JP2021042188A - Dinucleating ligand or dinuclear metal complex - Google Patents

Abstract

To provide a dinuclear metal complex that can be synthesized simply and easily and has a proper anticancer action.SOLUTION: The present disclosure provides a dinucleating ligand represented by the following formula (I) and a dinuclear metal complex thereof (where each X may be the same or different to represent H, Cl, OMe, or, Me, Y is H, a phenyl group, a substituted carbamoyl group or the like).SELECTED DRAWING: None

Description

The present invention relates to a dinuclearization ligand or a dinuclear metal complex having the dinuclearization ligand thereof.

Cisplatin is a metal complex that is clinically used as a chemotherapeutic agent for cancer. Cisplatin exhibits anticancer activity by directly binding to the DNA of cancer cells and distorting the three-dimensional structure of the DNA. However, cisplatin may show side effects such as vomiting and nephrotoxicity, and cisplatin-resistant cancer has also been reported in recent years. Therefore, a chemotherapeutic drug to replace cisplatin is required.

For example, bleomycin binds to iron in cancer cells to activate oxygen, thereby cleaving DNA strands and suppressing the growth of cancer cells (Non-Patent Document 1). Bleomycin is widely used in clinical medicine as an excellent chemotherapeutic agent for squamous cell carcinoma and malignant lymphoma of human skin, head and neck, cervix and the like. However, bleomycin is a water-soluble glycopeptide antibiotic obtained from the actinomycete Streptomyces Verticillus, and a chemotherapeutic agent obtained by a simple synthesis method independent of microorganisms is required.

Also, for example, an iron complex of an N4Py ligand that mimics the active center of bleomycin can react with hydrogen peroxide to form an active species, which oxidatively cleaves DNA to exhibit anticancer activity. It has been reported (Non-Patent Document 2). However, since this iron complex has high DNA cleavage activity even in the absence of hydrogen peroxide, it may not have selectivity between normal cells and cancer cells. Therefore, the development of a metal complex having selectivity between normal cells and cancer cells is required.

Cancer cells have a higher ROS concentration such as hydrogen peroxide (H ₂ O _{2) than normal cells.} Therefore, attention is focused on metal complexes that promote DNA oxidative cleavage by _{H 2} O ₂ toward the development of anticancer agents that do not act on normal cells and have no side effects that selectively kill cancer cells. _{The inventors of the novel dinuclear copper complex [Cu 2} (μ-OH) (bcamide)] (ClO ₄ ) _{2 in} which cyclen was introduced at the 2,6-position of p-cresol by an amide bond. Was successfully developed and _{oxidatively cleaved DNA by H 2} O ₂ (Patent Document 1). However, this complex has low cytotoxicity to HeLa cells, which are cancer cells, and needs improvement.

Japanese Unexamined Patent Publication No. 2018-135304

H. Umezawa, K. Maeda, T. Takeuchi, Y. Okami, J. Antibiot., 19 A, 200 (1966). Q. Li, M. G. P. Wijst, H. G. Kazemier, M. G. Rots, G. Roelfes, ACS Chem. Biol., 9, 1044-1051 (2014).

The present invention has been made in view of the above problems, and is a dinuclear metal complex having a dinuclearization ligand or a dinuclearization ligand thereof, which can be easily synthesized and has an accurate anticancer effect. The purpose is to provide.

The dinuclearized ligand according to the present invention is represented by the following chemical formula (I) or (II).

Here, (i) X is the same or different H, Cl, OMe, or Me, and (ii) in the chemical formula (I), Y is a hydrogen atom, a linear or branched alkyl having 1 to 8 carbon atoms. group, alkoxy group, alkoxyalkyl group, an ester group, an ester group, or a phenyl group, a pyridyl group, an amino group, a hydroxyl group, a thiol group, a fluorine atom, a chlorine atom, the amino group NR ₁ R ₁ 'group can described as, R ₁ and R ₁ 'are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group, (iii) formula In (II), R is a polycyclic aromatic heterocyclic compound or a polycyclic aromatic hydrocarbon compound, and n is an integer of 1 to 8.

The dinuclear metal complex according to the present invention is represented by the following chemical formula (IV) or (V).

Here, (i) M is Cu, Fe, Zn, Co, Mn, Re, Ru, Rh, Pd, Pt or Ce, and (ii) in chemical formula (V), R is a polycyclic aromatic heterocycle. It is a compound or a polycyclic aromatic hydrocarbon compound, and n is an integer of 1 to 8.

According to the present invention, a dinuclearized ligand or a dinuclear metal complex having little effect on normal cells and having an accurate nucleic acid cleaving action of cancer cells can be easily obtained.

It is a figure which shows ^{the 1} H NMR spectrum of 2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) -4-methylphenol (Hbdpamide). (2-9) It is a figure which shows the ^{1 H NMR spectrum of Hbpcp 4-Cl.} It is a figure which shows the ¹ H NMR spectrum of Hbpcp ^{4-OMe. 1} H NMR of 4- (8-N- (9-phenanthrene carbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -1,3-bis (N, N-bis (2-pyridylmeth-yl) carbamoyl) hydroxybenzene It is a figure which shows the spectrum. ESI-MS of 4- (8-N- (9-phenanthrenecarbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -1,3-bis (N, N-bis (2-pyridylmeth-yl) carbamoyl) hydroxybenzene It is a figure which shows the spectrum. ¹ H NMR spectrum of 4- (8-N- (9-acridinecarbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) hydroxybenzene It is a figure which shows. ESI-MS spectrum of 4- (8-N- (9-acridinecarbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) hydroxybenzene It is a figure which shows. ¹ H NMR spectrum of 4- (8-N- (9-pyrenecarbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) hydroxybenzene It is a figure which shows. ESI-MS spectrum of 4- (8-N- (9-pyrenecarbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) hydroxybenzene It is a figure which shows. Binuclear metal complex - a diagram showing the ESI-MS spectrum of _{[Cu 2 (μ-OAc)} 2 (bdpamide)] (OAc) (1). It is a figure which shows the X-ray single crystal structure of a dinuclear metal complex [Cu ₂ (μ-OAc) ₂ (bdpamide)] (ClO _{4) (2).} It is a figure which shows the X-ray single crystal structure of a dinuclear metal complex [Cu ₂ (μ-OAc) (μ-H ₂ O) (bdpamide)] (ClO ₄ ) _{2 (3).} Binuclear metal complex _{[Cu 2 (μ-OAc)} - 2 (bdpamide 4-Cl)] is a diagram showing an ESI-MS spectrum of (OAc) (4). Binuclear metal complex - a diagram showing the ESI-MS spectrum of _{[Cu 2 (μ-OAc)} 2 (bdpamide 4-OMe)] (OAc) (5). Binuclear metal complex - a diagram showing the ESI-MS spectrum of _{[Cu 2 (μ-OAc)} 2 (bdpamide-PEG3-phen)] (OAc) (6). Binuclear metal complex - a diagram showing the ESI-MS spectrum of _{[Cu 2 (μ-OAc)} 2 (bdpamide-PEG3-acr)] (OAc) (7). Binuclear metal complex - a diagram showing the ESI-MS spectrum of _{[Cu 2 (μ-OAc)} 2 (bdpamide-PEG3-pyr)] (OAc) (8). Binuclear metal complex _{[Cu 2 (μ-OAc)} - 2 (bdpamide)] (OAc) (1) is a diagram showing the DNA oxidation cleavage activity to catalyze. It is a figure which shows the DNA oxidative cleavage activity catalyzed by a dinuclear metal complex [Cu ₂ (μ-OAc) ₂ (bdpamide)] (ClO _{4) (2).} Binuclear metal complex _{[Cu 2 (μ-OAc)} - 2 (bdpamide-PEG3-phen)] (OAc) (6) is a diagram showing the DNA oxidation cleavage activity to catalyze. Binuclear metal complex _{[Cu 2 (μ-OAc)} - 2 (bdpamide-PEG3-acr)] (OAc) (7) is a diagram showing the DNA oxidation cleavage activity to catalyze. Binuclear metal complex _{[Cu 2 (μ-OAc)} - 2 (bdpamide-PEG3-pyr)] (OAc) (8) is a diagram showing the DNA oxidation cleavage activity to catalyze.

Hereinafter, embodiments of the present invention will be specifically described with reference to the accompanying drawings, but the embodiments are for facilitating understanding of the principles of the present invention, and the scope of the present invention is as follows. The present invention is not limited to the embodiment, and other embodiments in which those skilled in the art appropriately replace the configurations of the following embodiments are also included in the scope of the present invention.

As a result of diligent research, the present inventor has found as a new finding that the dinuclearization ligand according to the following formula has a high nucleic acid cleaving action, and completed the present invention based on such fact.

Here, (i) X is the same or different H, Cl, OMe, or Me, and (ii) in the chemical formula (I), Y is a hydrogen atom, a linear or branched alkyl having 1 to 8 carbon atoms. group, alkoxy group, alkoxyalkyl group, an ester group, an ester group, or a phenyl group, a pyridyl group, an amino group, a hydroxyl group, a thiol group, a fluorine atom, a chlorine atom, the amino group NR ₁ R ₁ 'group can described as, R ₁ and R ₁ 'are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group, (iii) formula In (II), R is a polycyclic aromatic heterocyclic compound or a polycyclic aromatic hydrocarbon compound. The polycyclic aromatic heterocyclic compound is a compound having a tricyclic type or more and containing one or more heterocycles, and has a highly planar structure of a π-conjugated system. The polycyclic aromatic hydrocarbon compound is a hydrocarbon compound in which an aromatic ring containing no heteroatom is condensed, and is preferably a tricyclic or higher compound. n is an integer of 1 to 8, preferably 1 to 3, and more preferably 2.

