the degree of saturation of the cells reached 90%, Compound 1 or Compound 2 was added at a concentration of 25 μM and cultured for 24 to 48 hours. After incubation, the medium was removed and the cells were washed with ice cold PBS. After washing, the culture medium was replaced with 0.4 ml of Annexin binding buffer containing adexin B and propidium iodide (PI) conjugated with Alexa Fluor 488 and then incubated at room temperature for 15 minutes (Life Technologies, V13241). The stained cells were harvested and analyzed using a flow cytometer (FACS caliber, BD Bioscience). The fluorescence wavelengths in the analyzes were set to 530 nm (ie, FL1) and> 575 nm (ie, FL3).

As a result, when Compound 1 was treated with SCC7 cells, which were cancer cells, and cultured for 24 hours, fluorescence of annexin V was observed, whereas IP color development was not observed, (Fig. 14). As the incubation time progressed, it was confirmed that the late apoptotic stage was progressing 48 hours after the treatment with Compound 1.

In vivo Triethoxypropylsilane - TPP  Inhibition of tumor growth by administration

It was confirmed that Compound 1 of the present invention can induce apoptosis through mitochondrial biocatalysis at the cell level in vitro, and it was confirmed in vivo that Compound 1 of the present invention can inhibit tumor growth.

First, an 8-week-old Balb / c-nu mouse (Orient Bio, Korea) was prepared to construct a tumor mouse model. The SCC7 tumor cell line was also cultured and subcutaneously injected into the mice prepared above. Tumor-bearing tumor mouse models were prepared by raising mice for 2 weeks. Compound 1 or Compound 2 was then administered to a mouse tumor at a dose of 50 mg / kg and bred in the same environment for 2 weeks. The mice were weighed, and the body weight and size of the mice were checked every 3 days and averaged. As a solvent control group, saline alone was administered.

As a result, as shown in FIG. 16, there was no significant change in the body weight of both the compound 1 administration group, the compound 2 administration group and the solvent control group (FIG. 16b), and the compound 2 administration group showed similar tumor volume to the solvent control group . In contrast, the compound 1-treated group showed that the size of the tumor did not grow, confirming that tumor growth was inhibited and significant mineralization was observed in the mitochondria in cancer cells (FIG. 16A).

Claims (12)

delete delete delete delete delete delete Triphenylphosphonium (TPP), a mitochondrial penetrating moiety; And
Triethoxysilane, which is a biomineralization inducing moiety, a mitochondria-targeted compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof, which is bound to the pentamidopropyl linkage A pharmaceutical composition for prevention or treatment of cancer, which is contained as an active ingredient
[Chemical Formula 1]

The pharmaceutical composition for preventing or treating cancer according to claim 7, wherein the compound forms silica particles through biomassing in the range of pH 7.0 to pH 10.0.
The pharmaceutical composition for preventing or treating cancer according to claim 7, wherein the compound is contained at a concentration of 1 to 50 mM.
The pharmaceutical composition for preventing or treating cancer according to claim 7, wherein the cancer is at least one selected from the group consisting of prostate, cervical cancer, breast cancer, liver cancer, stomach cancer, esophageal cancer, nasopharyngeal cancer, skin cancer and lung cancer .
Triphenylphosphonium (TPP), a mitochondrial penetrating moiety; And
Triethoxysilane, which is a biomineralization inducing moiety, which is conjugated with a pentamidopropyl linkage, and which comprises a mitochondria-targeted compound represented by the following formula (1) as an active ingredient, Or health functional food for improvement.
[Chemical Formula 1]

12. The method of claim 11, wherein the cancer is at least one selected from the group consisting of prostate, cervical cancer, breast cancer, liver cancer, gastric cancer, esophageal cancer, nasopharyngeal cancer, skin cancer and lung cancer. .

Images