JP2008290956A - New anticancer agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new anticancer agent. <P>SOLUTION: The anticancer agent comprises a benzoquinone derivative represented by general formula (I) (wherein R<SB>1</SB>-R<SB>3</SB>are each independently hydrogen or a 1-5C alkyl group; and n is an integer of 1-5) or its pharmacologically acceptable salt. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a novel anticancer agent, and more particularly to an anticancer agent using a novel benzoquinone derivative having a cell cycle regulating action.

In many cases, chemotherapy using an anticancer drug is used for the treatment of cancer. Anticancer agents are required to selectively kill cancer cells or act to prevent their growth, and have no adverse effects on normal cells. However, the number of deaths due to cancer continues to increase year by year, and the development of effective new anticancer agents is eagerly desired.
International Publication No. 98/17629 Pamphlet

  An object of the present invention is to provide a novel anticancer agent.

  The anticancer agent of the present invention comprises a benzoquinone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(In general formula (I), R _{1 to} R ₃ are each independently hydrogen or an alkyl group having 1 to 5 carbon atoms, and n is an integer of 1 to 5)
The cancer cell to be treated or prevented by the anticancer agent of the present invention is preferably at least one selected from liver cancer cells, breast cancer cells, colon cancer cells, and leukemia cells.

  In the anticancer agent of the present invention, the benzoquinone derivative is preferably 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] -benzoquinone represented by the following formula (II).

  The anticancer agent of the present invention preferably contains 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] -benzoquinone at a concentration in the range of 3 to 30 μM.

  The anticancer agent of the present invention exhibits a strong anticancer action against various cancer cells (preferably at least one selected from liver cancer cells, breast cancer cells, colon cancer cells, and leukemia cells), and cancer caused by chemotherapy It is expected that it can be suitably used for treatment.

  The anticancer agent of the present invention comprises a benzoquinone derivative represented by the following general formula (I).

In the general formula (I), R _{1 to} R ₃ are each independently hydrogen or an alkyl group having 1 to 5 carbon atoms, and among them, a methyl group, an ethyl group, or an isopropyl group is preferable. R ¹ and R ² are both preferably methyl groups, and R ³ is particularly preferably hydrogen. Moreover, in said general formula (I), n is an integer of 1-5.

  Among the benzoquinone derivatives represented by the above general formula (I), the anticancer agent of the present invention is 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] represented by the following formula (II): -Benzoquinone is preferred.

  The anticancer agent of the present invention may contain the above-described benzoquinone derivative in the form of a pharmaceutically acceptable salt. Here, pharmaceutically acceptable salts include, for example, hydrochloride, hydrobromide, sulfate, phosphonate, acetate, trifluoroacetate, lactate, pyruvate, malonate, succinate. Acid salts, glutarate salts, fumarate salts, tartrate salts, maleate salts, citrate salts, ascorbate salts, oxalate salts, methanesulfonate salts, camphorates, and the like. It is not something.

  The anticancer agent of the present invention containing the benzoquinone derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof has a potent anti-cancer activity against various cancer cells as demonstrated in the experimental examples described later. It shows cancer action and is expected to be suitably applicable to cancer treatment or prevention by chemotherapy. Here, the cancer cells to be treated or prevented by the anticancer agent of the present invention are not particularly limited, and examples thereof include liver cancer cells, breast cancer cells, colon cancer cells, leukemia cells, bladder cancer cells, and kidney cancer cells. And lung cancer cells, esophageal cancer cells, bile cancer cells, ovarian cancer cells, pancreatic cancer cells, gastric cancer cells, cervical cancer cells, thyroid cancer cells, prostate cancer cells, skin cancer cells and the like. Among these, it can particularly effectively act on at least one selected from liver cancer cells, breast cancer cells, colon cancer cells, and leukemia cells.

