JP2009057330A - Diphenyleneiodonium compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an anti-cancer drug which can inhibit cancer cells from not only multiplication but also invasion and metastasis, has an inhibitory effect on angiogenesis, and is less in side-effects; and to provide a diphenyleneiodonium compound. <P>SOLUTION: The anti-cancer drug comprises a salt composed of a compound (I) (wherein R<SP>1</SP>-R<SP>8</SP>are each independently a hydrogen atom etc.) and an anion. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a diphenylene iodonium compound and an anticancer agent.

  Although “cancer” occupies the top cause of death in various countries, especially developed countries, the current cure has not been established yet. As a method for treating cancer, excision is mainly performed by surgical operation, but radiation therapy is also performed in cases such as head and neck cancer where appearance or the like is impaired by excision. Furthermore, chemotherapy such as administration of an anticancer drug may be performed alone or in parallel with surgery or radiotherapy.

  Chemotherapy is considered to have relatively little pain and burden on patients compared to surgery and radiation therapy. However, there is still no specific medicine for cancer, and the search for better anticancer drugs continues.

  Cancer is particularly problematic because cancer cells proliferate against normal control and have the property of metastasizing to other tissues. For example, cancer cells that have developed in epithelial tissues grow on the spot, infiltrate the basal layer, and eventually invade capillaries. Then, it is transported by blood and adheres to the capillary wall of other tissues and infiltrates into the tissue from there to form a metastatic cancer focus. Furthermore, new blood vessels are formed up to the metastatic cancer focus, and nutrients are taken from the blood and continue to grow. Thus, even if most cancers are removed by surgery or the like, there is a possibility of recurrence or metastasis if only a few cancer cells remain. Therefore, in the treatment of cancer, it is very important to suppress cancer cell metastasis and angiogenesis as well as removal and reduction of cancer lesions.

  By the way, diphenylene iodonium is used as an intermediate for organic synthesis. In addition, it is also known to suppress the production of reactive oxygen species because it has an inhibitory action on nitric oxide synthase and an inhibitory action on NADH / NADPH oxidase.

  Patent Documents 1 and 2 describe the use of diphenylene iodonium as a therapeutic agent for spinal canal stenosis, cosmetics, or a therapeutic agent for inflammation based on these findings. However, diphenylene iodonium in Patent Documents 1 and 2 is only listed as an example of a nitric oxide synthase inhibitor, and the plant cell extract is used in the examples described in these documents. And the bioactivity of diphenyleneiodonium is not specifically demonstrated.

Patent Documents 3 and 4 describe diphenyleneiodonium, and also disclose cancer as a disease to be treated. However, diphenylene iodonium in Patent Document 3 is only one of a plurality of compounds listed as inhibitors of NADH / NADPH oxidase, and the test data is not clearly shown in the examples. Furthermore, cancer is only listed as one of many diseases in which reactive oxygen species are considered to be involved, and the technique of Patent Document 3 is mainly directed as a treatment target atheromatous. Cardiovascular diseases such as arteriosclerosis. Further, in Patent Document 4, diphenylene iodonium is exemplified as a kind of histamine, and it is said that the effect of cancer treatment can be enhanced by using it together with a surgical operation, but the effect has not been proved at all.
JP 2006-96665 A JP-A-9-124499 JP-T-2006-520326 JP 2002-534378

  As described above, since there is no sufficiently effective therapeutic means for cancer, a new anticancer agent is being demanded.

  Thus, the problem to be solved by the present invention is not only the ability to suppress the growth of cancer cells, but also the ability to suppress invasion and thus metastasis, and also have an anti-angiogenic action, and have few side effects. And a diphenylene iodonium compound.

  The present inventor has searched for compounds to solve the above-mentioned problems. As a result, although diphenylene compounds have little effect on normal cells such as quiescent hepatic stellate cells, they have an inhibitory effect on the growth of cancer cells and also suppress their invasion, metastasis, and angiogenesis. The present invention was completed by finding that it can exert a specific action on cancer cells.

