KR102272993B1 - Adjuvant for anti-cancer containing quinidine derivatives as an active ingredient - Google Patents

Abstract

The present invention relates to an anticancer adjuvant containing a quinidine derivative as an active ingredient, wherein the anticancer adjuvant is administered in combination with anticancer drugs, thereby sensitizing cancer cell death due to ferrotosis, thereby enhancing the anticancer effect of anticancer drugs. , can be usefully used as an anticancer adjuvant.

Description

An anticancer adjuvant containing quinidine derivatives as an active ingredient {Adjuvant for anti-cancer containing quinidine derivatives as an active ingredient}

The present invention relates to an anticancer adjuvant containing a quinidine derivative as an active ingredient.

Ferrotosis (ferroptosis) is a type of apoptosis, characterized by the accumulation of lipid peroxide and iron-related. Ferrotosis is a type of cell death that is morphologically, biochemically and genetically different from apoptosis, necroptosis, and autophagic cell death. Parkinson's disease , Huntington's disease, Alzheimer's disease, dementia, and other degenerative diseases. Ferrotosis is also proposed as a natural mechanism to inhibit tumor growth, since the p53 tumor suppressor gene induces ferrotosis to inhibit tumor growth.

Accordingly, many studies are being conducted to use ferrotosis to develop anticancer drugs, and in particular, ferrotosis is in the spotlight as a method for developing anticancer drugs targeting cancer cells that have resistance to existing apoptosis inducing agents. Cancer cells inhibit ferrotosis through the lipid peroxidase pathway, because inhibiting the lipid peroxidase pathway can induce ferrotosis to eliminate cancer cells.

Currently, ferrotosis inducers are divided into four types. Type 1 ferrotosis inducers work by depriving cells of cysteine, and sulfasalazine (FDA-approved drug) and erastin are type 1 ferrotosis inducers.

The mechanism of action of type 1 ferrotosis inducing agent will be described in detail as follows. GPX (glutathione peroxidase, glutathione peroxidase) has a lipid repair function to avoid ferrotosis by blocking the accumulation of lipid peroxide, glutathione (GSH) is a substrate and cofactor of GPX, and cysteine is a It is a component for biosynthesis. In addition, cystine-glutamate antiporter (transmembrane cystine-glutamate antiporter), System x _c ^- (System x _c ^- ) is a transmembrane that introduces cystine into the cell. Through this cystine influx, cysteine required for GSH synthesis is released. supply Therefore, when cysteine is insufficient, the activity of GPX can be reduced to induce ferrotosis. Type 1 ferrotosis inducers _{inhibit system x c} ⁻ to cause cysteine deficiency, thereby inducing ferrotosis.

The type 2 ferrotosis inducer works by directly inhibiting GPX4, and RSL3, one of the type 2 ferrotosis inducers, covalently interacts with selenocysteine of GPX4, thereby inhibiting the enzymatic activity of GPX4. Type 3 ferrotosis inducers act by causing a shortage of mevalonate derived from coenzyme Q10 (CoQ10). Type 4 ferrotosis inducers act by oxidizing iron to induce further lipid peroxidation. That is, the ferrotosis inducers _{act as targets for system x c} ⁻ , GPX or iron metabolism.

Meanwhile, quinidine is an alkaloid derived from cinchona tree bark, and is a diastereomer of quinine. Quinidine is used as an antiarrhythmic agent and is also an effective modulator of multidrug resistance, but is known to increase the cytotoxicity of the anticancer drug vincristine in relation to cancer. Also, THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 275, No. 45, Issue of November 10, pp. 35256-35263, 2000, it is also known that quinidine inhibits proliferation and induces apoptotic cell death in MCF-7, a breast cancer cell line, but does not disclose that it induces ferrotic apoptosis.

Cancer is a dangerous disease characterized by abnormal cell growth and can spread throughout the body. Types of cancer include childhood liver cancer, breast cancer, colon cancer, lung cancer, bladder cancer, prostate cancer, pancreatic cancer, cervical cancer, brain cancer, stomach cancer, and the like. More than 10 million people worldwide are diagnosed with cancer every year, and it is known that cancer kills more than 6 million people each year. Accordingly, there is a high need to study a method for treating cancer, and in particular, a lot of research on pharmaceutical compositions useful for preventing or treating cancer occurring in humans and other mammals is being conducted.

In particular, the combination administration method for cancer treatment has the advantage of attacking cancer cells through multiple means, and thus is widely used for cancer treatment. Korean Patent Publication No. 10-2014-0097607 discloses a pharmaceutical composition for combination administration for cancer treatment. have done The combined administration method can minimize the toxicity and side effects of the anticancer agent by reducing the amount of the administered anticancer agent while enhancing the efficacy of the anticancer agent, and is also useful when resistance to the anticancer agent is shown. Although many effective combination therapies have been identified over the past few decades, it is important to develop effective combination therapies in light of the continued increase in the number of people dying from cancer each year.

One object of the present invention is to provide an anticancer adjuvant.

Another object of the present invention is an anticancer agent; And to provide a combination preparation for anticancer comprising the anticancer adjuvant.

Another object of the present invention is to provide a pharmaceutical composition for enhancing the efficacy of anticancer drugs.

In order to achieve the above object,

One aspect of the present invention provides an anticancer adjuvant comprising a compound represented by the following Chemical Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

(In Formula 1,

R ¹ is C _1-10 straight-chain or branched alkoxy).

Another aspect of the present invention is an anticancer agent; and

It provides a combination preparation for anti-cancer comprising the anti-cancer adjuvant.