In formula (II), R is set to promote cell introduction of the complex and promote DNA oxidative cleavage _{of H 2} O _{2 by the complex.} The polycyclic aromatic heterocyclic compound is not particularly limited, but is, for example, acridine, xanthene or carbazole, preferably the acridine shown below. The bonding site of the polycyclic aromatic heterocyclic compound is not particularly limited. For example, as shown below, there are carbon atoms in which substituents can be introduced from the 1st to 9th positions in acridine, but any carbon atom can be used. It can be a bond site, preferably a carbon atom at the 9, 1 or 8 position.

The polycyclic aromatic hydrocarbon compound is not particularly limited, but is, for example, phenanthrene, pyrene, anthracene, tetracene, pentacene, benzopyrene, chrysene, triphenylene, corannulene, coronene or ovalene, and is preferably shown below. It is a phenanthrene. The bonding site of the polycyclic aromatic hydrocarbon compound is not particularly limited. For example, as shown below, phenanthrene has carbon atoms into which substituents can be introduced from the 1st to 10th positions, but any carbon atom can be used. It can be a bond site, preferably a carbon atom at the 9- or 10-position as shown in Examples below.

R is set to promote cell introduction of the complex and promote _{DNA oxidative cleavage of H 2} O ₂ by the complex, and is a polycyclic aromatic heterocyclic compound or a polycyclic aromatic hydrocarbon compound. In addition, it is also possible to use a minor groove binder, and specific examples thereof include distamycin A and netropsin. Molecules that bind in the minor groove of the DNA double helix have sequence selectivity. Therefore, it is possible to selectively act on the gene that caused the abnormality, which leads to the reduction of side effects caused by the anticancer drug.

The dinuclear ligand represented by the above formula is a compound having a novel structure. As will be described later, the dinuclear ligand and the dinuclear metal complex according to the present invention can cleave nucleic acids only by the reaction between the _{compound and H 2} O _2.

In the present invention, the dinuclearization ligand represented by the following chemical formula (III) is preferable.

In addition, the present inventor has found as a new finding that the dinuclear metal complex represented by the following chemical formula (IV) or (V) has a high nucleic acid cleavage action. Here, M is Cu, Fe, Zn, Co, Mn, Re, Ru, Rh, Pd, Pt or Ce, preferably Cu.

In the chemical formula (V), R is a polycyclic aromatic heterocyclic compound or a polycyclic aromatic hydrocarbon compound. n is an integer of 1 to 8, preferably 1 to 3, and more preferably 2.

In the present invention, a dinuclear metal complex represented by the following chemical formula (VI) or (VII) is preferable.

In the chemical formula (VII), R is a polycyclic aromatic heterocyclic compound or a polycyclic aromatic hydrocarbon compound. n is an integer of 1 to 8, preferably 1 to 3, and more preferably 2.

In the above, the nucleic acid to be cleaved is DNA or RNA.

Further, since the dinuclear ligand and the dinuclear metal complex according to the present invention have a high nucleic acid cleavage action, they can be used, for example, as a tool for analyzing gene structure.

In addition, the dinuclear ligand and the dinuclear metal complex according to the present invention can be used as an anticancer agent because they can cleave the nucleic acid of cancer cells. Cancer cells have higher _{H 2} O ₂ levels than normal details due to mitochondrial dysfunction and abnormal metabolism. Further and catalase is an exploded enzyme H ₂ O ₂ lowers the concentration of H ₂ O ₂ in normal cells. However, cancer cells are low in catalase and cannot degrade _{H 2} O _{2 like normal cells.} In addition, superoxide dismutase (SOD), which dismutates superoxide ions to _{produce H 2} O ₂ , is highly activated, and cancer cells have a higher H ₂ O ₂ concentration than normal cells. The dinuclear ligand and the dinuclear metal complex according to the present invention _{can cleave nucleic acids only by the reaction between the compound and H 2} O _2, and can specifically cleave the nucleic acids of cancer cells. Therefore, according to the present invention, the effect on normal cells is small. Further, the dinuclear ligand and the dinuclear metal complex according to the present invention have high _{H 2} O ₂ affinity because they bind _{H 2} O _{2 with two metal ions (for example, two copper ions).} Therefore, even when used in vivo, it _{reacts with a small amount of H 2} O ₂ and exhibits high nucleic acid cleavage activity.

In the dinuclearization ligand represented by the above chemical formula (I), Y is preferably a functional group attracted to the surface of cancer cells. Compared to normal cells, the surface of cancer cells contains more anionic compounds such as sialic acid and heparan sulfate and is negatively charged. So, for example, Y can be a functional group that is attracted to the negative charge on the surface of cancer cells.

The dinuclearized ligand and the dinuclear metal complex according to the present invention can be used for various cancers and are not particularly limited, but for example, colon cancer, gastric cancer, esophageal cancer, and the like. Colon cancer, liver cancer, pancreatic cancer, breast cancer, lung cancer, bile sac cancer, bile duct cancer, biliary tract cancer, rectal cancer, ovarian cancer, uterine cancer, renal cancer, bladder cancer, prostate It can be used for the treatment of cancer, osteosarcoma, brain tumor, leukemia, myoma, skin cancer, malignant melanoma, malignant lymphoma, tongue cancer, myeloma, thyroid cancer, skin metastatic cancer, skin melanoma, etc. ..

The administration form of the anticancer agent having the dinuclearization ligand and the dinuclear metal complex according to the present invention is not particularly limited, and either oral or parenteral administration form may be used. In addition, it can be made into an appropriate dosage form according to the administration form, for example, oral preparations such as injections, capsules, tablets, granules, powders, pills, fine granules, rectal administrations, oily suppositories. , Aqueous suppositories and the like.

Various preparations can be prepared by appropriately adding pharmacologically acceptable additives such as excipients, binders, lubricants, disintegrants, surfactants, and fluidity promoters. Excipients include lactose, fructose, glucose, corn starch, sorbitol, etc., binders include methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc., and lubricants include talc, magnesium stearate, polyethylene glycol, etc. Etc., as a disintegrant, starch, sodium alginate, gelatin, calcium carbonate, calcium citrate, dextrin, magnesium carbonate, synthetic magnesium silicate, etc., and as a surfactant, sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80. As the fluidity accelerator, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like can be used.

The dose of the anticancer agent having the dinuclear ligand and the dinuclear metal complex according to the present invention is appropriately determined in consideration of the usage, the age, sex, degree of symptoms, etc. of the patient, and is, for example, Adults 10 to 800 mg per day, preferably 100 to 200 mg, which can be administered once or in several divided doses per day.

(1) Synthesis of dinuclearized ligand (Hbdpamide)
(1-1) Synthesis of 2,6-bis (hydroxymethyl) -4-methylphenol
The rotor was placed in a 300 mL eggplant flask and dried under vacuum. P-cresol (15.0 g, 0.139 mol) and 5% aqueous NaOH solution (120 mL) were added to the reaction vessel, and the mixture was stirred at room temperature until the exotherm subsided. A 37% aqueous formaldehyde solution (23 mL) was added thereto, and the mixture was stirred at room temperature for 6 days. After adding 12 M HCl (10 mL), the precipitated precipitate was filtered through Nutche. This was recrystallized from EtOAc to give a yellow solid (11.9 g, Yield 51%).
^{1 1} H NMR (500 MHz, CDCl ₃ ); δ / ppm: 7.85 (s, 1H, OH), 6.88 (s, 2H, Ph), 4.78 (s, 4H, CH ₂ ), 2.46 (s, 2H, OH) ), 2.25 (s, 3H, CH ₃ ).

(1-2) Synthesis of 1-methoxy-2,6-bis (hydroxymethyl) -5-methylbenzene
The rotor was placed in a 200 mL eggplant flask, and an aqueous solution prepared by dissolving 2,6-bis (hydroxymethyl) -4-methylphenol (10.3 g, 61.3 mmol) and NaOH (3.57 g, 89.3 mmol) in 33 mL of distilled water was added. .. Dimethyl sulfate (6.0 mL, 63.3 mmol) was added and the mixture was stirred for 30 minutes. After 30 minutes, suction filtration was performed with a Kiriyama funnel, and dimethyl sulfate (3.0 mL, 31.6 mmol) was slowly added while stirring the filtrate. After 90 minutes, suction filtration was performed with a Kiriyama funnel to obtain a solid. This was vacuum dried to give the desired product as a white solid (4.33 g, Yield 39%).
¹ H NMR (500 MHz, acetone-d ₆ ); δ / ppm: 7.18 (s, 2H, Ph), 4.64 (s, 4H, CH ₂ ), 3.74 (s, 3H, OCH ₃ ), 2.28 (s, 3H, CH ₃ ).