  The anticancer agent of the present invention is characterized by comprising a salt comprising the following compound (I) and an anion.

[Wherein, R ^{1 to} R ⁸ independently represent a hydrogen atom, or C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, the di (C ₁ -C ₆ alkyl) amino, C ₁ -C ₇ acylamino, carbamoyl, C ₁ -C ₇ acyl, C ₁ -C ₆ alkylthio, cyano, carboxy, hydroxy, mercapto and halogen 1 type or 2 or more types of substituents selected from the group which consists of an atomic group are shown. ]

In the present invention, C ₁ -C ₆ alkyl means a linear or branched aliphatic hydrocarbon having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like. Preferably a C ₁ -C ₄ alkyl, more preferably C ₁ -C ₂ alkyl, most preferably methyl.

C ₂ -C ₆ alkenyl means a linear or branched aliphatic hydrocarbon having at least one double bond and having 2 to 6 carbon atoms. For example, vinyl, 1-methylvinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, pentenyl, hexenyl and the like. Preferably C ₂ -C ₅ alkenyl, more preferably a C ₂ -C ₄ alkenyl, most preferably 2-propenyl (allyl).

C ₂ -C ₆ alkynyl means a linear or branched aliphatic hydrocarbon having at least one triple bond and having 2 to 6 carbon atoms. For example, ethynyl, 1-methylethynyl, 1-propynyl, 2-propynyl, 1-methyl-1-propynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butynyl, pentynyl, hexynyl and the like. Preferably C ₂ -C ₅ alkynyl, more preferably C ₂ -C ₄ alkynyl.

C ₁ -C ₆ alkoxy means a linear or branched aliphatic hydrocarbon oxy group having 1 to 6 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexoxy and the like, preferably a C ₁ -C ₄ alkoxy, more preferably C ₁ -C ₂ alkoxy, and most Preferably it is methoxy.

C ₁ -C ₆ alkylamino means an amino group substituted by one of the above C ₁ -C ₆ alkyl. For example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, t-butylamino, pentylamino, hexylamino and the like. Preferably C ₁ -C ₄ alkylamino, more preferably C ₁ -C ₂ alkylamino.

Di (C ₁ -C ₆ alkyl) amino means an amino group substituted by two of the above C ₁ -C ₆ alkyl. For example, dimethylamino, diethylamino, methylpropylamino, ethylpropylamino, methylisopropylamino, methylbutylamino, methylpentylamino, methylhexylamino and the like. Di (C ₁ -C ₄ alkyl) amino is preferred, and di (C ₁ -C ₂ alkyl) amino is more preferred.

C ₁ -C ₇ acyl carbon atoms means a 1-7 group a remaining atomic group obtained by removing OH of the carboxyl group from a carboxylic acid. For example, formyl, acetyl, propionyl, isopropionyl, butyryl, valeryl, pentylcarbonyl, hexylcarbonyl and the like. Preferably a C ₁ -C ₄ acyl, more preferably C ₁ -C ₂ acyl, most preferably acetyl.

C ₁ -C ₇ acylamino means one of the above C ₁ -C ₇ substituted amino group acyl. For example, formylamino, acetylamino, propionylamino, isopropionylamino, butyrylamino, valerylamino, pentylcarbonylamino, hexylcarbonylamino and the like. Preferably a C ₁ -C ₄ acylamino, more preferably a C ₁ -C ₂ acylamino, most preferably acetylamino.

Carbamoyl refers to the group H ₂ N (C═O) —.

C ₁ -C ₆ alkylthio means a linear or branched aliphatic hydrocarbon thio group having 1 to 6 carbon atoms. For example, methylthio, ethylthio, propitylthio, isopropylthio, butylthio, isobutylthio, t-butylthio, pentylthio, hexylthio and the like. Preferably C ₁ -C ₄ alkylthio, more preferably a C ₁ -C ₂ alkylthio.

  The “halogen atom group” includes a fluorine atom group, a chlorine atom group, a bromine atom group and an iodine atom group, more preferably a fluorine atom group or a chlorine atom group, and most preferably a fluorine atom group.