Another aspect of the present invention provides a pharmaceutical composition for enhancing the efficacy of an anticancer agent containing the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The anticancer adjuvant containing the quinidine derivative according to the present invention as an active ingredient is co-administered with anticancer drugs, thereby sensitizing cancer cell death due to ferrotosis, thereby enhancing the anticancer effect of anticancer drugs. It is useful as an anticancer adjuvant. Can be used.

1a is a graph showing that Huh6 and MDA-MB-231 cells were treated with sulfasalazine alone, and cell viability decreased as the concentration increased.
1b is a graph showing that cell viability decreases as the concentration of quinidine increases when Huh6 cells are treated with quinidine alone or co-administered with 300 μM sulfasarazine.
1c is a graph showing that cell viability decreases as the concentration of quinidine increases when MDA-MB-231 cells are treated with quinidine alone or co-administered with 300 μM sulfasarazine.
1d is a photograph showing the morphological change of Huh6 and MDA-MB-231 cells, each of which was treated with vehicle or co-administered with 300 μM sulfasarazine and 10 μM quinidine, and taken 48 hours later.
FIG. 2a is a graph showing that cell viability decreases as the concentration of erastin increases by treating Huh6 cells with erastin alone or co-administering 10 μM quinidine.
FIG. 2b is a graph showing that cell viability decreases as the concentration of erastin increases by treating MDA-MB-231 cells with erastin alone or by co-administering 10 μM quinidine.
Figure 3a is a graph showing that the cell viability decreases as the concentration of RSL3 increases when RSL3 is treated alone or 30 μM quinidine is co-administered to Huh6 cells.
FIG. 3b is a graph showing that cell viability decreases as the concentration of RSL3 increases when RSL3 is treated alone or 30 μM quinidine is co-administered to MDA-MB-231 cells.
FIG. 3c is a graph showing that cell viability decreases as the concentration of RSL3 increases by treating SW620 cells with RSL3 alone or co-administering 30 μM quinidine.
Figure 3d shows that Huh6 cells were treated with either 10 μM or 30 μM quinine, or 0.01 μM or 0.03 μM RSL3 alone, or 10 μM quinine and 0.01 μM RSL3, 10 μM quinine and 0.03 μM RSL3, 30 μM quinine and 0.01 μM RSL3 or 30 μM quinine and It is a graph showing cell viability compared to the case of co-administration of 0.03 μM RSL3 or treatment with vehicle alone.
Figure 4a shows Huh6 cells 300 μM β-mercaptoethanol (β-ME), 10 μM ferrostatin-1 or 10 μM necrostatin-1 (necrostatin-1), which are inhibitors of apoptosis in Huh6 ( n=3~5) was treated 1 hour before, and then 300 μM sulfasarazine and 10 μM quinidine were co-administered, or the vehicle was administered after the pre-treatment, or only the vehicle was administered without the pre-treatment, and the cell viability decreased after 72 hours. It is a graph showing the degree of decrease by comparison.
Figure 4b is a ferrotic apoptosis inhibitor 300 μM β-mercaptoethanol (β-ME), 10 μM ferrostatin-1 (ferrostatin-1) or 10 μM necrostatin-1 in MDA-MB-231 cells. -1) (n = 3-5) was treated 1 hour before, and then 300 μM sulfasarazine and 10 μM quinidine were co-administered, or the vehicle was administered after the pre-treatment, or only the vehicle was administered without the pre-treatment, for 72 hours. It is a graph showing the degree of decrease in cell viability after comparison.
Figure 4c shows Huh6 cells after treatment with 25 μM deferoxamine, 20 μM Z-VAD-FMK, or 10 μM bafilomycin (n=3) (n=3), which are inhibitors of ferrotosis apoptosis, 1 hour before, 300 μM sulfasarazine and 10 μM quinidine are co-administered, the vehicle is administered after the pre-treatment, or only the vehicle is administered without the pre-treatment, and it is a graph showing the degree of decrease in cell viability after 72 hours.
Figure 4d shows MDA-MB-231 cells with 25 μM deferoxamine, 20 μM Z-VAD-FMK, or 10 μM bafilomycin (n=3), which are inhibitors of apoptosis in ferrotosis, for 1 hour. After treatment before, 300 μM sulfasarazine and 10 μM quinidine were co-administered, the vehicle was administered after the pre-treatment, or only the vehicle was administered without the pre-treatment. It is a graph showing the degree of decrease in cell viability after 72 hours.
Figure 5a is shown by administering vehicle, 300 μM sulfasarazine, and 10 μM quinidine alone to Huh6 cells, or co-administering 300 μM sulfasarazine and 10 μM quinidine, and staining the cells with C11-BODIPY dye after 48 hours. The fluorescence intensity of C11-BODIPY is expressed as a histogram, and the level of lipid peroxide is compared and shown.
FIG. 5b is a graph showing the comparison of lipid peroxide levels by quantifying the fluorescence intensity of C11-BODIPY, which is a result of treating Huh6 cells by the method of FIG. 5a.
FIG. 6a shows MDA-MB-231 cells with vehicle, 300 μM sulfasarazine, and 10 μM quinidine alone or with 300 μM sulfasarazine and 10 μM quinidine, 48 hours later, cells with C11-BODIPY dye. It is a graph showing the fluorescence intensity of C11-BODIPY shown by staining with a histogram to compare the level of lipid peroxide.
Figure 6b is a graph showing the comparison of the level of lipid peroxide by quantifying the fluorescence intensity of C11-BODIPY, a result of treating MDA-MB-231 cells by the method of Figure 6a.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides an anticancer adjuvant.