(1-3) Synthesis of 2-methoxy-5-methylisophthalic acid
The rotor was placed in a 200 mL eggplant flask, and 1-methoxy-2,6-bis (hydroxymethyl) -5-methylbenzene (3.72 g, 20.4 mmol) and KOH (0.420 g, 7.48 mmol) were dissolved in 95 mL of distilled water. An aqueous solution was added. The eggplant flask was placed in an ice bath and stirred. _{KMnO 4} (8.86 g, 56.1 mmol) was added in small portions every few minutes. After 30 minutes, the mixture was stirred at room temperature for 1 hour. HCHO (68 μL, 0.91 mmol) was added, stirring was stopped after 30 minutes, and the mixture was filtered through formaldehyde using Nutche. The filtrate was concentrated. When HCl was added and the pH was set to 1, a white solid was precipitated. This was suction filtered with a Kiriyama funnel and vacuum dried to obtain the desired product as a white solid (2.24 g, Yield 52%).
^{1 1} H NMR (500 MHz, DMSO-d ₆ ); δ / ppm: 7.62 (s, 2H, Ph), 3.76 (s, 3H, OCH ₃ ), 2.31 (s, 3H, CH ₃ ).

(1-4) Synthesis of 2-hydroxy-5-methylisophthalic acid
The rotor was placed in a 200 mL eggplant flask, and 2-methoxy-5-methylisophthalic acid (2.57 g, 12.2 mmol) and 30% HBr / AcOH (12 mL, 61.2 mmol) were added. The reflux tube was connected to an eggplant flask without a ball stopper, soaked in an oil bath and stirred, and the temperature was gradually raised from 50 ° C. to 120 ° C. over 1 hour and 45 minutes until no gas was emitted. Then, the oil bath was removed and stirring was continued until room temperature was reached. When the temperature dropped to room temperature, stirring was stopped, and when distilled water was added, a bluish-purple solid was precipitated. This was suction-filtered using a Kiriyama funnel, washed with distilled water, and the obtained solid was vacuum-dried. The desired product was obtained as a pale purple solid (1.93 g, Yield 80%).
^{1 1} H NMR (500 MHz, DMSO-d ₆ ); δ / ppm: 7.77 (s, 2H, Ph), 2.25 (s, 3H, CH ₃ ).

(1-5) 2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) -4-methylphenol (Hbdpamide)
2-hydroxy-5-methylisophthalic acid (1.00 g, 5.10 mmol) and SOCl ₂ (50 mL) were added to a 300 mL eggplant flask containing a rotor, a reflux device was attached, and the mixture was stirred at 60 ° C. for 4 hours. .. _{Then, SOCL 2} was distilled off at 40 ° C. and vacuum dried to obtain a yellow oily substance. Subsequently, the rotor was placed in a 300 mL three-mouth reaction vessel, and K ₂ CO ₃ (4.50 g, 32.6 mmol), di (2-pyridylmethyl) amine (2.10 g, 10.5 mmol), and dry CH ₂ Cl ₂ (50 mL) were added. added. A solution prepared by dissolving the yellow oily substance obtained earlier in dry CH ₂ Cl ₂ (50 mL) was added to this solution under a nitrogen atmosphere, and the mixture was degassed and replaced with nitrogen, and then stirred overnight. After confirming that no raw material remained by ESI-MS, filtration through Nutche gave a pale yellow-green filtrate. Transfer this filtrate to a 300 mL separatory funnel and divide with distilled water (3 x 10 mL). Distilled. _{Na 2} SO ₄ was added to the organic layer for dehydration, filtration was performed, the filtrate was concentrated with a rotary evaporator, and vacuum dried to obtain a brown solid. The solid was dissolved in a minimum amount of CHCl ₃ (2 mL) and purified by alumina column chromatography (gradient CHCl ₃ / MeOH from 100/0 to 50/1). Fractions containing the desired material were collected, concentrated on a rotary evaporator and vacuum dried to give a pale yellow solid (2.64 g, Yield 93%). ^{The 1} H NMR spectrum of this solid is shown in FIG.
^{1 1} H NMR (500 MHz, CDCl ₃ ); δ / ppm: 11.6 (s, H, OH), 8.49 (d, J = 5.2 Hz, 4H, CH), 7.73 (t, J = 5.7, 7.5 Hz, 2H) , CH), 7.64 (t, J = 7.5 Hz, 2H, CH), 3.52 (d, J = 7.5 Hz, 2H, CH), 7.24-7.26 (m, 2H, CH), 7.18 (s, 2H, CH) ), 7.15-7.19 (m, 4H, CH), 4.95 (s, 4H, CH ₂ ), 4.66 (s, 4H, CH ₂ ), 2.21 (s, 3H, CH ₃ ).

(2) Synthesis of dinuclear ligand (Hbdpamide ^4-Cl )
(2-1) Synthesis of 2-methoxycarbonyl-4-chloropyridine
In a 200 mL eggplant flask, picolinic acid (10.0 g, 81.2 mmol), SOCl ₂ (50 mL) and dry DMF (4 mL) were added, and the mixture was refluxed in an oil bath at about 80 ° C. for 2 days. After stopping the reflux, SOCL ₂ was distilled off under reduced pressure in an oil bath at about 40 ° C. using an aspirator. After distillation under reduced pressure, dry toluene (20 mL) and dry MeOH (10 mL) were added under an ice bath, and the mixture was replaced with degassed nitrogen, and the mixture was stirred at room temperature for about 3 hours. After stopping the stirring, the reaction solution was filtered through Nutche, and the precipitated solid was collected by filtration. The solid was _{neutralized with saturated aqueous Na 2} CO ₃ solution and separated with CHCl ₃ (3 x 100 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , filtered off, and the filtrate was concentrated on a rotary evaporator and vacuum dried. The desired product was obtained as a pale yellow solid (6.50 g, Yield 47%).

(2-2) Synthesis of 2-hydroxymethyl-4-chloropyridine
Place the rotor, 2-methoxycarbonyl -4-chloropyridine (20.0 g, 0.117 mol), CaCl ₂ (52.0 g, 0.469 mol), and dry MeOH-THF (120: 70 mL) in a 100 mL eggplant flask and place in an ice bath. NaBH ₄ (8.8 g, 0.233 mol) was added slowly, replaced with degassed nitrogen, and then stirred at room temperature overnight. _{After stopping the stirring, H 2} O was added under an ice bath, and the mixture was stirred at room temperature for 2 hours to decompose _{excess Na BH 4.} The reaction solution was concentrated on a rotary evaporator, H ₂ O (200 mL) was added, and the mixture was separated with EtOAc (3 x 200 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, and the filtrate was concentrated on a rotary evaporator. The residue was vacuum dried to give a white solid (16.3 g, Yield 97%).

(2-3) Synthesis of 2-formyl-4-chloropyridine
_{Add MnO 2} (90 g), 2-hydroxymethyl-4-chloropyridine (8.00 g, 55.7 mmol), and dry CHCl ₃ (96 mL), which have been vacuum-dried by heating with a rotor and a heat gun, to a 100 mL eggplant flask. After degassing and nitrogen replacement, the mixture was refluxed in an oil bath at about 80 ° C. for about 36 hours. After stopping reflux, the reaction solution was filtered through Celite and washed well with _{CHCl 3.} The filtrate was concentrated on a rotary evaporator and dried in vacuo to give a yellow solid (6.55 g, Yield 83%).

(2-4) Synthesis of 2-chloromethyl-4-chloropyridine
A rotator, 2-hydroxymethyl-4-chloropyridine (8.00 g, 55.7 mmol) and dry CH ₂ Cl ₂ (40 mL) were placed in a 50 mL eggplant flask. _{SOCL 2} (30 mL) was slowly added to this in an ice bath, and the mixture was refluxed in an oil bath at 50 ° C. for 3 hours. After stopping the reflux, SOCL ₂ was removed by vacuum distillation using an ejector. The solid precipitated by distillation under reduced pressure _{was diluted with saturated acrylamide 3} aqueous solution (100 mL) and separated with CHCl ₃ (3 x 300 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, and the filtrate was concentrated on a rotary evaporator and vacuum dried. The desired product was obtained as a dark yellow liquid (9.17 g, Yield 98%).

(2-5) Synthesis of 2-azidomethyl-4-chloropyridine
Rotor, 2-chloromethyl-4-chloropyridine (9.17 g, 56.6 mmol), dry DMF (180 mL), NaN ₃ (10.0 g, 0.154 mol) were added to a 50 mL eggplant flask, replaced with degassed nitrogen, and then 60. The mixture was stirred overnight in an oil bath at ° C. Stirring was stopped, saturated aqueous acrylamide solution (300 mL) was added to the reaction solution, and the solution was separated with AcOEt-hexane (1: 1) (3 x 300 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, and the filtrate was concentrated on a rotary evaporator and vacuum dried. The desired product was obtained as a dark brown liquid (8.54 g, Yield 89%).

(2-6) Synthesis of 2-aminomethyl-4-chloropyridine
Place the rotor in a 100 mL two-mouth reaction vessel, add 2-azidomethyl-4-chloropyridine (8.54 g, 50.6 mmol), dry THF (72.7 mL), and PPh ₃ (20.0 g, 76.3 mmol) under an ice bath. Was slowly added and replaced with degassed nitrogen, and the mixture was stirred at room temperature for about 3 hours. After confirming that no raw material remained by DART, H ₂ O (4 mL, 0.222 mol) was added and replaced with degassed nitrogen. Then, it was stirred at room temperature overnight. After confirming that no intermediate remained by DART, the reaction solution was concentrated with an evaporator and separated with CHCl ₃ (100 mL) and 1 M HCl aqueous solution (3 × 100 mL). An aqueous layer was collected, neutralized with 2 M aqueous NaOH solution, and separated with CHCl ₃ (3 x 300 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, the filtrate was concentrated on an evaporator and vacuum dried to give a brown liquid (6.50 g, Yield 90%).