  When the compound (I) has a plurality of substituents, these two or more substituents may be the same or different from each other. In addition, although the number of substituents is 1-8, it is 1-4 suitably, More preferably, it is 1-2.

  The cancer cell growth inhibitory action, invasion inhibitory action, and angiogenesis inhibitory action of unsubstituted compound (I), that is, diphenyleneiodonium, have been demonstrated with experimental data in Examples described later. The compound (I) having the above substituent may have a similar or higher cancer cell growth inhibitory action and the like, and side effects such as toxicity to normal cells may be further reduced. Further, the compound (I) having a substituent is useful as an intermediate for the synthesis of a further derivative of diphenyleneiodonium.

  The compound (I) of the present invention has an infiltration suppressing action and an angiogenesis induction suppressing action as well as a cancer cell proliferation suppressing action. Therefore, the compound (I) of the present invention is also useful as a cancer cell infiltration inhibitor and an angiogenesis inhibitor.

  The anticancer agent of the present invention is preferably an anion that can form a salt with compound (I) and that contains a pharmaceutically acceptable one. This is because such salts are more stable. The type of the anion is not particularly limited. For example, halide ions such as fluoride ion, chloride ion, bromide ion, iodide ion; nitrate ion, nitrite ion, acetate ion, bicarbonate ion, carbonate ion, phosphorus ion Examples thereof include inorganic acid ions such as acid ions, monohydrogen phosphate ions, dihydrogen phosphate ions, hydrogen sulfate ions, and sulfate ions. In particular, sulfate ion is preferable because it can form a salt with compound (I) to increase its water solubility.

  The anticancer agent of the present invention is particularly useful for treating at least one cancer selected from the group consisting of liver cancer, colon cancer, lung cancer, stomach cancer and skin cancer.

  Compound (I) of the present invention and pharmaceutically acceptable salts thereof may be in the form of a solvate such as a hydrate, and these are included in the scope of the present invention.

  The diphenylene iodonium compound of the present invention is represented by the following compound (II).

[Wherein, R ^{9 to} R ¹⁶ independently represent the same substituents as those of the compound (I). However, R ^{9 to} R ¹⁶ are not all hydrogen atoms. ]

That is, compound (II) is substantially the same as compound (I) except that R ^{9 to} R ¹⁶ are not all hydrogen atoms.

  The diphenylene iodonium compound and pharmaceutically acceptable salt thereof of the present invention have an inhibitory effect on invasion and metastasis and an inhibitory effect on angiogenesis in addition to an inhibitory action on cancer cell proliferation. In addition, it has little effect on normal cells. Therefore, the diphenylene iodonium compound of the present invention and a pharmaceutically acceptable salt thereof are very useful as an anticancer agent.

  The unsubstituted compound (I), i.e., diphenylene iodonium, is a known compound and is also commercially available, so that it can be easily obtained. Further, the compound (I) having a substituent can be easily synthesized from diphenyleneiodonium by a known electrophilic aromatic substitution reaction.

  A salt of compound (I) and an anion can also be easily produced by a known technique. For example, the compound (I) may be dissolved in a solvent having an appropriate solubility and then the anion is added, and then the solvent is distilled off, or the salt may be precipitated by adding a poor solvent.

  For the treatment of cancer, the compounds (I) and pharmaceutically acceptable salts thereof of the present invention are pharmaceutically acceptable, such as organic or inorganic solid or liquid excipients suitable for oral or parenteral administration. And can be used in the form of a pharmaceutical composition containing the compound as an active ingredient. The said pharmaceutical composition can be made into dosage forms, such as a capsule, a tablet, a sugar-coated tablet, a granule, an inhalant, a suppository, a solution, a dispersion liquid, and an emulsion. If necessary, auxiliaries, stabilizers, wetting and emulsifying agents, buffering agents and other commonly used additives may be incorporated into these preparations. In addition, since the salt consisting of the compound (I) of the present invention and an anion, particularly the salt consisting of the compound (I) of the present invention and a sulfate ion is particularly excellent in water solubility, it can be dissolved in water and used as an injection. it can.