  The anticancer agent of the present invention is a benzoquinone derivative represented by the above general formula (I) at a concentration in the range of 3 to 30 μM (more preferably 10 to 30 μM) (in particular, 5- (2 represented by the above formula (II)). -Hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] -benzoquinone) or a pharmaceutically acceptable salt thereof. When a benzoquinone derivative or a pharmaceutically acceptable salt thereof is contained at a concentration within the above range, as described later in the experimental examples, among the cell cycles of cancer cells, cells in the S phase and G2 / M phase (especially G2 / It shows a cell cycle regulating action that significantly increases M phase cells).

  Here, FIG. 1 is a diagram schematically showing a general cell cycle of a cell together with related cell cycle regulatory proteins. As shown in FIG. 1, somatic cell division is roughly divided into an M phase (M (mitosis) phase), which is a time when mitosis occurs, and an interphase between M phase and M phase. The interphase is further divided into a G1 phase (G1 (gap1) phase), an S phase (S (synthesis) phase), and a G2 phase (G2 (gap2) phase). The S phase is a time when nuclear DNA replication occurs, and the G1 phase is the first gap phase between the M phase and the S phase. Further, the period from the S period to the next M period is the G2 period, which is the second gap period. Cells that do not continue to divide do not enter the S phase from the M phase, go out of the cell cycle, and are in a state similar to the G1 phase (G0 phase). The G2 / M phase is a general term for the states of the G2 phase and the M phase in the cell cycle.

  It is known that the cell cycle shown in FIG. 1 proceeds while being controlled by various cell cycle regulatory proteins. The cell cycle regulatory proteins that are central to the control of the cell cycle are cyclin and cyclin dependent protein kinase (Cdk). When the cell is stimulated for growth, it shifts from the G0 phase to the G1 phase, and cyclin D is synthesized in the cell to form a complex with cyclin-dependent protein kinase-4 (Cdk-4). The complex of cyclin D and cyclin-dependent protein kinase-4 is phosphorylated and activated by cyclin-dependent protein kinase activating kinase (CAK), thereby inducing the expression of cyclin E. When cyclin E forms a complex with cyclin-dependent protein kinase-2 (Cdk-2), it shifts to S phase. When entering S phase, cyclin E is degraded, and cyclin A, whose expression has been induced, forms a complex with cyclin-dependent protein kinase-2 and enters G2 phase. In the G2 phase, cyclin A first forms a complex with cyclin-dependent protein kinase-1 (Cdk1). Thereafter, cyclin B whose expression has been induced forms a complex with cyclin-dependent protein kinase-1. The complex of cyclin B with cyclin-dependent protein kinase-1 is phosphorylated at threonine position 14, tyrosine position 15, and threonine position 161 by cyclin-dependent protein kinase activating kinase (CAK). Furthermore, the M phase is initiated by dephosphorylation of threonine position 14 and tyrosine position 15 (low phosphorylation state, activity) by the protein tyrosine phosphatase CDC25. Thereafter, cyclin A that has formed a complex with cyclin-dependent protein kinase is degraded. Thus, the cyclic conversion of the amount of cyclin becomes a driving force for starting the cell cycle.

  When the anticancer agent of the present invention is allowed to act at a concentration of 3 to 30 μM, the expression of cyclin A is significantly reduced, and the inactive highly phosphorylated cyclin-dependent protein kinase-2 (Cdk-2) and cyclin Dependent protein kinase-4 (Cdk-4) is significantly reduced (described later in experimental examples). That is, a benzoquinone derivative represented by the above general formula (I) (particularly preferably, 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1 represented by the above formula (II) at a concentration within the above range. , 4] -benzoquinone) or a pharmaceutically acceptable salt thereof, by administering a preferred anticancer agent of the present invention, cyclin dependence in a complex of cyclin A and cyclin dependent protein kinase-2 (Cdk-2) By inhibiting the action of protein tyrosine phosphatase CDC25, which dephosphorylates and activates protein kinase-2, the cell cycle is significantly stagnated in the G2 / M phase, and the cancer cell cycle is delayed thereby It is thought to show cancer action.