(2-7) Synthesis of 1-tert-butoxycarbonyl-bis (4-chloropyrid-2-ylmethyl) amine
Place the rotor in a 100 mL 2-necked eggplant flask and dry MeOH (6.28 g, 44.2 mmol) and 2-formyl-4-chloropyridine (6.55 g, 46.5 mmol) while flowing nitrogen. It was added to 50 mL) under an ice bath, replaced with degassed nitrogen, and the resulting solution was stirred under an ice bath for about 1 hour. To this, NaBH ₄ (4.18 g, 0.110 mol) was added under an ice bath to replace with degassed nitrogen, and the mixture was stirred under an ice bath for about 3 hours. A 6 M HCl aqueous solution was gradually added to this reaction solution in an ice bath _{to decompose excess NaBH 4} , and then concentrated with an evaporator. After concentration, the mixture was separated _{using CH 2 Cl 2} and a saturated _{aqueous solution of Na 2} CO ₃ , the organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, and the filtrate was concentrated with an evaporator and dried in vacuum. Obtained the liquid. This was dissolved in CH ₂ Cl ₂ (90 mL) and placed in a 300 mL eggplant flask, which contained the rotor. While immersing this solution in an ice bath and stirring, slowly add a solution of _{Boc 2} O (16.4 g, 75.1 mmol) and Et ₃ N (10.5 mL, 75.1 mmol) in CH ₂ Cl _{2 (90 mL).} After degassing and nitrogen substitution, the mixture was stirred overnight at room temperature. The reaction solution was concentrated with an evaporator and separated into a saturated aqueous solution of _{LVDS 3 and CH 2} Cl ₂ . The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, the filtrate was concentrated with an evaporator and vacuum dried to obtain a reddish brown liquid. This was _{purified by SiO 2} column chromatography (CHCl ₃ : MeOH = 50: 1) to give a brown liquid (9.76 g, Yield 60%).

(2-8) Synthesis of bis (4-chloropyrid-2-ylmethyl) amine
Put the rotor in a 100 mL eggplant flask, dissolve 1-tert-butoxycarbonyl-bis (4-chloropyrid-2-ylmethyl) amine (1.60 g, 4.36 mmol) in EtOH (90 mL), and add 12 M HCl aqueous solution (12 M HCl aqueous solution). 30 mL) was added and replaced with degassed nitrogen, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated with an evaporator and dried under vacuum to obtain a reddish brown solid. This was _{diluted with a saturated aqueous solution of K 2} CO ₃ and separated using CH ₂ Cl ₂ . The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, and the filtrate was concentrated on an evaporator. This was vacuum dried to give a reddish brown liquid (1.00 g, Yield 86%).

(2-9) Synthesis of Hbpcp ^4-Cl
The rotor was placed in a 10 mL eggplant flask, 2-hydroxy-5-methylisophthalic acid (43.9 mg, 0.224 mmol) and SOCL ₂ (3 mL) were added, and the mixture was refluxed in an oil bath at about 60 ° C. for about 4 hours. Reflux was stopped, SOCl ₂ was distilled off under reduced pressure using an aspirator, and then vacuum dried to obtain a yellow solid. Place the rotor in a 30 mL 2-necked eggplant flask, add bis (4-chloropyrid-2-ylmethyl) amine (150 mg, 0.560 mmol) and K ₂ CO ₃ (255 mg, 1.85 mmol), and dry CH ₂ Cl. _The above yellow solid dissolved in 2 (5 mL) was added, replaced with degassed nitrogen, and then stirred overnight in a water bath at about 30 ° C. Stirring was stopped, the reaction solution _{was dissolved in a small amount of CH 2} Cl ₂ and filtered through a Kiriyama funnel, and the remaining solid was washed with a _{small amount of CH 2} Cl _2. The filtrate was collected, CH ₂ Cl ₂ was added to make 100 mL, and the _{mixture was separated and washed with H 2} O (30 mL × 3). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, the filtrate was concentrated on an evaporator and then vacuum dried to give a brown solid. This was purified by column chromatography using alumina (CHCl ₃ : MeOH = 50: 1). The desired product was obtained as a brown solid (102 mg, Yield 65%). ^{The 1} H NMR spectrum of this solid is shown in FIG.

(3) Synthesis of dinuclear ligand (Hbdpamide ^4-OMe )
(3-1) Synthesis of 2-hydroxymethyl-4-methoxypyridine
The rotor was placed in a 100 mL two-mouth reaction vessel, a Dimroth condenser was attached, and the mixture was vacuum dried while heating using a heat gun. 2-hydoroxymethyl-4-chloropyridine (3.00 g, 20.9 mmol) was added thereto, and dry MeOH (60 mL) was added under an _{N 2 atmosphere.} MeONa (24.0 g, 444 mmol) was added thereto, and the mixture was degassed and replaced with nitrogen, and then heated under reflux at 80 ° C. overnight. ^{After confirming that no raw material remained by 1} H NMR, the reaction vessel was returned to room temperature and carefully adjusted to pH 7-8 with a 12 M HCl aqueous solution. After removing the precipitate by filtration through Celite, the filtrate was concentrated on a rotary evaporator and then vacuum dried to give a pale yellow solid (2.24 g, Yield 77%).

(3-2) Synthesis of 2-formyl-4-methoxypyridine
_{A rotor and MnO 2} (23.1 g, 70% assay, 184 mmol) were placed in a 100 mL two-mouth reaction vessel, a Dimroth condenser was attached, and the mixture was vacuum dried while heating with a heat gun. To this, 2-hydroxymethyl-4-methoxypyridine (2.14 g, 15.4 mmol) and dry CHCl ₃ (25 mL) were added, and the mixture was heated under reflux at 80 ° C. for 24 hours. ^{After confirming that no raw material remained by 1} H NMR, the reaction vessel was returned to room temperature. After removing MnO ₂ by Celite filtration _{, the filtrate was thoroughly washed with CHCl 3} , concentrated on a rotary evaporator, and vacuum dried to obtain a brown oily substance (1.87 g, Yield 89%).

(3-3) Synthesis of 2-choloromethyl-4-methoxypyridine
Place the rotor in a 100 mL dual reaction vessel, add 2-hydloxymethyl-4-methoxypyridine (2.19 g, 15.7 mmol), CH ₂ Cl ₂ (12 mL), SOCl ₂ (10 mL) in that order, and attach a perfusion tube. The mixture was stirred at 50 ° C. for 4 hours. _{SOCl 2} was distilled off using an aspirator and vacuum dried to obtain a yellow solid. This was dissolved in saturated LVDS ₃ (50 mL) and separated with CHCl ₃ (3 x 150 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, concentrated on a rotary evaporator and vacuum dried to give an orange oil (2.43 g, Yield 98%).

(3-4) Synthesis of 2-azidomethyl-4-methoxypyridine
Rotor was placed in a 100 mL eggplant flask, 2-chloromethyl-4-methoxypyridine (2.43 g, 15.4 mmol), NaN ₃ (3.10 g, 47.7 mmol) and dry DMF (50 mL) were added, and degassed and replaced with nitrogen. After that, it was stirred at 50 ° C. overnight. After returning the reaction vessel to room temperature, a saturated acrylamide ₃ aqueous solution (100 mL) was added, and the mixture was separated with EtOAc (3 × 300 mL). After removing the organic layer, the solution was separated with a saturated aqueous NaCl solution (2 x 300 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, concentrated on a rotary evaporator and vacuum dried to give a brown oil (2.37 g, Yield 94%).

(3-5) Synthesis of 2-aminomethyl-4-methoxypyridine
Place the rotor in a 100 mL dual reaction vessel and soak in an ice bath, then 2-azidomethyl-4-methoxypyridine (2.37 g, 14.4 mL), dry THF (18 mL), PPh ₃ (5.89 g, 22.5 mmol). Was degassed and replaced with nitrogen, and the mixture was stirred at 0 ° C. for 1 hour. Then, the mixture was stirred at room temperature for 2 hours, and after confirming that no raw material remained by DART, H ₂ O (2 mL) was added, degassed and replaced with nitrogen, and then the mixture was stirred at 30 ° C. overnight. After confirming that no raw material remained by DART, THF was concentrated on a rotary evaporator and vacuum dried to obtain a yellow solid. This _{was dissolved in CHCl 3} (50 mL) and separated by 1 M HCl aqueous solution (3 x 50 mL). After removing the aqueous layer, the pH was adjusted to 11 with a 4M NaOH aqueous solution. The aqueous layer was separated with CHCl ₃ (3 x 200 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, concentrated on a rotary evaporator and vacuum dried to give an orange oil (1.84 g, Yield 92%).

(3-6) Synthesis of 1-tert-butoxycarbonyl-bis (4-methoxypyrid-2-ylmethyl) amine
Place the rotor in a 100 mL dual reaction vessel and immerse in an ice bath to 2-aminomethyl-4-methoxypyridine (1.59 g, 11.5 mmol), 2-formyl-4-methoxypyridine (1.72 g, 12.5 mmol), dry MeOH ( 13.5 mL) was added, and the mixture was degassed and replaced with nitrogen, and then stirred at 0 ° C. for 1 hour. After confirming the formation of imine and the absence of 2-aminomethyl-4-methoxypyridine by ¹ _{H NMR, NaBH 4} (1.03 g, 27.2 mmol) was added, degassed and replaced with nitrogen, and then at 0 ° C. for 2 hours. Stirred. ^{After confirming that no imine remained by 1} H NMR, the pH was adjusted to 1 with a 6 M HCl aqueous solution while maintaining 0 ° C. After concentrating this with a rotary evaporator, water remained to some extent, and then the solution was separated with CH ₂ Cl ₂ (3 x 200 mL) _{using a saturated aqueous solution of Na 2} CO _3. The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, the filtrate was concentrated on a rotary evaporator and vacuum dried to give a yellow oil (3.00 g).