  The dose of the compound (I) effective for treatment depends on the age, sex, severity, etc. of the patient, but it is usually sufficient to administer about 0.05 to 0.25 mg / kg body weight per day. Administration is not limited to once per day, and may be divided into multiple doses. The administration method is not particularly limited, and may be appropriately selected depending on the severity of the patient, such as oral administration of tablets or the like and injection administration of liquids.

  The anticancer agent of the present invention has an excellent inhibitory action against the invasion or metastasis and angiogenesis in addition to the cancer cell growth inhibitory action. That is, most cancer cells do not have the ability to metastasize, but at least some of them can metastasize due to their original ability or mutation. More specifically, cancer cells having metastatic potential can adhere to the basal layer because they have receptors of constituent components of the basal layer, for example, have an enzyme that degrades the basal layer, and further have a basal layer It has the ability to move from the disassembly part. The compound (I) of the present invention is thought to inhibit any of these metastasis mechanisms and inhibit cancer cell invasion or metastasis. In addition, even when cancer cells have metastasized, the anticancer agent of the present invention also has an angiogenesis-inhibiting action, thus inhibiting cancer cell angiogenesis and cancer recurrence. Can also be prevented.

  The type of cancer to be treated by the anticancer agent of the present invention is not particularly limited. Examples of the therapeutic target of the anticancer agent according to the present invention include blood cancer such as leukemia and malignant lymphoma; malignant brain tumor; head and neck cancer such as pharyngeal cancer and oral cancer; esophageal cancer; stomach cancer; appendix Colorectal cancer; liver cancer; gallbladder cancer; pancreatic cancer; mesothelioma; thyroid cancer; kidney cancer; lung cancer; osteosarcoma; prostate cancer; malignant testicular tumor; Examples include cancer; bladder cancer; skin cancer such as melanoma; breast cancer, cervical cancer, ovarian cancer, and the like. At least, the anticancer agent according to the present invention has excellent effects of inhibiting the growth of liver cancer cells, colon cancer cells, lung cancer cells, gastric cancer cells and skin cancer cells, and the invasion / metastasis inhibition effect of liver cancer cells. Therefore, the anticancer agent of the present invention is very excellent as a therapeutic agent for at least liver cancer, colon cancer, lung cancer, stomach cancer and skin cancer.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention.

Example 1 Cancer Cell Growth Inhibition Experiment In a liquid medium (manufactured by Nissui Pharmaceutical Co., Ltd., product name “MEM Dulbecco Liquid Medium”), a salt of diphenyleneiodonium and ½ sulfate ion is 1 × 10 ⁻⁹ M, 1 It was added and dissolved at a concentration of × 10 ⁻⁸ M, 1 × 10 ⁻⁷ M, 1 × 10 ⁻⁶ M or 1 × 10 ⁻⁵ M. Each medium was added in an amount of 6 mL to a sterile petri dish (product name “Cell Star”, manufactured by Greiner) having a diameter of 6 cm. For comparison, a medium supplemented only with DMSO not containing diphenyleneiodonium salt was also prepared. To each medium, hepatoma cell lines HepG2 (obtained from American Type Culture Collection (ATCC)) and Huh-7 (obtained from ATCC), fibroblastoma cell line HT1080 (obtained from RIKEN), and Hepatic stellate cells, which are normal cells, were seeded at a concentration of about 1 × 10 ⁵ cells / mL. Hepatic stellate cells are a group of sinusoidal wall cells that produce an extracellular matrix such as collagen upon activation. In addition, hepatic stellate cells were obtained from rat hepatocytes by an in situ digestion method using collagenase (manufactured by Wako Pure Chemical Industries, Ltd.) and pronase E (manufactured by Merck) and a concentration gradient method using Nicodents (manufactured by Daiichi Kagaku). Separated from. After each cell was cultured at 37 ° C. for 3 days, 0.2% trypsin / 0.02% EDTA was added to release the cells, and the number of cells in each petri dish was counted using a microscope. The reduction rate (%) of the number of cells relative to the case where no diphenylene iodonium salt was added was calculated by the following formula. The results are shown in FIG.