Specifically, it provides an anticancer adjuvant containing a compound represented by the following Chemical Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In Formula 1,

R ¹ is C _1-10 straight-chain or branched alkoxy.

^{R 1} in Formula 1 may be C _1-5 straight-chain or branched alkoxy, C _1-3 straight-chain or branched alkoxy, or methoxy.

Preferred examples of the compound represented by Formula 1 according to the present invention include compounds represented by Formula A or Formula B below:

(One)

[Formula A]

(S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methanol;

(2)

[Formula B]

(R)-(6-Methoxyquinolin-4-yl)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methanol.

The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to prepare pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, isomers, hydrates, and the like, which can be prepared therefrom.

The term “hydrate” refers to a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolec μLar forces. or salts thereof. The hydrate of the compound represented by Formula 1 of the present invention may include a stoichiometric or non-stoichiometric amount of water that is bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably, 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing the compound represented by Formula 1 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

The term “solvate” means a compound of the invention or a salt thereof which contains either a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include solvents that are volatile, non-toxic, and/or suitable for administration to humans.

The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or sterically. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.

In the anticancer adjuvant according to the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations during clinical administration. In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

The anticancer adjuvant can enhance the efficacy of the anticancer agent, and more specifically, by accumulating lipid peroxide, it can sensitize ferrotic cell death (see Experimental Examples 2-5 and Table 1).

Here, the anticancer agent may be a ferrotosis inducing agent, and the ferrotosis inducing agent is commonly known and may be co-administered together without limitation, as long as it is a ferrotosis inducing agent widely known to those skilled in the art, for example, sulfasarazine ( selected from the group consisting of sulfasalazine), erastin, RSL3, sorafenib, ML162, ML210, Butioninesulfoimine, Acetaminophen, Lanperisone and FIN56 It may be administered in combination with one or more ferrotosis inducing agents, but is not limited thereto.

The anti-cancer adjuvant may be administered simultaneously or sequentially with the anti-cancer agent, and when administered sequentially, the anti-cancer agent may be added after the anti-cancer adjuvant is injected, and the anti-cancer adjuvant may be added after the anti-cancer agent is added. However, the administration method is only an example, and the administration method may be changed to enhance the anticancer effect.

The anticancer adjuvant can accumulate lipid peroxides, thereby sensitizing ferrotic cell death, and exhibiting an effect of enhancing the anticancer effect of an anticancer agent (see Experimental Example 4, FIGS. 5b and 6b).

In this case, the anticancer adjuvant may be administered in combination with an anticancer agent to prevent or treat cancer.

The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer , parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Breast cancer, breast cancer, triple negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord Cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood It may be at least one selected from the group consisting of cancer and thymic cancer.

The anticancer adjuvant may be co-administered with a ferrotosis inducing agent-based anticancer agent, and may be co-administered together without limitation, as long as it is a commonly known anticancer agent widely known to those skilled in the art.

At this time, the ferrotosis inducer-based anticancer agent is sulfasalazine, erastin, RSL3, sorafenib, ML162, ML210, butioninesulfoimine, acetaminophen, It may be at least one selected from the group consisting of Lanperisone and FIN56, but is not limited thereto.

Another aspect of the present invention provides a combination preparation for anticancer.

Specifically, it provides an anticancer agent and a combination agent for anticancer comprising the anticancer adjuvant.

The specific description of the anticancer agent, the anticancer adjuvant, and the combination is the same as the specific description of the anticancer adjuvant.

Another aspect of the present invention provides a pharmaceutical composition for enhancing the efficacy of an anticancer agent.

Specifically, it provides a pharmaceutical composition for enhancing the efficacy of an anticancer agent containing a compound represented by Formula 1 below, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

The ^{definition for R 1} in Formula 1 is the same as the specific description for Formula 1 in the anticancer adjuvant.

In addition, the specific description of the pharmaceutical composition for enhancing the efficacy of the anticancer agent is the same as the specific description of the anticancer adjuvant.

Another aspect of the present invention provides a pharmaceutical composition for sensitizing ferrotosis.

Specifically, there is provided a ferrotosis sensitizing pharmaceutical composition comprising a compound represented by the following Chemical Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

The ^{definition for R 1} in Formula 1 is the same as the specific description for Formula 1 in the anticancer adjuvant.

In addition, the specific description of the pharmaceutical composition for enhancing the efficacy of the anticancer agent is the same as the specific description of the anticancer adjuvant.

Another aspect of the present invention provides a method for preventing or treating cancer, comprising administering an anticancer adjuvant and an anticancer agent to a subject in need thereof.

Another aspect of the present invention provides a use of an anticancer adjuvant and an anticancer agent in the prevention or treatment of cancer.

Another aspect of the present invention provides a combination therapy for the treatment of cancer comprising administering an anticancer adjuvant and an anticancer agent to a subject in need thereof.

Quinidine, when used in combination with type 1 and type 2 ferrotosis inducers, promotes pherototic cell death by accumulating lipid peroxides in hepatocellular carcinoma, breast and colon cancer cell lines. Thus, quinidine may be used in combination with _{a type 1 ferrotosis inducer, which induces ferrotosis by inhibiting system x c} ⁻ , or a type 2 ferrotosis inducer, which induces ferrotosis by inhibiting GPX4, to induce ferrotosis. It can be usefully used as a sensitizing anticancer adjuvant. In addition, when quinine, a diastereomer of quinidine, is used together with a type 2 ferrotosis inducing agent, it promotes apoptosis in hepatocellular carcinoma cell lines, so it can be usefully used as an anticancer adjuvant to sensitize ferrotosis. (See Experimental Examples 2-1 to 2-5).