The oil _{was dissolved in CH 2} Cl ₂ (24 mL), soaked in an ice bath and then Et ₃ N (3.26 mL, 23.4 mmol) was added. _{Boc 2} O (5.09 g, 23.3 mmol) dissolved in CH ₂ Cl ₂ (40 mL) was _{added thereto under an N 2} atmosphere, and the mixture was degassed and replaced with nitrogen, and then stirred at 0 ° C. overnight. _{CH 2} Cl ₂ (36 mL) was added to this reaction solution, and the mixture was separated _{with a saturated aqueous solution of LVDS 3} (3 × 30 mL). The organic layer was collected, _{dehydrated with Na 2} SO ₄ , removed by filtration, the filtrate was concentrated on a rotary evaporator and vacuum dried to give a brown oily substance. This was purified by alumina column chromatography (developing solvent: EtOAc), the fraction containing the desired product was collected, concentrated on a rotary evaporator, and vacuum dried to obtain a yellow oily substance (2.80 g, Yield 68%). ).

(3-7) Synthesis of bis (4-methoxypyrid-2-ylmethyl) amine
Place the rotator in a 100 mL eggplant flask and add 1-tert-butoxycarbonyl-bis (4-chloropyrid-2-ylmethyl) amine (150.0 mg, 0.417 mmol), EtOH (12 mL), 12 M HCl (4 mL). After deaeration and nitrogen substitution, the mixture was stirred overnight. The reaction solution was concentrated on a rotary evaporator and vacuum dried to obtain a brown solid. This _{was dissolved in a saturated aqueous solution of K 2} CO ₃ (20 mL) and separated by CH ₂ Cl ₂ (3 × 50 mL). _{After dehydrating by adding Na 2} SO ₄ to the organic layer, the mixture was filtered through Nutche, the filtrate was concentrated on a rotary evaporator, and vacuum dried to obtain a dark yellow oily substance (84.2 mg, Yield 50%).

(3-8) Synthesis of Hbpcp ^4-OMe
The rotor was placed in a 30 mL eggplant flask, 2-hydroxy-5-methylisophthalic acid (25.5 mg, 0.130 mmol) and SOCl ₂ (1.5 mL) were added, and the mixture was heated under reflux at 60 ° C. for 4 hours. _{SOCl 2} was distilled off using an aspirator and then vacuum dried to obtain a yellow solid.

Subsequently, the rotor was placed in a 100 mL two-mouth reaction vessel, and bis (4-methoxypyrid-2-ylmethyl) amine (84.2 mg, 0.325 mmol), K ₂ CO ₃ (158.2 mg, 1.14 mmol), dry CH ₂ Cl. ₂ (2 mL) was added, _{and the above sample dissolved in dry CH 2} Cl ₂ (2 mL) was added thereto, and the mixture was degassed and replaced with nitrogen, and then stirred overnight at room temperature. The remaining solid was removed by suction filtration, the filtrate was concentrated on a rotary evaporator and vacuum dried to give a yellow solid. This is purified by alumina column chromatography (developing solvent: gradient from CHCl ₃ : MeOH = 1: 0 to 50: 1), the fraction containing the desired product is collected, concentrated on a rotary evaporator, and vacuum dried to form a yellow solid. Was obtained (46.2 mg, Yield 53%). ^{The 1} H NMR spectrum of this solid is shown in FIG.

(4) Synthesis of dinuclear ligand (Hbdpamide-PEG3-phen)
(4-1) 1,10-ditosyl-1,4,7,10-tetraoxadecane
P-toluene sulfonyl chloride (87.0 g, 0.456 mol), triethylene glycol (31.0 mL, 0.233 mol) and CH ₂ Cl ₂ (750 mL) were added to a 2000 mL three-mouth reaction vessel containing a rotor. This was stirred while being immersed in an ice bath, powdered KOH (110 g, 1.96 mol) was added little by little, _{a balloon containing N 2} was attached, and the mixture was stirred for 3 hours while being kept at 0 ° C. _{Add H 2} O (450 mL) to the reaction vessel, separate _{it with CH 2} Cl ₂ (3 x 225 mL), _{add Na 2} SO _4- to the organic layer, dehydrate, and filter with Nutche. The mixture was washed with a small amount of CH _{2 Cl 2} , the filtrate was collected, and the filtrate was concentrated on a rotary evaporator to obtain a white solid. When this was dissolved in acetone while warming in a water bath at 80 ° C and recrystallized, a white solid was obtained (92.5 g, Yield 88%). ^{1 1} H NMR is shown in Fig. 1.
^{1 1} H NMR (500 MHz, CDCl ₃ ); δ / ppm: 7.79 (d, J = 8.0 Hz, 4H, Ph), 7.34 (d, J = 8.0 Hz, 4H, Ph), 4.12-4.16 (m, 4H) , CH ₂ ), 3.64 --3.68 (m, 4H, CH ₂ ), 3.53 (s, 4H, CH ₂ ), 2.45 (s, 6H, CH ₃ ).

(4-2) 1,8-diazido-3,6-dioxaoctane
1,10-ditosyl-1,4,7,10-tetraoxadecane (46.7 g, 0.102 mol), tetrabuthylammonium iodide (1.94 g, 5.26 mmol), sodium azide (27.1 g, 0.417) in a 300 mL eggplant flask containing a rotor. In addition to mol) _{, DMF (150 mL) was further added in an N 2} atmosphere, a three-way cock and a balloon were attached, and the mixture was degassed and replaced with nitrogen, and then stirred at 80 ° C. for 24 hours. After returning the reaction vessel to room temperature, DMF was distilled under reduced pressure to obtain a milky white solid. Et ₂ O (340 mL) was added thereto, the insoluble salt was filtered through Nutche, and the filtrate was separated by H ₂ O (3 × 135 mL). _{After dehydrating by adding Na 2} SO _4- to the organic layer, the mixture was filtered through a Kiriyama funnel _{, washed with a small amount of Et 2} O, and the filtrate was concentrated with a rotary evaporator to obtain a yellow liquid (18.5 g, Yield 91). %).
^{1 1} H NMR (500 MHz, CDCl ₃ ); δ / ppm: 3.70 (t, J = 4.9 Hz, 4H, CH ₂ ), 3.69 (s, 4H, CH ₂ ), 3.40 (t, J = 4.9 Hz, 4H) , CH ₂ ).

(4-3) 1-amino-8-azido-3,6-dioxaoctane
1,8-diazido-3,6-dioxaoctane (18.5 g, 92.4 mmol), EtOAc (130 mL) and 1 M HCl (164 mL) were added to a 1000 mL eggplant flask containing a rotor. A 200 mL isobaric dropping funnel was attached, and a solution of triphenylphosphine (23.2 g, 88.5 mmol) dissolved in EtOAc (130 mL) was placed therein and slowly added dropwise with vigorous stirring. After 12 hours, the reaction solution was transferred to a 1000 mL separatory funnel, the EtOAc layer was removed, and the remaining aqueous layer was separated and washed with EtOAc (3 x 100 mL). The EtOAc layer was removed, the pH of this aqueous layer was adjusted to 14 with a 1 M NaOH aqueous solution, and then the solution was separated with CHCl ₃ (3 x 240 mL). The organic layer was _{dehydrated by adding Na 2} SO ₄ , filtered through Nutche, washed with a small amount of CHCl ₃ , and the filtrate was concentrated on a rotary evaporator to give a yellow liquid (13.6 g, Yield 84%).
^{1 1} H NMR (500 MHz, CDCl ₃ ); δ / ppm: 3.70 (t, J = 5.2 Hz, 2H, CH ₂ ), 3.62-3.68 (m, 4H, CH ₂ ), 3.52 (t, J = 5.2 Hz) , 2H, CH ₂ ), 3.40 (t, J = 5.2 Hz, 2H, CH ₂ ), 2.88 (t, J = 5.2 Hz, 2H, CH ₂ ), 1.28 (brs, 2H, NH ₂ ).

(4-4) 3,5-diformyl-4-hydroxybenzoic acid
A rotor was placed in a 1 L three-mouth reaction vessel, and 4-hydroxybenzoic acid (10.1 g, 73.1 mol), hexamethylenetramine (84.1 g, 0.600 mol), and CF ₃ COOH (180 mL) were added. At this time, the color of the solution was yellow. Reflux at 110 ° C. for 2 days (no nitrogen substitution) turned into a viscous orange solution. After returning to room temperature, 4 M HCl (450 mL) was added and the mixture was stirred at 30 ° C. overnight. The solids were collected by suction filtration with Nutche, _{washed with H 2} O and then vacuum dried to give a yellow solid (9.88 g, Yield 70%).
^{1 1} H NMR (500 MHz, DMSO-d ₆ ); δ / ppm: 10.3 (s, 2H, CH), 8.54 (s, 2H, CHO).