As shown in FIG. 1, when the diphenylene iodonium salt according to the present invention was added to the culture medium, no growth inhibitory effect was observed on hepatic stellate cells in the stationary phase (3 days in culture), but a clear growth inhibition was observed. The effect is obtained. The concentration of diphenyleneiodonium salt required to suppress the cell number to 50% is 5 × 10 ⁻⁹ M for HepG2, 5 × 10 ⁻⁸ M for Huh-7, and 1 × 10 ⁻⁸ M for HT1080. Effective at low concentrations. Therefore, it was demonstrated that the anticancer agent of the present invention exhibits a very excellent selectivity of inhibiting the proliferation of malignant cells while not affecting the number of normal cells.

Example 2 Cancer Cell Growth Inhibition Experiment A salt of diphenyleneiodonium and chloride ions was added to the liquid medium used in Example 1 above at 1 × 10 ⁻⁸ M, 1 × 10 ⁻⁷ M, or 1 × 10 ^−6. Added at a concentration of M and dissolved. For comparison, a medium supplemented only with DMSO not containing diphenyleneiodonium salt was also prepared. Under the same conditions as in Example 1 above, HepG2, which is a hepatoma cell line, was added to 0 M, 1 × 10 ⁻⁷ M, and 1 × 10 ⁻⁶ M media at 0 M, 1 × 10 ⁻⁸ M, and 1 ×. A 10 ⁻⁷ M medium was inoculated with HT1080, a fibroblastoma cell line, and cultured for 3 days. Furthermore, for HT1080, a medium supplemented with DNase was used as a positive control. The occurrence of apoptosis was confirmed by the TUNEL method. A photograph of HepG2 after 3 days is shown in FIG. 2, and a photograph of HT1080 is shown in FIG.

As shown in FIG. 2, the anticancer agent of the present invention inhibited the growth of cancer cells and caused cell death even at a low concentration of 1 × 10 ⁻⁷ M, and the effect was dose-dependent. In addition, as shown in FIG. 3, (1) When only DMSO was added, cancer cells did not undergo apoptosis, while (2) the nuclear fragmentation image of the positive control in which apoptosis was induced by addition of DNase. (3) When 1 × 10 ⁻⁸ M of the anticancer agent of the present invention is added, apoptosis is observed, and (4) When 1 × 10 ⁻⁷ M of the anticancer agent of the present invention is added The incidence of apoptosis was further increased. Therefore, it was demonstrated that the anticancer agent of the present invention causes apoptosis in cancer cells.

Example 3 Invasion / metastasis suppression experiment of cancer cells 1 × 10 ⁻⁷ M or 1 of a salt of diphenyleneiodonium and chloride ion in a liquid medium (manufactured by Nissui Pharmaceutical Co., Ltd., product name “MEM Dulbecco liquid medium”) It was added and dissolved at a concentration of × 10 ^-6 M. For comparison, a medium supplemented only with DMSO not containing diphenyleneiodonium salt was also prepared. Each liquid medium is placed in the upper chamber of a Matrigel invasion chamber (product name “BioCoat Matrigel Invasion Chamber” manufactured by Becton Dickinson Co., Ltd.), to which a Matrigel layer as a reconstituted basement membrane is applied at the bottom. .5 mL was added, and HepG2 (obtained from ATCC), which is a liver cancer cell line, was inoculated. To the lower chamber, 0.5 mL of the same liquid medium and 0.75 mL of a dedicated chemical migration inducing solution were added. After culturing at 37 ° C. for 3 days, the number of hepatoma cells invading the porous filter at the bottom of the upper chamber and moving to the bottom was observed. The results are shown in FIG.