In addition, when the cancer cell lines were treated with quinidine and a ferrotosis-inducing agent in combination, but the ferrotosis apoptosis inhibitor was treated 1 hour before, a decrease in cell viability of cancer cells was prevented. It can be clearly confirmed that cell death was promoted through (see Experimental Example 3).

On the other hand, cancer cells decompose lipid peroxide through the lipid peroxidase pathway and inhibit ferrotosis. By increasing oxidative stress on cancer cells to accumulate lipid peroxide, it can induce ferrototic cell death. Accordingly, the accumulation of lipid peroxide was increased when quinidine and the ferrotosis inducer were administered in combination to the cancer cell lines than when administered alone, so that the combined administration caused a synergistic effect in inhibiting cancer cell proliferation, and quinidine It can be seen that it can be usefully used as an anticancer adjuvant used together with this anticancer agent (see Experimental Example 4)

Hereinafter, the present invention will be described in detail through experimental examples.

However, the experimental examples described below are merely illustrative of the present invention in detail in one aspect, and the present invention is not limited thereto.

< Experimental example 1> Cell culture and reagent processing

Cells used in the following experimental examples were prepared as follows, and were treated with the following reagents.

The hepatoblastic cell line, Huh6, was purchased from the Korean Cell Line Bank (Seoul, Korea). MDA-MB-231, a breast cancer cell line, and SW620, a colon cancer cell line, were obtained from the American Type Culture Collection (Manassas, VA, USA). The cell lines maintained regular confirmation without mycoplasma contamination.

Humidified 5% CO ₂ incubator (5% CO ₂ humidified incubator) in a 37 ℃, Huh6 cells were cultured in DMEM medium, different cells with 10% fetal bovine serum, 2 mM L- glutamine (L-glutamine), 100 Cultured in RPMI-1640 medium containing U/mL penicillin and 100 μg/mL streptomycin. Culture ware, media, and reagents were supplied from Thermo Fisher (Waltham, MA, USA).

Huh6 and MDA-MB-231 cells were cultured at 750 cells per well, and SW620 cells were cultured at 2000 cells per well in 96-well plates. After 24 hours of incubation, sulfasarazine, elastin or RSL3 were treated alone, or they were combined with quinidine or quinine and treated simultaneously. In addition, the cells were cultured in the same manner as above and 24 hours passed, but apoptosis inhibitors β-mercaptoethanol, ferrostatin-1, necrostatin-1 ), treated with chloroquine or Z-VAD-FMK 1 hour before each (pretreatment), and then treated with sulfasarazine, elastin or RSL3 alone, or co-treated with quinidine, or ferrotosis The vehicle was administered without treatment with an inducer and quinidine, or the vehicle was administered without treatment with the above reagents including an apoptosis inhibitor. The reagents were purchased from Millipore Sigma (Burlington MA, USA) or Selectchem (Houston, TX, USA).

< Experimental example 2> quinidine ( quinidine ) and ferrotosis ferroptosis inducers In case of co-administration, ferrototic cell death synergistic effect analysis

To determine whether the co-administration of quinidine and a ferrotosis inducer according to the present invention has a synergistic effect in inhibiting the proliferation of Huh6, hepatoblastic cells, MDA-MB-231, breast cancer, or SW620, colon cancer cells For this purpose, the following experiments were performed, and the results are shown in FIGS. 1A to 3C. In particular _{, it was analyzed whether quinidine sensitizes the system x c} ^- inhibitors sulfasarazine and erastin, and the ferrotic cell death induced by the GPX4 inhibitor RSL3.

In the following experimental examples, cell viability was measured as follows.

Paired control cells were treated with PBS or DMSO as a vehicle, and cell viability was ^{measured by CellTiter Glo ®} assay (Promega, Madison, WI, USA) according to the manufacturer's instructions. Luminescence was ^{measured using an EnVision ®} multimode plate reader (PerkinElmer). Cell death was measured after staining the cells with 1 μg/ml propidium iodide (PI) for 30 minutes in the dark.

Brightness and fluorescence images (excitation/emission maxima at 535/617 nm) were obtained with an EVOS ^TM FL automated imaging system (Thermo Fisher Scientific, Waltham, MA, USA). Synergistic effects were measured using CalcuSyn software (Biosoft, Palo Alto, CA, USA) according to the Chou-Talalay method. Combination index (CI) value of 0.1 to 0.3 indicates strong synergism, 0.3 to 0.7 indicates synergism, and 0.7 to 0.85 indicates relatively moderate synergism. .

In addition, data of the following experimental examples including this experimental example were expressed as mean ± standard deviation (SD), and n denotes the number of individual in vitro experiments for a specific experimental set. P < 0.05 was considered to indicate statistical significance. To compare groups, The mann-Whitney U test and Kruskal-Wallis test were used. Using the Bonferroni method, adjustments were made for multiple comparisons. All statistical analyzes were performed using SPSS for Windows software (Ver. 22; SPSS Inc., Chicago, IL, USA).

( Experimental example 2-1) quinidine and sulfasarazine Comparison between single administration and combination administration

In order to confirm whether the co-administration of quinidine and the ferrotosis inducer according to the present invention has a synergistic effect in inhibiting the proliferation of Huh6, a hepatoblastic cell, and MDA-MB-231, a breast cancer cell, quinidine and sulfa Experiments were performed to compare the cases in which Saran was administered alone and when administered in combination.