(4-5) N- (8-azido-3,6-dioxaoctyl) -2,6-diformyl-1-hydroxy-4-benzamide
Place the rotor in a 2 L three-mouth reaction vessel and immerse it in an ice bath to obtain 3,5-diformyl-4-hydroxybenzoic acid (4.57 g, 23.5 mmol), CHCl ₃ (920 mL), 1-amino-8-azido- 3,6-dioxaoctane (13.6 g, 78.1 mmol), EDC · HCl (15.0 g, 78.2 mmol) and Et ₃ N (10.7 mL, 76.8 mmol) were added. At this time, the color of the solution was orange. After degassing and replacing with nitrogen, the color of the solution changed to yellow when stirred for 24 hours. After confirming that no raw material remains and the formation of an amide bond by DART, add 1 M HCl (480 mL), react at 30 ° C, and react with TLC (silica gel, developing solvent: EtOAc / MeOH 10: 1). Tracking confirmed that there were few by-products. The reaction mixture was transferred to a 2 L separatory funnel to remove the organic layer and the aqueous layer was extracted with _{CHCl 3. After dehydrating by adding Na 2} SO ₄ to the organic layer, the mixture was filtered through Nutche _{, washed with a small amount of CHCl 3} , and the filtrate was collected, concentrated on a rotary evaporator, and vacuum dried. This _{was dissolved in CHCl 3} (120 mL) and separated by H ₂ O (3 x 40 mL). _{After dehydrating by adding Na 2} SO ₄ to the organic layer, the mixture was filtered through Nutche, the filtrate was concentrated on a rotary evaporator, and vacuum dried to obtain an orange solid (6.52 g, Yield 79%).
^{1 1} H NMR (500 MHz, CDCl ₃ ); δ / ppm: 11.9 (s, H, OH), 10.3 (s, 2H, CHO), 8.46 (s, 2H, CH), 6.84 (s, H, NH) , 3.73 (t, J = 5.2 Hz, 2H, CH ₂ ), 3.69 --3.72 (m, 8H, CH ₂ ), 3.41 (t, J = 5.2 Hz, 2H, CH ₂ ).

(4-6) 4- (N- (8-azido-3,6-dioxaoctyl)) carbamoyl) -2-hydroxyisophthalic acid
_{N- (8-azido-3,6-dioxaoctyl) -2,6-diformyl-1-hydroxy-4-benzamide (4.41 g, 12.6 mmol), Ag 2} O (8-azido-3,6-dioxaoctyl) -2,6-diformyl-1-hydroxy-4-benzamide (4.41 g, 12.6 mmol) in a 300 mL eggplant flask containing a rotor. 8.89 g, 38.3 mmol) was added, _{and NaOH (4.66 g, 0.116 mol) dissolved in H 2} O (96 mL) was added thereto, and the mixture was stirred overnight at 60 ° C. This was filtered through a Kiriyama funnel while washing with the minimum amount of hot H _{2 O (17 mL).} At this time, the filtrate was orange. When the pH was adjusted to 1 with 12 M HCl while immersing the filtrate in an ice bath, a white precipitate was obtained. This was collected by filtration through a Kiriyama funnel and vacuum dried to give a white solid (4.72 g, Yield 66%).
^{1 1} H NMR (500 MHz, DMSO-d ₆ ); δ / ppm: 8.53 (s, H, NH), 8.47 (s, 2H, CH), 3.60 (t, J = 5.2 Hz, 2H, CH ₂ ), 3.54-3.58 (m, 4H, CH ₂ ), 3.52 (t, J = 6.3 Hz, 2H, CH ₂ ), 3.39 (t, J = 6.3 Hz, 2H, CH ₂ ), 3.37 (t, J = 5.2 Hz) , 2H, CH ₂ ).

(4-7) N- (8-azido-3,6-dioxaoctyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamyyl) -1-hydroxy-4-benzamide
Place the rotor in a 50 mL eggplant flask and add 4- (N- (8-azido-3,6-dioxaoctyl)) carbamoyl) -2-hydroxyisophthalic acid (0.201 g, 0.525 mmol) and SOCl ₂ (10 mL). After that, a reflux device was attached, and the mixture was stirred at 60 ° C. for 4 hours. Then, SOCl ₂ was distilled off and vacuum dried to obtain a yellow oily substance. Subsequently, the rotor was placed in a 50 mL eggplant flask, and K ₂ CO ₃ (0.659 g, 4.76 mmol), dipyridylmethylamine (0.284 g, 1.42 mmol), and dry CH- ₂ Cl ₂ (10 mL) were added. A solution prepared by dissolving the yellow oily substance obtained earlier in dry CH ₂ Cl ₂ (10 mL) was added to this solution under a nitrogen atmosphere, and the mixture was degassed and replaced with nitrogen, and then stirred overnight. After confirming that no raw material remained by ESI-MS, filtration through Nutche gave a dark yellow filtrate. The filtrate was transferred to a 100 mL separatory funnel and separated with distilled water (3 x 15 mL). _{After dehydrating by adding Na 2} SO ₄ to the organic layer, the mixture was filtered through Nutche, the filtrate was concentrated with a rotary evaporator, and dried under vacuum to obtain a dark yellow oily substance. The oil was dissolved in a minimum amount of CHCl ₃ (1 mL) and purified by alumina column chromatography (gradient CHCl ₃ / MeOH from 100/0 to 30/1). Fractions containing the desired material were collected, concentrated on a rotary evaporator and vacuum dried to give a pale yellow solid (0.163 g, Yield 41.7%).
^{1 1} H NMR (500 MHz, DMSO-d ₆ ); δ / ppm: 8.51 (d, J = 3.4 Hz, 2H, CH), 8.44 (d, J = 3.4 Hz, 2H, CH), 7.92 (t, J) = 7.5 Hz, 2H, CH), 7.83 (s, 2H, Ph), 7.72 (t, J = 7.5 Hz, 2H, CH), 7.58 (d, J = 7.5 Hz, 2H, CH ₂ ), 7.39 (t) , J = 3.4, 7.5 Hz, 2H, CH), 7.22-7.25 (m, 4H, CH), 4.81 (s, 4H, CH ₂ ), 4.54 (s, 4H, CH ₂ ), 3.60-3.47 (m, 10H, CH ₂ ).

(4-8) N- (8-amino-3,6-dioxaoctyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamyyl) -1-hydroxy-4-benzamide
The rotor was placed in a 100 mL eggplant flask, a three-way cock and a balloon were attached, and the mixture was vacuum dried. N- (8-azido-3,6-dioxaoctyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) -1-hydroxy-4-benzamide (375 mg, 0.503 mmol) in the reaction vessel , 10% Pd / C (418 mg), dry MeOH (5 mL) was added, H _{2 was} substituted, and the mixture was vigorously stirred for 30 minutes. After confirmation by ESI-MS, filtration through Celite, concentration by rotary evaporator, and vacuum drying gave a yellow solid (301 mg, Yield 83%).
^{1 1} H NMR (500 MHz, DMSO-d ₆ ); δ / ppm: 8.47 (d, J = 4.6 Hz, 2H, CH), 8.37 (d, J = 4.6 Hz, 2H, CH), 7.95 (d, J) = 7.5 Hz, 2H, CH), 7.84 (m, 2H, CH), 7.66 (m, 2H, CH), 7.61 (s, 2H, Ph), 7.25-7.32 (m, 4H, CH), 7.19 (ddd) , J = 4.6 Hz, 6.3, 7.5 Hz, 2H, CH), 4.50 - 4.80 (m, 8H, CH 2), 3.44-3.56 (m, 8H, CH 2), 2.80 (t, 2H, CH 2).

(4-9) 4- (8-N- (9-phenanthrenecarbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -1,3-bis (N, N-bis (2-pyridylmeth-yl) carbamoyl) hydroxybenzene (Hbdpamide-PEG3-phen ligand)
Rotor, N- (8-amino-3,6-dioxaoctyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) -1-hydroxy-4-benzamide in a 100 mL two-necked eggplant flask After adding (178 mg, 0.247 mmol) and dissolving in dry THF (17 mL), Et ₃ N (158 μL) was added and the solution turned orange. It was slowly added in a solution of phenanthrene-9-carbonyl chloride (54.2 mg, 0.225 mmol) in THF (15 mL) with Pasteur in an ice bath with vigorous stirring. After the addition, a three-way cock with a nitrogen-substituted balloon was attached, and after degassing nitrogen replacement, the mixture was stirred while being immersed in an ice bath. After stirring for 1 hour, the temperature was returned to room temperature and the mixture was stirred overnight. When THF was distilled off with a rotary evaporator, a white solid was formed. The solid _{was dissolved in CHCl 3} (20 mL), separated by H ₂ O (3 x 5 mL), and dehydrated by adding _{Na 2} SO _{4 to the organic layer.} A white solid was obtained by suction filtration using Nutche and vacuum drying. The solid was dissolved in a minimum amount of CHCl ₃ and purified by alumina column chromatography (gradient CHCl ₃ / MeOH from 100/0 to 30/1). Fractions containing the desired material were collected, concentrated on a rotary evaporator and vacuum dried to give a white solid (128 mg, Yield 62%). ¹ H NMR and ESI-MS spectra are shown in FIGS. 4 and 5, respectively.