As shown in FIG. 4, it can be observed that (1) HepG2 having invasive ability permeates the basement membrane and invades the bottom surface. However, (2) when 1 × 10 ⁻⁷ M of the anticancer agent of the present invention is added, infiltration of HepG2 is suppressed, and (3) when 1 × 10 ⁻⁶ M is added, HepG2 It can be seen that infiltration is completely suppressed. Therefore, it was proved that the anticancer agent of the present invention can suppress infiltration of cancer cells.

Example 4 Mechanism Confirmation Experiment of Invasion / Metastasis Suppressing Effect In a liquid medium (manufactured by Nissui Pharmaceutical Co., Ltd., product name “MEM Dulbecco's liquid medium”), a salt of diphenyleneiodonium and chloride ion is in a concentration of 1 × 10 ⁻⁶ M. And dissolved. For comparison, a medium supplemented with the same amount of PBS as the diphenylene iodonium salt was also prepared. 6 mL of each liquid medium was added to a sterile petri dish having a diameter of 6 cm (product name “Cellstar” manufactured by Greiner), and further, Huh-7 (obtained from ATCC), a hepatoma cell line, was inoculated and incubated at 37 ° C. 3 Cultured for days. Total RNA was extracted from the cells, and the expression states of CD31, which is an invasion inducing factor for cancer cells, and VEGF, which is an angiogenesis inducing factor, were determined by quantifying the mRNA encoding each by real-time RT-PCR. The results are shown in FIG.

  As shown in FIG. 5, the anticancer agent of the present invention strongly suppressed the expression of CD31 and VEGF. Therefore, it was found that the anticancer agent of the present invention inhibited the invasion of cancer cells by suppressing at least the expression of the invasion inducing factor. In addition, since the anticancer agent of the present invention also suppresses the expression of angiogenesis-inducing factors, even if cancer cells have metastasized, they can inhibit angiogenesis by cancer cells in the field, and thus proliferation. Proved.

Example 5 Cancer Cell Growth Inhibition Experiment Nude Mouse BALB / c (obtained from CLEA Japan, body weight: about 80 g) HT1080 (obtained from RIKEN), a fibroblastoma cell line, subcutaneously on the dorsal part of two animals About 1 × 10 ⁷ transplanted. After the tumor diameter reached 6 to 10 mm, a DMSO solution of 0.004 mg of a salt of diphenyleneiodonium and chloride ions was intraperitoneally injected twice or three times a week. Control received only DMSO. FIG. 6 shows the results of changes in tumor volume in control mice and mice administered with the drug of the present invention from the start of administration to 22 days, and FIG. The tumor volume was calculated by the following formula.
Tumor volume = (tumor major axis) x (tumor minor axis) ³ x 1/2

  As shown in FIG. 6, the tumor diameter began to shrink around the sixth day after the start of administration of the anticancer agent of the present invention, and the tumor was reduced to about 16% compared to the control mice on the 22nd day from the start of administration. Reduced. Further, as shown in FIG. 7, the tumor of the mouse administered with the anticancer agent of the present invention is clearly reduced as compared with the control mouse. Therefore, the cancer suppressive effect of the anticancer agent according to the present invention was also demonstrated in an in vivo experiment.

Example 6 Cancer Cell Growth Inhibition Experiment About 1 × 10 ⁷ HepG2, a hepatoma cell line, was transplanted subcutaneously into the dorsal region of three nude mice similar to those used in Example 5 above. After the tumor diameter reached 6 to 10 mm, 0.02 mg or 0.004 mg of an aqueous solution of diphenyleneiodonium sulfate was injected into the peritoneal cavity three times a week. PBS was administered as a control. The results are shown in FIG. As a result of FIG. 8, it was demonstrated that liver cancer can be suppressed by administering the anticancer agent according to the present invention.

Example 7 Experiment for Confirming Mechanism of Invasion / Metastasis Inhibiting Effect A sample was collected from the tumor site of the mouse used in Example 6 above, and its total RNA was extracted to obtain CD31, which is a cancer cell invasion-inducing factor, and angiogenesis. The expression state of VEGF as an inducing factor was examined by quantifying mRNA encoding each by real-time RT-PCR. The results are shown in FIG.