  The anticancer agent of the present invention can be administered orally or parenterally as the benzoquinone derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as it is, or as various pharmaceutical compositions. The dosage form for preparing a pharmaceutical composition is not particularly limited, and examples thereof include tablets, pills, powders, granules, capsules, injections, drops and the like. Formulation into each of the above-mentioned dosage forms can be carried out using an appropriate method widely known in the art, and conventionally known appropriate additives (for example, within a range not impairing the effects of the present invention (for example, Excipients, lubricants, binders, disintegrants, suspending agents, tonicity agents, emulsifiers, absorption enhancers, etc.) may be added. The anticancer agent of the present invention may also contain a pharmaceutically acceptable carrier, such as water, distilled water for injection, physiological saline, glucose, fructose, sucrose, mannitol, lactose, Starch, corn starch, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glycerin fatty acid ester, etc. Any conventionally known appropriate carrier can be selected and used according to the type of the preparation within a range not impairing the effects of the present invention, and is not particularly limited.

  The dose and frequency of administration of the anticancer agent of the present invention can be appropriately selected according to the cancer cells to be treated or prevented, administration route, treatment period, patient age, body weight, etc., and are not particularly limited. Absent.

  In addition, the anticancer agent of the present invention exerts an effective cancer treatment or prevention effect even if administered alone, but is used in combination with other conventionally known appropriate anticancer agents as long as the effects of the present invention are not inhibited. Of course, it is possible. In this case, the anticancer agent of the present invention may be administered before, simultaneously with, or after administration of the other anticancer agent.

  Hereinafter, although an example of an experiment is given and the present invention is explained in detail, the present invention is not limited to these.

<Production example>
In the scheme shown below, 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone was synthesized.

(1) Synthesis of 2,3-dimethyl-1,4-benzoquinone 2,3-dimethyl-1,4-hydroquinone (1.38 g, 10 mmol) was dissolved in 50 ml of chloroform and stirred under ice cooling. A solution prepared by dissolving ceric ammonium nitrate (CAN) (6 g, 11 mmol) in 50 ml of water was slowly added dropwise thereto. Then, it stirred at room temperature for 1 hour and isolate | separated the organic layer. The organic layer was washed with water using a separatory funnel, dried and concentrated to obtain crude 2,3-dimethyl-1,4-benzoquinone.

(2) Synthesis of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone Crude 2,3-dimethyl-1,4-benzoquinone (10 mmol) obtained in (1) above Was dissolved in 40 ml of ethanol, and 2-mercaptoethanol (1.4 ml, 20 mmol) was added dropwise under an argon stream. The mixture was stirred at room temperature for 18 hours, ethanol was concentrated after confirming the completion of the reaction. The obtained oily substance was dissolved in 50 ml of chloroform and stirred with ice cooling, and an aqueous solution (50 ml) of ceric ammonium nitrate (6 g, 11 mmol) was slowly added dropwise. After the reaction at room temperature, the organic layer was fractionated, washed with water, dried, concentrated, and purified by silica gel column chromatography (chloroform: methanol = 20: 1). The compound thus obtained (1.14 g (53%)) was a reddish brown solid having a melting point of 92 ° C. As a result of ¹ H-NMR using ECP-400 (manufactured by JEOL Ltd.), 5 It was confirmed that-(2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.90 (t, 1H, J = 6Hz, -OH), 2.04 (s, 6H, CH ₃ × 2), 3.0 (t, 2H, J = 6Hz, -SCH _2- ), 3.91 (q, 2H, J = 6Hz, -CH ₂ OH), 6.43 (s, 1H, -C (O) -CH = C-), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 12. 3 (-CH ₃ ), 12.4 (-CH ₃ ), 33.1 (-CH ₂ S-), 59.7 (-CH ₂ OH), 125.2 (C = CH), 140.8 (-C (CH ₃ ) = C-) , 151.3 (C (O) -C (SCH ₂ CH ₂ OH), 184.0 (O = C-), 184.1 (O = C-).
<Experimental example 1>
The strength of anticancer activity against cultured cancer cells was evaluated using 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone obtained as described above. As cultured cancer cells, human breast cancer cell MCF-7 (obtained from Dainippon Pharmaceutical Co., Ltd.), human colon epithelial cell HT-29 (obtained from Dainippon Pharmaceutical Co., Ltd.), human hepatoma cell Hep-G2 (Dainippon Pharmaceutical Co., Ltd.) Obtained from the company), acute myeloid leukemia cells HL-60 (obtained from Dainippon Pharmaceutical Co., Ltd.), and human lymphoblast IM-9 (obtained from Dainippon Pharmaceutical Co., Ltd.).