(5) Synthesis of dinuclear ligand (Hbdpamide-PEG3-acr)
(5-1) 9-acridine carbonyl chloride
9-acridinecarboxylic acid n-hydrate (0.104 g, 0.466 mmol) and SOCl ₂ (2 mL, 28 mmol) were added to a 50 mL eggplant flask, and the mixture was stirred in an oil bath at 80 ° C. for 2 hours. SOCl ₂ was distilled off under reduced pressure and dried under vacuum to obtain a yellowish brown solid (0.116 g, Yield quant.).
^{1 1} H NMR (500 MHz, CDCl ₃ ); δ / ppm: 9.28 (d, J = 8.6 Hz, 2H, CH), 8.19-8.28 (m, 4H, CH), 7.96-8.02 (m, 2H, CH) ..

(5-2) 4- (8-N- (9-acridinecarbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) hydroxybenzene ( Hbdpamide-PEG3-acr ligand)
The rotor was placed in a 100 mL two-mouth reaction vessel, a three-way cock and a balloon were attached, and the mixture was vacuum dried. N- (8-amino-3,6-dioxaoctyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) -1-hydroxy-4-benzamide (92.4 mg, 0.129 mmol) in the reaction vessel _{Et 3} N (72.4 μL, 0.515 mmol) was added to the solution of the mixture in dry THF (10 mL). The mixture was placed in an ice bath, N ₂ flowed, 9-acridine carbonyl chloride (31.3 mg, 0.130 mmol) was dissolved in dry THF, slowly added, N ₂ substituted, shaded, and stirred overnight. Concentrated with a rotary evaporator and vacuum dried to give a pale yellow solid. This solid was purified by alumina column chromatography (CHCl ₃ : MeOH = 100: 0 → 100: 1 → 10: 1), concentrated on a rotary evaporator, and vacuum dried to obtain a yellowish brown solid. Further purification was performed by HPLC to obtain a yellow solid (46.9 mg, Yield 39%). ¹ H NMR and ESI-MS spectra are shown in FIGS. 6 and 7, respectively.
^{1 1} H NMR (500 MHz, CDCl ₃ ); δ / ppm: 12.3-12.7 (brs, 1H, OH), 8.39-8.46 (m, 4H, CH), 8.15 (d, J = 8.9 Hz, 2H, CH) , 8.11 (d, J = 8.9 Hz, 2H, CH), 7.81 (s, 2H, Ph), 7.72 (ddd, J = 1.2, 6.7, 8.9 Hz, 2H, CH), 7.64-7.70 (m, 3H, Ph) NH, CH), 7.55-7.62 (m, 2H, CH), 7.52 (ddd, J = 1.2, 6.7, 8.9 Hz, 2H, CH), 7.32-7.38 (m, 2H, CH), 7.19-7.24 (m) , 2H, CH), 7.09-7.13 (m, 2H, CH), 7.03-7.07 (m, 2H, CH), 6.72 (t, J = 5.4 Hz, 1H, NH), 4.71 (s, 4H, CH ₂₎ ), 4.49 (s, 4H, CH 2), 3.85 - 3.90 (m, 2H, CH 2), 3.82-3.85 (m, 2H, CH 2), 3.75-3.79 (m, 2H, CH 2), 3.67- 3.72 (m, 2H, CH ₂ ), 3.54-3.59 (m, 2H, CH ₂ ), 3.45-3.51 (m, 2H, CH ₂ ).

(6) Synthesis of dinuclear ligand (Hbdpamide-PEG3-pyr)
(6-1) pyrene-1-carbonyl chloride
Add 1-pyrenecarboxylic acid (0.103 g, 0.419 mmol), dry CH ₂ Cl ₂ (20 mL), SOCl ₂ (0.5 mL, 6.85 mmol), and 3 drops of dry DMF to a 100 mL eggplant flask and place in an oil bath at 60 ° C. Stirred for 1 hour. Concentrated on a rotary evaporator and vacuum dried to give a yellow solid (0.110 g, Yield quant.).
¹ H NMR (500 MHz, CDCl ₃ ); δ / ppm: 9.10 (d, J = 8.6 Hz, 1H, CH), 8.96 (d, J = 8.6 Hz, 1H, CH), 8.37-8.40 (m, 3H) , CH), 8.29 (d, J = 8.6 Hz, 1H, CH), 8.25 (d, J = 8.6 Hz, 1H, CH), 8.11-8.16 (m, 2H, CH).

(6-2) 4- (8-N- (9-pyrenecarbamoyl) -3,6-dioxaoctyl) -N-carbamoyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) hydroxybenzene ( Hbdpamide-PEG3-pyr ligand)
The rotor was placed in a 100 mL two-mouth reaction vessel, a three-way cock and a balloon were attached, and the mixture was vacuum dried. N- (8-amino-3,6-dioxaoctyl) -2,6-bis (N, N-bis (2-pyridylmethyl) carbamoyl) -1-hydroxy-4-benzamide (103 mg, 0.143 mmol) in the reaction vessel Et ₃ N (80.7 μL, 0.574 mmol) was added. The mixture was placed in an ice bath, N ₂ flowed, pyrene-1-carbonyl chloride (37.7 mg, 0.142 mmol) was dissolved in dry THF, slowly added, N ₂ substituted, shielded from light, and stirred overnight. Concentrated with a rotary evaporator and vacuum dried to give a light brown solid. This solid was purified by alumina column chromatography (CHCl ₃ : MeOH = 100: 0 → 100: 1 → 10: 1), concentrated on a rotary evaporator, and vacuum dried to obtain a yellowish brown solid. Further purification was performed by HPLC to obtain a yellow solid (46.9 mg, Yield 39%). ¹ H NMR and ESI-MS spectra are shown in FIGS. 8 and 9, respectively.
¹ H NMR (500 MHz, CDCl ₃ ); δ / ppm: 12.3-12.7 (brs, 1H, OH), 8.59 (d, J = 9.5 Hz, 2H, CH), 8.40-8.44 (m, 4H, CH) , 8.15-8.22 (m, 2H, CH), 7.98-8.12 (m, 5H, CH) 7.92 (s, 2H, Ph), 7.58-7.68 (m, 2H, CH), 7.50-7.55 (m, 2H, CH) CH), 7.28-7.35 (m, 3H, NH, CH), 7.14-7.18 (m, 2H, CH), 7.05-7.14 (m, 4H, CH), 6.81 (t, J = 5.4 Hz, 2H, NH ), 4.82 (s, 4H, CH ₂ ), 4.53 (s, 4H, CH ₂ ), 3.76-3.84 (m, 4H, CH ₂ ), 3.72-3.75 (m, 2H, CH ₂ ), 3.65-3.69 ( m, 2H, CH ₂ ), 3.57-3.61 (m, 2H, CH ₂ ), 3.47-3.52 (m, 2H, CH ₂ ).

(7) Synthesis of dinuclear metal complex
(7-1) binuclear metal complex - Synthesis of _{[Cu 2 (μ-OAc)} 2 (bdpamide)] (OAc) (1)
A rotator was placed 100 mL eggplant flask, CH ₃ Cu ^II dissolved in _{CN (12 mL) (CH 3} COO) 2 (61.1 mg, 0.336 mol) was added, Hbdpamide then dissolved in CH ₃ CN (12 mL) Slow addition of (64.5 mg, 0.0865 mmol) with a pasteur changed the color of the solution to dark green. After confirming the absence of ligands and mononuclear complexes by ESI-MS, the mixture was concentrated on a rotary evaporator and a small amount of Et ₂ O was added to precipitate a dark green solid. This was suction filtered with a Kiriyama funnel to give a dark green solid (77.5 mg). The ESI-MS spectrum is shown in FIG.

(7-2) Synthesis of dinuclear metal complex [Cu ₂ (μ-OAc) ₂ (bdpamide)] (ClO ₄ ) (2) _{Dissolve complex 1 in CH 3} CN, _{add NaCl O 4} and add CH ₃ CN / Recrystallization under Et ₂ O conditions gave a brown single crystal. This X-ray single crystal structure is shown in the ORTEP diagram of FIG. As a result of single crystal structure analysis, it was clarified that two acetate ions were cross-linked at the center of the dinuclear copper, and it was found that the cross-linking mode was a double cross-linking of a monoatomic crosslink and a syn-syn type crosslink. It was issued. The τ values calculated from the coupling angles around copper were 0.378 and 0.471, respectively, indicating that they have a distorted quadrangular pyramid structure.

(7-3) Synthesis of dinuclear metal complex [Cu ₂ (μ-OAc) (μ-H ₂ O) (bdpamide)] (ClO ₄ ) ₂ (3)
^{Cu II} (CH ₃ COO) ₂ (48 mg, 0.264 mmol) dissolved in Milli-Q water (4 mL) was added to 100 mL Meyer, and then Hbpcp (48.5 mg, 48.5 mg,) dissolved in Milli-Q water (4 mL). When 0.0868 mmol) was added slowly with a pasteur, the color of the solution changed to dark green. To replace the counter _{, dissolve NaClO 4} · H ₂ O (64.1 mg, 0.456 mmol) in Milli-Q water (2 mL), heat it with a dryer for several minutes, and let it stand to analyze the X-ray single crystal structure. A green solid suitable for the above was precipitated. After 2 days, the precipitated crystals were filtered to give green crystals (43.1 mg). The crystal structure is shown in the ORTEP diagram of FIG. As a result of single crystal structure analysis, it was clarified that acetate ion is cross-linked by syn-syn type cross-linking and water is cross-linked at the center of dinuclear copper. In addition, the τ values calculated from the coupling angles around copper were 0.309 and 0.251, respectively, and it was clarified that they had a distorted quadrangular pyramid structure.