An experiment was performed to measure the change in cell viability upon treatment with sulfasarazine alone, and the results are shown in FIG. 1A . Huh6 and MDA-MB-231 cells were treated with sulfasalazine (SASP) alone, and cell viability was measured after 72 hours. In the graph of FIG. 1a, the group treated with sulfasarazine in Huh6 cells is indicated by a circle, and MDA The group treated with -MB-231 cells with sulfasarazine is indicated by a triangle. As the concentration of sulfasarazine to be treated increased, the cell viability of Huh6 and MDA-MB-231 cells decreased. Specifically, IC ₅₀ of sulfasarazine against Huh6 and MDA-MB-231 cells was 350 μM (see FIG. 1a ). ).

This indicates that administration of sulfasarazine alone induces apoptosis in a dose-dependent manner in Huh6 and MDA-MB-231 cells.

Experiments were performed to measure changes in cell viability when quinidine was treated alone and when administered in combination with sulfasarazine, and the results are shown in FIGS. 1B and 1C.

Huh6 and MDA-MB-231 cells were each treated with quinidine alone or co-administered with 300 μM sulfasarazine, and cell viability was measured after 72 hours. However, the vehicle group treated alone was marked in black, and the group in which quinidine and 300 μM sulfasarazine were co-administered was marked in white. As the concentration of quinidine to be treated increased, the cell viability of Huh6 and MDA-MB-231 cells decreased. Specifically, when 10 μM quinidine was administered alone, significant changes in cell viability were observed in Huh6 and MDA-MB-231 cells. and 30 μM quinidine alone reduced the cell viability of Huh6 cells by 50% and the cell viability of MDA-MB-231 cells by 40%. However, when quinidine and 300 μM sulfasarazine were co-administered, when 10 μM quinidine was administered, the cell viability of Huh6 cells was reduced by 90% and the cell viability of MDA-MB-231 cells was reduced by 70%. (see FIGS. 1b and 1c).

This indicates that the effect of inhibiting the proliferation of Huh6 and MDA-MB-231 cells is small when 300 μM sulfasarazine is administered alone, but when administered in combination with quinidine, the ferrotic apoptosis effect is more excellent.

An experiment was performed to confirm cell morphological changes when sulfasarazine and quinidine were co-administered and when vehicle was treated, and the results are shown in FIG. 1D.

Huh6 and MDA-MB-231 cells were treated with vehicle or co-administered with 300 μM sulfasarazine and 10 μM quinidine, respectively, and photographed after 48 hours to show a change in cell morphology, specifically, quinidine and sulfa In the case of co-administration of saline, there was no interaction between cells and cells were reduced and separated compared to the case of vehicle treatment (see Fig. 1d).

This indicates that when sulfasarazine and quinidine are co-administered, there is an effect of inhibiting cell proliferation.

The above results indicate that quinidine and sulfasarazine, when administered in combination, had a better ferrotic apoptosis effect than when administered alone, resulting in a synergistic effect in inhibiting the proliferation of Huh6 and MDA-MB-231 cells. From this, it can be seen that quinidine can be usefully used as an anticancer adjuvant used together with an anticancer agent.

( Experimental example 2-2) Comparison between the case of single administration of erastin and the case of coadministration with quinidine

In order to determine whether the combined administration of quinidine and elastin according to the present invention has a synergistic effect in inhibiting the proliferation of Huh6, a hepatoblastoma cell, and MDA-MB-231, a breast cancer cell, when erastin is treated alone And experiments were performed to measure changes in cell viability when co-administered with quinidine, and the results are shown in FIGS. 2A and 2B. In the above experiments, 3 to 5 independent experiments were performed, and each experiment was performed in triplicate. Data are expressed as mean ± standard deviation.

Huh6 and MDA-MB-231 cells were treated with erastin alone or co-administered with 10 μM quinidine, and cell viability was measured after 72 hours. In the graphs of FIGS. 2a and 2b, cells were treated with only erastin alone. The vehicle group was marked in black, and the group in which elastin and 10 μM quinidine were co-administered was marked in white. In the case of erastin alone, the cell viability of Huh6 and MDA-MB-231 cells was not significantly affected until the dose was 1 μM, and the cell viability of Huh6 and MDA-MB-231 cells was not significantly affected when the dose was 3 μM. decreased by more than 80%. However, when erastin and 10 μM quinidine were co-administered, the cell viability of Huh6 cells decreased by 95% and the cell viability of MDA-MB-231 cells decreased by 50% when 1 μM erastine was administered ( 2a and 2b).

This indicates that erastin alone induces apoptosis in a dose-dependent manner in Huh6 and MDA-MB-231 cells, but when co-administered with 10 μM quinidine, the ferrotic apoptosis effect is superior. The above results indicate that the ferrototic cell death effect was better when erastin was administered in combination with quinidine than when administered alone, indicating that a synergistic effect occurred in inhibiting the proliferation of Huh6 and MDA-MB-231 cells, From this, it can be seen that quinidine can be usefully used as an anticancer adjuvant used together with an anticancer agent.