  As in FIG. 9, the anticancer agent of the present invention suppressed the expression of CD31 and VEGF as in the results of Example 4 above. Therefore, it was found that the anticancer agent of the present invention can inhibit the invasion of cancer cells by suppressing the expression of at least the invasion inducing factor. It has also been demonstrated that cancer cells can inhibit angiogenesis and thus proliferation.

It is a figure which shows the growth inhibitory effect of the cancer cell by the anticancer agent which concerns on this invention. It can be seen that the proliferation of hepatoma cells and fibroblastoma cells is remarkably suppressed. It is a figure which shows the growth inhibitory effect of the cancer cell by the anticancer agent which concerns on this invention. (1) is control, (2) is when 1 × 10 ⁻⁷ M of the anticancer agent of the present invention is added, and (3) is when 1 × 10 ⁻⁶ M of the anticancer agent of the present invention is added. is there. It is a figure which shows the growth inhibitory effect of the cancer cell by the anticancer agent which concerns on this invention. (1) is a negative control, (2) is a positive control, (3) is when 1 × 10 ⁻⁸ M of the anticancer agent of the present invention is added, (4) is 1 × of the anticancer agent of the present invention. This is the case when 10 ⁻⁷ M is added. It is a photograph which shows the result of the invasion / metastasis suppression experiment of cancer cells. (1) is control, (2) is when 1 × 10 ⁻⁷ M of the anticancer agent of the present invention is added, and (3) is when 1 × 10 ⁻⁶ M of the anticancer agent of the present invention is added. is there. It is a figure which shows the result of the mechanism confirmation experiment of the invasion and metastasis suppression effect of cancer cells. It is a figure which shows the result of the in vivo experiment using the fibroblast sarcoma cell for demonstrating the cancer inhibitory effect of the anticancer agent which concerns on this invention. It is a photograph of a mouse demonstrating the cancer suppressing effect of the anticancer agent according to the present invention. The upper row is a photograph of a control mouse transplanted with fibroblastic sarcoma, and the lower row is a photograph of a mouse administered with the anticancer agent of the present invention. It is a figure which shows the result of the in vivo experiment using the liver cancer cell for demonstrating the cancer inhibitory effect of the anticancer agent which concerns on this invention. It is a figure which shows the result of the mechanism confirmation experiment of an infiltration / metastasis suppression effect.

Claims (7)

The anticancer agent characterized by including the following compound (I).
[Wherein, R ^{1 to} R ⁸ independently represent a hydrogen atom, or C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, di (C ₁ -C _6-alkyl) amino, C ₁ -C ₇ acylamino, carbamoyl, C ₁ -C ₇ acyl, C ₁ -C ₆ alkylthio, cyano, carboxy, hydroxy, mercapto and halogen 1 type or 2 or more types of substituents selected from the group which consists of an atomic group are shown. ]   The anticancer agent according to claim 1, which suppresses infiltration of cancer cells.   The anticancer agent according to claim 1 or 2, which suppresses angiogenesis by cancer cells.   The anticancer agent according to any one of claims 1 to 3, further comprising a pharmaceutically acceptable anion which can form a salt with the compound (I).   The anticancer agent according to claim 4, wherein the anion is a sulfate ion.   The anticancer according to any one of claims 1 to 5, which is for treating at least one cancer selected from the group consisting of liver cancer, colon cancer, lung cancer, stomach cancer and skin cancer. Agent. The diphenylene iodonium compound of the following compound (II).
[Wherein, R ^{9 to} R ¹⁶ independently represent a hydrogen atom, or C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, di (C ₁ -C ₆ alkyl) amino, C ₁ -C ₇ acylamino, carbamoyl, C ₁ -C ₇ acyl, C ₁ -C ₆ alkylthio, cyano, carboxy, hydroxy, mercapto and halogen 1 type or 2 or more types of substituents selected from the group which consists of an atomic group are shown. However, R ^{9 to} R ¹⁶ are not all hydrogen atoms. ]