(7-4) binuclear metal complex - Synthesis of _{[Cu 2 (μ-OAc)} 2 (bdpamide 4-Cl)] (OAc) (4)
The rotor was placed in a 100 mL eggplant flask, and Cu (OAc) ₂ (20.8 mg, 0.115 mmol) and MeCN (2 mL) were added and dissolved. ^{To this, Hbpcp 4-Cl} (30.0 mg, 0.0431 mmol) dissolved in MeCN (4 mL) was slowly added using Pasteur. After stirring at room temperature for 1 hour, MeCN was concentrated to some extent with a rotary evaporator, and then Et ₂ O was added with stirring, and a green precipitate was formed. This was filtered through a membrane and vacuum dried to obtain a green solid. The ESI-MS spectrum is shown in FIG.

(7-5) binuclear metal complex - Synthesis of _{[Cu 2 (μ-OAc)} 2 (bdpamide 4-OMe)] (OAc) (5)
The rotor was placed in a 100 mL eggplant flask, and Cu (OAc) ₂ (34.8 mg, 0.192 mmol) and MeCN (3 mL) were added and dissolved. ^{To this, Hbpcp 4-OMe} (43.4 mg, 0.0639 mmol) dissolved in MeCN (3 mL) was slowly added using Pasteur. After stirring at room temperature for 1 hour, MeCN was concentrated to some extent with a rotary evaporator, and then Et ₂ O was added with stirring, and a green precipitate was formed. This was filtered through a membrane and vacuum dried to obtain a green solid. The ESI-MS spectrum is shown in FIG.

(7-6) binuclear metal complex _{[Cu 2 (μ-OAc)} - 2 (bdpamide-PEG3-phen)] Synthesis of (OAc) (6)
The rotor was placed in a 100 mL eggplant flask, and Cu (OAc) ₂ (7.1 mg, 39.1 μmol) and MeCN (1 mL) were added and dissolved. Hbdpamide-PEG3-phen (17.8 mg, 19.3 μmol) dissolved in MeCN (1.5 mL) was slowly added thereto using Pasteur. The mixture was stirred at room temperature for 1 hour. After concentrating MeCN to some extent on a rotary evaporator, Et ₂ O was added with stirring to produce a green precipitate. This was filtered through a membrane and vacuum dried to obtain a green solid. The ESI-MS spectrum is shown in FIG.

(7-7) binuclear metal complex - Synthesis of _{[Cu 2 (μ-OAc)} 2 (bdpamide-PEG3-acr)] (OAc) (7)
The rotor was placed in a 200 mL eggplant flask, and Cu (OAc) 2 (18.5 mg, 102 μmol) and MeCN (2.0 mL) were added and dissolved. Hbdpamide-PEG3-acr (46.9 mg, 50.8 μmol) dissolved in MeCN (1 mL) was slowly added thereto using Pasteur. Stirring at room temperature for 2 hours, reducing the amount of solution _{and adding EtO 2} while stirring resulted in a green precipitate. This was filtered through a membrane and vacuum dried to give a glossy green solid (54.2 mg, Yield 92%). The ESI-MS spectrum is shown in FIG.

(7-8) binuclear metal complex _{[Cu 2 (μ-OAc)} - 2 (bdpamide-PEG3-pyr)] Synthesis of (OAc) (8)
The rotor was placed in a 200 mL eggplant flask, and Cu (OAc) ₂ (30.2 mg, 166 μmol) and MeCN (2.5 mL) were added and dissolved. Hbdpamide-PEG3-pyr (78.6 mg, 83.0 μmol) dissolved in MeCN (1.5 mL) was slowly added thereto using Pasteur. Stirring at room temperature for 2 hours, reducing the amount of solution, and then _{adding EtO 2} while stirring gave a green precipitate. This was filtered through a membrane and vacuum dried to give a glossy green solid (79.2 mg, Yield 76%). The ESI-MS spectrum is shown in FIG.

_{(8) The H 2} O ₂ concentration-dependent complex 1 of the oxidative cleavage reaction of the dinuclear metal complex 1 was subjected to oxidative cleavage of DNA by _{H 2} O _{2 as shown below.} For this measurement, [NaCl] = 10 mM, [buffer] = 10 mM (pH 6.0 (MES)), [complex] = 10 μM, [pUC19 DNA] = 50 μM bp, [H ₂ O ₂ ] = 0 The solution was prepared to have a pH of -50 μM and measured.

The result is shown in FIG. H ₂ O DNA in ₂ only blank experiment not at all cut is heading our laboratory, complex 1 were found to of H ₂ O ₂ concentration dependence to cleavage activity is greatly improved. Since complex 1 with binuclear structure, two copper ions are bonded to two oxygen atoms of H ₂ O _2, to produce a readily binuclear copper hydroperoxide oxo complexes even of H ₂ O ₂ concentration lower DNA Is thought to oxidatively cleave.

(9) For the complex concentration-dependent complexes 2, 6, 7, 8 of the oxidative cleavage reaction of the dinuclear metal complex 2, 6, 7, 8, DNA oxidative cleavage by _{H 2} O _{2 was performed as shown below.} It was. For this measurement, [NaCl] = 10 mM, [buffer] = 10 mM (pH 6.0 (MES)), [complex] = 0-20 μM, [pUC19 DNA] = 10 μM bp, [H ₂ O ₂ ] = The solution was prepared to a pH of 10 μM and measured. In the reaction under the condition of hydrogen peroxide concentration of 10 μM, take a part of the reaction solution every 0, 5, 10, 20, 30, 40, 60 minutes, and check the cleavage status of pUC19 DNA at each time on agarose gel electrophoresis. Measured by electrophoresis.

The results are shown in FIGS. 19, 20, 21 and 22. In the nuclear complex, it was found that the cleavage activity was greatly improved depending on the complex concentration. It was also found that when the complex concentration was 20 μM, the formation rate of Form III was 0% for complex 2, 10.3% for 6, 4.1% for 7, and 9.2% for 8 after 1 hour. From this, the dinuclear copper complexes 6, 7, and 8 introduced with the DNA intercalators phenanthrene, aclysine, and pyrene bind more strongly to the DNA than complex 2, and their positions are fixed, so that they are cleaved first. It is considered that the DNA oxidative cleavage activity was high because a structure was formed in which the DNA near the position where the DNA was formed could be cleaved again.

Bleomycin catalyzes oxidative cleavage of DNA. Bleomycin is an antibiotic (anticancer antibiotic) that exhibits high anticancer activity. This is because bleomycin oxidatively cleaves the DNA of cancer cells, causing them to die. Here, bleomycin is an iron complex, and in the iron (III) state, _{it reacts with H 2} O ₂ to rapidly produce an active form of bleomycin called active bleomycin. It is believed to be a hydroperoxo complex of iron (III). Furthermore, it is presumed that cleavage of the OO bond of hydroperoxo produces an oxidatively active species. Bleomycin also has a DNA minor groove binder and a spacer site to bind it. Thus, complex 1-8, which has a similar structure, is considered to be useful as a new anticancer agent to replace bleomycin, which acts as an oxidizing agent for _{H 2} O _2.

It can be used as an anticancer drug.

Claims (10)

A dinuclearized ligand represented by the following chemical formula (I) or (II) (in the following formula, (i) X is the same or different H, Cl, OMe, or Me, and ( ii) In the chemical formula (I), Y is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, an alkoxy group, an alkoxyalkyl group, an ester group, an ester alkyl group, or a phenyl group or a pyridyl group. an amino group, a hydroxyl group, a thiol group, a fluorine atom, a chlorine atom, the amino group 'can described as group, R ₁ and R _1' NR ₁ R ₁ are each independently a hydrogen atom, a substituted or unsubstituted alkyl A group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group, and (iii) in the chemical formula (II), R is a polycyclic aromatic heterocyclic compound or a polycyclic aromatic hydrocarbon compound. And n is an integer of 1 to 8).

The dinuclearization ligand according to claim 1, which is represented by the following chemical formula (III).

The dinuclearization ligand according to claim 1, wherein the polycyclic aromatic heterocyclic compound is an acridine, xanthene, carbazole or porphyrin and a derivative thereof. The dinuclearization according to claim 1 or 3, wherein the polycyclic aromatic hydrocarbon compound is phenanthrene, pyrene, anthracene, tetracene, pentacene, benzopyrene, chrysen, triphenylene, corannulene, coronene or ovalene. Logen. A nucleic acid cleavage agent comprising the dinuclearization ligand according to any one of claims 1 to 4. An anticancer agent comprising the dinuclearization ligand according to any one of claims 1 to 4. A dinuclear metal complex represented by the following chemical formula (IV) or (V) (in the following formula, (i) M is Cu, Fe, Zn, Co, Mn, Re, Ru, Rh, Pd, It is Pt or Ce, and (ii) in the chemical formula (V), R is a polycyclic aromatic heterocyclic compound or a polycyclic aromatic hydrocarbon compound, and n is an integer of 1 to 8).

The dinuclear metal complex according to claim 7, which is represented by the following chemical formula (VI) or (VII) (in chemical formula (VII), R is a polycyclic aromatic heterocyclic compound or a polycyclic aromatic compound. It is a hydrocarbon compound, and n is an integer of 1 to 8).

A nucleic acid cleavage agent comprising the dinuclear metal complex according to claim 7 or 8. An anticancer agent comprising the dinuclear metal complex according to claim 7 or 8.

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