( Experimental example 2-3) RSL3 Comparison between single administration and co-administration with quinidine

In order to confirm whether the combined administration of quinidine and RSL3 according to the present invention has a synergistic effect in inhibiting the proliferation of Huh6, a hepatoblastoma cell, MDA-MB-231, a breast cancer cell, and SW620, a colon cancer cell, RSL3 alone Experiments were performed to measure changes in cell viability when treated and co-administered with quinidine, and the results are shown in FIGS. 3A to 3C. In the above experiments, 3 to 5 independent experiments were performed, and each experiment was performed in triplicate. Data are expressed as mean ± standard deviation.

Huh6 and MDA-MB-231 cells were treated with RSL3 alone or co-administered with 10 μM quinidine, and SW620 cells were treated with RSL3 alone or co-administered with 30 μM quinidine, and cell viability was measured after 72 hours. However, in the graphs of FIGS. 3A to 3C, the vehicle group in which only RSL3 was treated with cells was indicated in black, and the group in which RSL3 and quinidine were co-administered was indicated in white. RSL3 monotherapy is Huh6, MDA-MB-231 and I ordered suppressed cell viability of SW620 cells at a dose dependent manner, in particular IC ₅₀ for Huh6 cell is 0.05 μM, MDA-MB-231 IC 50 for the cell is in the range of 0.1 μM, IC ₅₀ for SW620 cells was 2.5 μM. However, when Huh6 cells were co-administered with 10 µM quinidine and 0.03 µM RSL3, MDA-MB-231 cells were co-administered with 10 µM quinidine and 0.1 µM RSL3, and SW620 cells were co-administered with 30 µM quinidine and 1 µM. When RSL3 was co-administered, the cell viability of each cell was reduced by more than 70% (see FIGS. 3A to 3C ).

This indicates that RSL3 alone induces apoptosis in a dose-dependent manner in Huh6, MDA-MB-231 and SW620 cells, but when co-administered with quinidine, the ferrotic apoptosis effect is superior. The above results indicate that a synergistic effect occurred in inhibiting Huh6, MDA-MB-231 and SW620 cell proliferation when RSL3 was administered in combination with quinidine rather than when administered alone, and from this, quinidine was combined with an anticancer agent. It can be seen that it can be usefully used as an anticancer adjuvant used.

( Experimental example 2-4) RSL3 When administered alone and quinine ( quinene ) and the case of co-administration

In order to check whether the combined administration of quinine and RSL3, which are diastereomers of quinidine, causes a synergistic effect in inhibiting the proliferation of hepatoblastic cells, Huh6, RSL3 or quinidine alone and RSL3 and quinidine in combination Experiments were performed to measure changes in cell viability when administered, and the results are shown in FIG. 3D . For the above experiments, two independent experiments were performed, and each experiment was performed in triplicate. Data are expressed as mean ± standard deviation.

Huh6 cells were treated with either 10 μM or 30 μM quinine, or 0.01 μM or 0.03 μM RSL3 alone, or 10 μM quinine and 0.01 μM RSL3, 10 μM quinine and 0.03 μM RSL3, 30 μM quinine and 0.01 μM RSL3 or 30 μM quinine and 0.03 μM RSL3 was co-administered, or only vehicle was treated, and cell viability was measured after 72 hours. When 0.01 μM or 0.03 μM RSL3 was administered alone, cell viability was not changed, and when 10 μM quinine was administered alone, cell viability was not significantly changed, but when 30 μM quinine was administered alone, cell viability was 46 % reduced. However, when 0.03 μM RSL3 and 30 μM quinine were administered in combination, the cell viability was reduced by more than 90% (see FIG. 3D ).

This indicates that quinine alone induces apoptosis in a dose-dependent manner in Huh6 cells, but when administered in combination with RSL3, the ferrotic apoptosis effect is superior. The above results indicate that a synergistic effect occurred in inhibiting Huh6 cell proliferation when quinine and RSL3 were administered in combination than when quinine or RSL3 was administered alone, and from this, quinine is useful as an anticancer adjuvant used together with anticancer agents. It can be seen that it can be used

( Experimental example 2-5) sulfa gone , elastin and RSL3 Synergistic effect when administered in combination with quinidine

The following combination index shows the synergistic effect of sulfasarazine, elastin and RSL3 co-administered with quinidine for Huh6 and MDA-MB-231 cells, respectively, from mild (C) to strong (A) It is evaluated and shown, and the synergistic effect when RSL3 and quinidine are co-administered to SW620 cells is evaluated and shown from mild (C) to strong (A) (Table 1).

Combination index Huh6 cells MDA-MB-231 cells SW620 cells Sulfasalazine (μM):quinidine (μM) 300:1 0.703/C 0.967 - 300:3 0.564/B 0.917 - 300:10 0.366/B 0.829/C - 300:30 0.245/A 0.520/B - Elastin (μM):quinidine (μM) 0.1:10 0.447/B 12.403 - 0.3:10 0.606/B 2.081 - 1:10 0.196/A 0.577 /B - 3:10 0.253 / A 0.421/B - RSL3 (μM):quinidine (μM) 0.003:10 0.713/C - - 0.03:10 0.035/A 0.257 / A - 0.1:10 0.100/A 0.133/A 0.311 / B
(RSL3(μM):quinidine=(μM)0.1:30) 0.3:10 0.291 / A 0.318/B 0.576/B
(RSL3(μM):quinidine (μM)=1:30)

In Table 1, the synergistic effect was measured using CalcuSyn software (Biosoft, Palo Alto, CA, USA) according to the Chou-Talalay method. If the combination index (CI) value is 0.1 to 0.3, strong synergism (A), 0.3 to 0.7, synergism (B), and 0.7 to 0.85, moderate synergism. It means that (C) is relatively represented.