5- (2-Hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is added to each cancer cell 1 × 10 ⁴ cells / well, and after 24 hours, washed with PBS (−). The Calcein / AM solution was reacted at 37 ° C. for 30 minutes using CCK-F (manufactured by Dojindo Laboratories). Fluorescence emission due to Calcein / AM degradation of intracellular esterase was measured using a CytoFluor fluorometer (PerSeptive Biosystems), and a concentration (μM) at which the survival rate of each cancer cell was 50% (IC ₅₀ ) was determined. The measurement wavelengths were an excitation filter of 490 nm and a measurement filter of 515 nm. For human breast cancer cell MCF-7 and human colon epithelial cell HT-29, 48 hours have passed after adding 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone. The same was done for the case of. FIG. 2 is a graph showing the results of Experimental Example 1, in which the vertical axis represents cancer cell survival rate (%) and the horizontal axis represents 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1, 4] Benzoquinone concentration (μM). Table 1 shows the IC ₅₀ concentration (μM) of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone obtained in Experimental Example 1 together with the hill coefficient.

From the results shown in FIG. 2 and Table 1, the IC ₅₀ concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is in the range of 3 to 19 μM for all cancer cells. It was suggested that it exhibits sufficient toxic effects on cancer cells. Among them, 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is 3 for leukemia cells (acute myeloid leukemia cells HL-60 and human lymphoblasts IM-9). It showed very strong anticancer activity of ˜7 μM, suggesting an effect as a leukemia therapeutic agent. On the other hand, 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is used for breast cancer cells (human breast cancer cell MCF-7) and colon cancer cells (human colon epithelial cell HT-29). In addition, strong anticancer activity was also exhibited against hepatoma cells (human hepatoma cell Hep-G2), and results suggesting that these cells also act as effective anticancer agents.

<Experimental example 2>
Using 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone obtained as described above, the influence on the cell cycle of human colon epithelial cells HT-29 was examined. 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone at concentrations of 0 μM, 10 μM, 20 μM, 50 μM and 100 μM were added to human colon epithelial cells HT at 1.3 × 10 ⁶ cells / well. -Bromo-2'-deoxyuridine was added at a concentration of 10 g / L and incorporated into S phase cells. The cells were collected and labeled with a mouse anti-BrdU antibody to observe whether human colon epithelial cells HT-29 are in the G1, S or G2 / M phase of the cell cycle. Asked. Whether the human colon epithelial cells HT-29 are in the G1, S, or G2 / M phase of the cell cycle is quantified by flow cytometry using FACS Calibur (Becton Dickinson). I confirmed that.

  FIG. 3 is a graph showing the relationship between each concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone and the cell cycle of human colon epithelial cells HT-29; 3A shows the ratio (%) for the G1 period, FIG. 3B shows the ratio for the S period, and FIG. 3C shows the G2 / M period. 3 (a) to 3 (c), the vertical axis represents each period in the entire human colon epithelial cell HT-29 used in Experimental Example 2 (FIG. 3 (a) is in the G1 period, and FIG. 3 (b) is in the S period. 3 (c) shows the ratio (%) of G2 / M phase, and the horizontal axis represents the concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone (μM). ).