Specifically, when a strong synergistic effect (A) appears, when co-administered to Huh6 cells, sulfasarazine (μM):quinidine (μM) = 300:30; when elastine:quinidine=1:10; when elastine:quinidine=3:10; when RSL3:quinidine=0.03:10; when RSL3:quinidine=0.1:10; and RSL3:quinidine=0.3:10; and RSL3:quinidine=0.03:10 when co-administered to MDA-MB-231 cells; and when RSL3:quinidine=0.03:10;

When a synergistic effect (B) is observed, sulfasarazine:quinidine = 300:3 when co-administered to Huh6 cells; when sulfasarazine:quinidine=300:10; when elastine:quinidine=0.1:10; and when erastine:quinidine=0.3:10; and when co-administered to MDA-MB-231 cells, when sulfasarazine:quinidine=300:30; when elastine:quinidine=1:10; when elastine:quinidine=3:10; and RSL3:quinidine=0.3:10; and RSL3:quinidine=0.1:30 when co-administered to SW620 cells; and when RSL3:quinidine=1:30;

When a mild synergistic effect (C) is observed, sulfasarazine:quinidine = 300:1 when co-administered to Huh6 cells; and RSL3:quinidine=0.003:10, and sulfasarazine:quinidine=300:10 when co-administered to MDA-MB-231 cells (see Table 1).

The above results indicate that quinidine has _{the effect of sensitizing ferrotic apoptosis induced by system x c} ^- inhibitors such as sulfasarazine and erastin or GPX4 inhibitors such as RSL3. It can be seen that Dean can be usefully used as an anticancer adjuvant used together with an anticancer agent.

.

< Experimental example 3> quinidine and ferrotosis inducer Determining the type of cell death when co-administered

In order to clearly confirm whether the co-administration of quinidine and a ferrotosis inducer according to the present invention promotes apoptosis through ferrotosis in Huh6, a hepatoblastoma cell, and MDA-MB-231, a breast cancer cell, ferrotosis cells Death inhibitors β-mercaptoethanol (β-mercaptoethanol, β-ME), ferrostatin-1, necrostatin-1, Z-VAD-FMK, deferoxamine Alternatively, an experiment was performed to measure cell viability when co-administered with quinidine and sulfasarazine by adding a process of treating bafilomycin 1 hour before (see Experimental Example 1 and Experimental Example 2), and the The results are shown in Figs. 4a to 4d. In the experiment, 3 to 5 independent experiments were performed, and each experiment was performed in triplicate. Data are expressed as mean ± standard deviation.

To describe the above inhibitors in detail, β-mercaptoethanol is a reducing agent that rescues cells when L-cystine is insufficient due to _{system x c} ^{- inhibition, and ferostatin-1 has radical scavenging activity} is a lipophilic antioxidant that prevents lipid peroxide formation, necrostatin-1 is a RIPK1 inhibitor, Z-VAD-FMK is a pan-caspase inhibitor, and deferoxamine is an iron chelator ( iron chelator), and bafilomycin is an autophagy inhibitor that reduces autophagosome-lysosome fusion. Chemical inhibitors that inhibit apoptosis. If the decrease in cell viability that occurs when co-administering quinidine and a ferrotosis inducer is prevented through such a ferrototic cell death inhibitor, it can be clarified that the combined administration has an effect of inducing ferrototic cell death. .

In Huh6 and MDA-MB-231 cells, 300 μM β-mercaptoethanol (β-ME), 10 μM ferrostatin-1, 10 μM necrostatin-1 (necrostatin- 1) (n=3~5), 25 μM deferoxamine, 20 μM Z-VAD-FMK, or 10 μM bafilomycin (n=3) 1 hour before treatment (pretreatment) , 300 μM sulfasarazine and 10 μM quinidine were co-administered, the vehicle was administered after the pre-treatment, or only the vehicle was administered without the pre-treatment, and the degree of cell viability decreased after 72 hours was measured.

Specifically, compared to the case in which quinidine and sulfasarazine were co-administered without undergoing the pre-treatment, β-mercaptoethanol, ferostatin-1, deferoxamine and necrostatin-1 were pretreated with quinidine and Although reduction in cell viability of Huh6 and MDA-MB-231 cells due to co-administration of sulfasarazine was prevented, when pre-treatment with Z-VAD-FMK or bafilomycin, cells induced by co-administration of quinidine and sulfasarazine killing was not prevented (see FIGS. 4A and 4D ).

When β-mercaptoethanol, ferrostatin-1, deferoxamine and necrostatin-1 were pretreated, reduction in cell viability of Huh6 and MDA-MB-231 cells due to co-administration of quinidine and sulfasarazine was prevented. , It can be seen that the co-administration of quinidine and sulfasarazine induced ferrotic cell death in Huh6 and MDA-MB-231 cells. The above results indicate that when quinidine and a ferrotosis inducer are co-administered, there is an effect of inducing ferrotosis cell death. can be known

< Experimental example 4> quinidine and sulfasarazine Changes in the level of lipid peroxide when administered in combination

Co-administration of quinidine and a ferrotosis inducing agent according to the present invention induces apoptosis by increasing oxidative stress in Huh6 hepatoblasts or MDA-MB-231 in breast cancer cells to accumulate lipid peroxides. In order to confirm whether the redox state was measured and an experiment was performed to detect lipid peroxide, the results are shown in FIGS. 5A to 6B .

In this experimental example, lipid peroxide was detected through the following procedure.

Intracellular glutathione (GSH) levels were measured using a glutathione fluorescence assay kit (BioVision, Milpitas, CA) according to the manufacturer's instructions. Briefly, 1x10 ⁶ cells were pooled, precipitated with 6N perchloric acid, and centrifuged at 13000 g for 2 min. Of the separated solution, the supernatant was neutralized with 3N KOH and centrifuged at 10000 g for 2 minutes. Then, 10 μl of the supernatant of the separation solution was diluted with 80 μl assay buffer, and then incubated with 10 μl o-phthalaldehyde probe for 40 minutes. Fluorescence (excitation/emission at 340/420 nm ^{) was measured with an Infinite ®} 200 Pro (Tecan, Switzerland). The relative amount of GSH was calculated as the ratio of the vehicle-treated group to the drug-treated group.

Lipid peroxide was detected with Image-iT ^{™. Lipophilic BODIPY ®} 581/591 C11 probe (Thermo Fisher Scientific, Waltham, MA, USA) was used as a lipid peroxide kit. After treating the compounds to be tested as described above, 1 μM fluorescent probe was added and incubated at 37° C. for 30 minutes. Fluorescence (excitation/emission at 340/420 nm) was measured from 5000 cells using Guava easyCyte flow cytometers (MilliporeSigma, Burlington MA, USA) and analyzed using InCyte2.6 software (MilliporeSigma, Burlington MA, USA). did.

Vehicle, 300 μM sulfasarazine or 10 μM quinidine was administered alone to Huh6 and MDA-MB-231 cells, or 300 μM sulfasarazine and 10 μM quinidine were co-administered, and after 48 hours, the cells were washed with C11-BODIPY dye. After staining, the GSH level was measured according to the measurement method of the redox state, and the fluorescence intensity of C11-BODIPY was expressed as a histogram and then quantified to measure the level of lipid peroxide. Specifically, when 300 μM sulfasarazine or 10 μM quinidine was administered alone, there was no significant change in the level of lipid peroxide detected by C11-BODIPY. However, when 300 μM sulfasarazine and 10 μM quinidine are co-administered to Huh6 and MDA-MB-231 cells, about 2.5 times that of 300 μM sulfasarazine alone, when 10 μM quinidine is administered alone About three times more, lipid peroxide was found to accumulate (see FIGS. 5A-6B ).

This indicates that in Huh6 and MDA-MB-231 cells, when quinidine and sulfasalazine were administered in combination, compared to when quinidine and sulfasalazine were administered alone, ferrotosis was further promoted by accumulating more lipid peroxide. It is shown that when the ferrotosis inducers are administered in combination rather than when administered alone, it induces apoptosis by increasing oxidative stress on cancer cells and causing lipid peroxide to accumulate, and from this, quinidine is used together with anticancer agents. It can be seen that it can be usefully used as an anticancer adjuvant.

< Formulation example 1> powdery Produce

2 g of a compound represented by Formula 1

1 g lactose

The above ingredients were mixed and filled in an airtight cloth to prepare a powder.

< Formulation example 2> Preparation of tablets

100 mg of the compound represented by Formula 1

Corn Starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above ingredients, tablets were prepared by tableting according to a conventional method for manufacturing tablets.

< Formulation example 3> Preparation of capsules

100 mg of the compound represented by Formula 1

Corn Starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above ingredients, the capsules were prepared by filling in gelatin capsules according to a conventional manufacturing method of capsules.

< Formulation example 4> Preparation of injections

100 mg of the compound represented by Formula 1

mannitol 180 mg

Na ₂ HPO ₄ ㆍ2H ₂ O 26 mg

distilled water 2974 mg

According to a conventional method for preparing injections, injections were prepared by containing the above ingredients in the indicated amounts.

< Formulation example 5> Preparation of ointment

5 g of a compound represented by Formula 1

20 g cetyl palmitate

40 g cetanol

40 g stearyl alcohol

80 g myristane isopropyl

60 g polysorbate

1 g of propyl paraoxybenzoate

1 g of methyl paraoxybenzoate

Appropriate amount of phosphoric acid and purified water

According to a conventional method for preparing an ointment, an ointment was prepared by containing the above ingredients in the indicated amounts.

Claims (12)

It contains a compound represented by the following formula (1), an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
An anticancer adjuvant, characterized in that it enhances the anticancer efficacy of an anticancer agent that induces ferrotosis by inhibiting System xc- or GPX4:
[Formula 1]

(In Formula 1,
R ¹ is C _1-10 straight-chain or branched alkoxy).
According to claim 1,
Anti-cancer adjuvant, characterized in that the R ¹ in the formula (1) is methoxy.
According to claim 1,
The compound represented by Formula 1 is an anticancer adjuvant, characterized in that any one selected from the group of compounds:
(1) (S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methanol;
(2) (R)-(6-Methoxyquinolin-4-yl)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methanol.
delete delete According to claim 1,
The anti-cancer adjuvant, characterized in that it can be administered simultaneously or sequentially with the anti-cancer adjuvant.
According to claim 1,
The anticancer adjuvant is an anticancer adjuvant, characterized in that it accumulates lipid peroxide.
According to claim 1,
The anticancer adjuvant is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma , ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneum Cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer , duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, triple negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, Spinal cord cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, An anticancer adjuvant, characterized in that it prevents or treats one or more cancers selected from the group consisting of blood cancer and thymus cancer.
delete delete an anticancer agent that induces ferrotosis by inhibiting System xc- or GPX4; and
A combination preparation for anticancer, characterized in that it comprises the anticancer adjuvant of claim 1.



delete

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