  As can be seen from FIG. 3 (c), by adding 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone, G2 / M phase human colon epithelial cells HT- A significant increase of 29 was observed (especially when the concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone was 10 μM, 50 μM, 100 μM). On the other hand, human colon epithelial cells HT-29 in S phase show a significant increase only when 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone having a concentration of 10 μM is added. Although observed, no change was observed at other concentrations (FIG. 3B). In addition, no change was observed in all concentrations of G1 human colon epithelial cells HT-29 (FIG. 3 (a)). From the above, 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is mainly a cell in the G2 / M phase during the cell cycle of human colon epithelial cell HT-29. This suggests the possibility of specifically increasing

<Experimental example 3>
From the results of Experimental Example 2, 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is human colon epithelial cell HT- in the S phase and the G2 / M phase in the cell cycle. The possibility of specifically increasing 29 was suggested. In this experimental example, the relationship between cell cycle control protein related to the increase mechanism of S phase and G2 / M phase and 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone Was examined. The cells were serum-starved and the cell cycle was once stagnated in the G1 phase, and then 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl at each concentration of 0 μM, 10 μM, 20 μM, 50 μM, and 100 μM. -[1,4] benzoquinone was added to 1.3 × 10 ⁶ cells / well of human colon epithelial cells HT-29, collected, and cyclin A was used as a cell cycle control protein using an antibody against each cell cycle control protein. Cyclin-dependent protein kinase-2 (Cdk-2) and cyclin-dependent protein kinase-4 (Cdk-4) were extracted and purified, and their expression levels were examined by SDS-PAGE. For cyclin-dependent protein kinase-2 and cyclin-dependent protein kinase-4, 10 μL of Protein G-Sepharose 4B Fast Flow recombinant protein G (manufactured by SIGMA) was added, and immunoprecipitation was performed. ) Cell cycle stagnation was detected.

  FIG. 4 is a photograph showing the results of Experimental Example 3, in which 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4 at respective concentrations of 0 μM, 10 μM, 20 μM, 50 μM and 100 μM. The expression of cyclin A, cyclin-dependent protein kinase-2 and cyclin-dependent protein kinase-4 is shown for the case where benzoquinone is added. As shown in FIG. 4, the expression of cyclin A is the lowest when the concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is 10 μM, and the concentration is It increased with the increase. In addition, cyclin-dependent protein kinase-2 in a highly phosphorylated state shows a decrease when the concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is 20 μM. It was. In addition, cyclin-dependent protein kinase-4 in the highly phosphorylated state also decreases when the concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is 20 μM. Admitted. From these results, when 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone was allowed to act at a low concentration, cyclin A and cyclin-dependent protein kinase 1 (Cdk It was suggested that cell cycle stagnation was caused in the G2 phase through suppression of the expression of cyclin A in the complex with -1). This suppression of cyclin A expression results from inhibition of the action of protein tyrosine phosphatase CDC25, which changes the complex of cyclin A and cyclin-dependent protein kinase 1 from an inactive high phosphorylation state to an active low phosphorylation state. It was thought to do. In addition, when 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone is allowed to act at a high concentration, the cell cycle is different from when it is allowed to act at a low concentration as described above. It was thought that it may exhibit a regulating effect.

<Experimental example 4>
In the same manner as in Experimental Example 2, using 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone, the effect of human hepatoma cell Hep-G2 on the cell cycle was examined. 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone at concentrations of 0 μM, 3 μM, 10 μM, 20 μM and 30 μM were added at 1.5 × 10 ⁶ cells / well of human hepatoma cell Hep- Each was added to G2, and 5-bromo-2′-deoxyuridine was added to a concentration of 10 μg / L and incorporated into S-phase cells. The cells are collected, labeled with a mouse anti-BrdU antibody, and the human hepatoma cell Hep-G2 is observed in the G1 phase, S phase, or G2 / M phase in the cell cycle, and the ratio is determined. It was. It should be noted that whether the human hepatoma cell Hep-G2 is in the G1 phase, S phase, or G2 / M phase in the cell cycle was confirmed by the same method as in Experimental Example 2.

  FIG. 5 is a graph showing the relationship between each concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone and the cell cycle of human hepatoma cell Hep-G2. 5 (a) shows the ratio (%) for the G1 period, FIG. 5 (b) shows the S period, and FIG. 5 (c) shows the G2 / M period. 5 (a) to (c), the vertical axis represents each period in the entire human hepatoma cell Hep-G2 used in Experimental Example 4 (FIG. 5 (a) is the G1 period, FIG. 5 (b) is the S period, FIG. 5 (c) shows the ratio (%) of G2 / M phase, and the horizontal axis represents the concentration (μM) of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone. It is.

  As can be seen from FIG. 5 (c), in the case of human hepatoma cell Hep-G2, by adding 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone, A significant increase in the G2 / M phase ratio was observed. On the other hand, in the case of the human hepatoma cell Hep-G2, there was a tendency for the ratios of the G1 phase and the S phase to decrease (FIGS. 5A and 5B).

  The embodiments and experimental examples disclosed this time should be considered as illustrative in all points and not restrictive. The scope of the present invention is defined by the terms of the claims, rather than the description above, and is intended to include any modifications within the scope and meaning equivalent to the terms of the claims.

FIG. 2 schematically illustrates a cell's general cell cycle with associated cell cycle regulatory proteins. It is a graph which shows the result of Experimental example 1, a vertical axis | shaft is the survival rate (%) of a cancer cell, and a horizontal axis is 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone. Concentration (μM). FIG. 3 is a graph showing the relationship between each concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone and the cell cycle of human colon epithelial cell HT-29, FIG. ) Is the G1 period, FIG. 3B is the S period, and FIG. 3C is the G2 / M period. 3 (a) to 3 (c), the vertical axis represents each period in the entire human colon epithelial cell HT-29 used in Experimental Example 2 (FIG. 3 (a) is in the G1 period, and FIG. 3 (b) is in the S period. 3 (c) shows the ratio (%) of G2 / M phase, and the horizontal axis represents the concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone (μM). ). It is a photograph which shows the result about Experimental example 3, and adds 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone at each concentration of 0 μM, 10 μM, 20 μM, 50 μM and 100 μM. The expression of cyclin A, cyclin-dependent protein kinase-2 and cyclin-dependent protein kinase-4 is shown. Fig. 5 (a) is a graph showing the relationship between each concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone and the cell cycle of human hepatoma cell Hep-G2. Indicates the ratio (%) for the G1 period, FIG. 5 (b) indicates the S period, and FIG. 5 (c) indicates the G2 / M period. 5 (a) to (c), the vertical axis represents each period in the entire human hepatoma cell Hep-G2 used in Experimental Example 4 (FIG. 5 (a) is the G1 period, FIG. 5 (b) is the S period, FIG. 5 (c) shows the ratio (%) of G2 / M phase, and the horizontal axis represents the concentration (μM) of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] benzoquinone. It is.

Claims (4)

An anticancer agent comprising a benzoquinone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(In general formula (I), R _{1 to} R ₃ are each independently hydrogen or an alkyl group having 1 to 5 carbon atoms, and n is an integer of 1 to 5)   The anticancer agent according to claim 1, wherein the cancer cells to be treated or prevented are at least one selected from liver cancer cells, breast cancer cells, colon cancer cells, and leukemia cells. The benzoquinone derivative is 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] -benzoquinone represented by the following formula (II): The anticancer agent described.

  The anticancer agent according to claim 3, wherein the concentration of 5- (2-hydroxy-ethylsulfanyl) -2,3-dimethyl- [1,4] -benzoquinone is in the range of 3 to 30 µM.

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