Application of diazaphenanthrene protonated dimer cation or diazaphenanthrene protonated dimer salt in preparation of medicine for treating leukemia

Abstract

According to the application of the diazaphenanthrene protonated dimer cation or the diazaphenanthrene protonated dimer salt in preparation of the medicine for treating leukemia, the diazaphenanthrene protonated dimer cation and the diazaphenanthrene protonated dimer salt can effectively reduce the activity of leukemia cells, and the anti-leukemia effect is achieved, and the application of the diazaphenanthrene protonated dimer cation or the diazaphenanthrene protonated dimer salt in preparation of the medicine for treating the leukemia is provided. And a compound basis and a technical support are provided for research and development of new drugs for treating leukemia.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and specifically relates to the application of phenanthroline protonated dimer cation or phenanthroline protonated dimer salt in the preparation of drugs for treating leukemia. Background Art

[0002] Leukemia is a malignant clonal disease of hematopoietic stem cells in the bone marrow, also known as blood cancer. Clinically, it is mainly divided into two categories: acute leukemia and chronic leukemia, which can be further divided into four types: chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia and acute lymphocytic leukemia. Acute leukemia progresses rapidly, has a high mortality rate, and a short survival time, usually only three to six months; although the survival period of chronic leukemia is relatively long, its average survival time is only about three to five years. It can be seen that leukemia poses a great threat to people's health.

[0003] The causes of leukemia are relatively complex, and it is difficult to determine the exact cause of each patient. But in general, the onset of leukemia is related to the following factors: 1. Radiation; 2. Some drugs and chemicals, such as ethidium bromide for the treatment of skin diseases, have the possibility of inducing leukemia; 3. Family hereditary factors; 4. Low immune function, such as unhealthy lifestyles and bad emotions can affect immune function, leading to confusion and low immune function.

[0004] At present, the medical field is gradually pursuing standardized diagnosis and treatment of leukemia, such as standardized diagnosis based on the existing fine classification and typing of genetic abnormalities, through bone marrow morphology, cellular immunology, cytogenetics and molecular genetics, and classified treatment based on standardized diagnostic results. Chronic leukemia usually uses molecular targeted therapy, while acute leukemia is mainly treated with chemotherapy, and commonly used chemotherapy drugs include anthracyclines and cytarabine.

[0005] Although there are some relatively effective leukemia treatment drugs, more new leukemia treatment drugs still need to be developed in order to better inhibit the occurrence and development of leukemia and reduce the cost of leukemia treatment drugs. Summary of the invention

[0006] The object of the present invention is to provide the use of a phenanthroline protonated dimer cation or a phenanthroline protonated dimer salt in the preparation of a drug for treating leukemia. The phenanthroline protonated dimer and its salt can effectively inhibit the activity of leukemia cells and have concentration dependence, thereby achieving an anti-leukemia effect.

[0007] The present invention provides the use of a protonated dimer salt of phenanthroline in the preparation of a drug for treating leukemia. The protonated dimer cation of phenanthroline has a structure of formula I, wherein "------" in the formula I is a covalent bond or a non-covalent bond.

[0008]

[0009] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, methyl, phenyl, cyano, amino, nitro or chloro;

[0010] The protonated dimer salt of phenanthroline comprises a protonated dimer cation of phenanthroline and an anion, wherein the anion is at least one of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a sulfide ion, a nitrate ion, a sulfate ion, a sulfite ion, a thiosulfate ion, a persulfate ion, a selenate ion, a phosphate ion, a carbonate ion, a hexafluorophosphate ion, a hexafluorosilicate ion, an acetate ion, a sulfonate ion, a benzoate ion and a polyphosphate ion.

[0011] Preferably, the protonated dimer salt of phenanthroline has a structure of Formula II, wherein k=1 to 3, and X is at least one of hexafluorophosphate ion, hexafluorosilicate ion, chloride ion and sulfate ion;

[0012]

[0013] Preferably, k=1.

[0014] Preferably, the protonated dimer salt of phenanthroline has a structure of any one of Formulas III to VI:

[0015]

[0016] Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen;

[0017]

[0018] Among them, R 1 is hydrogen, R 2 Methyl, R 3 Methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 Methyl, R 7 Methyl, R 8 is hydrogen, R 11 is hydrogen, R 12 Methyl, R 13 Methyl, R 14 is hydrogen, R 15 is hydrogen, R 16 Methyl, R 17 Methyl, R 18 is hydrogen;

[0019]

[0020] Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 Nitro, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 Nitro, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen;

[0021]

[0022] Among them, R 1 Methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 Methyl, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

[0023] Preferably, the leukemia comprises acute leukemia.

[0024] Preferably, the acute leukemia includes acute myeloid leukemia and / or acute lymphocytic leukemia.

[0025] Preferably, the acute myeloid leukemia includes one or more of acute undifferentiated lineage leukemia, acute minimally differentiated myeloblastic leukemia, acute partially differentiated myeloblastic leukemia, acute promyelocytic leukemia, acute myelo-monocytic leukemia, acute monocytic leukemia, erythroleukemia and acute megakaryocytic leukemia.

[0026] Preferably, the acute lymphoblastic leukemia includes B-lineage acute lymphoblastic leukemia and / or T-lineage acute lymphoblastic leukemia.

[0027] Preferably, the effective concentration of the protonated dimer salt of phenanthroline is at least 0.00625 mg / mL

[0028] The present invention also provides a drug for treating leukemia, wherein the active ingredient of the drug comprises a protonated phenanthroline dimer cation or a protonated phenanthroline dimer salt; the protonated phenanthroline dimer cation has a structure of formula I, wherein is a covalent bond or a non-covalent bond,

[0029]

[0030] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R17 and R 18 are each independently hydrogen, methyl, phenyl, cyano, amino, nitro or chloro;

[0031] The protonated dimer salt of phenanthroline comprises a protonated dimer cation of phenanthroline and an anion, wherein the anion is at least one of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a sulfide ion, a nitrate ion, a sulfate ion, a sulfite ion, a thiosulfate ion, a persulfate ion, a selenate ion, a phosphate ion, a carbonate ion, a hexafluorophosphate ion, a hexafluorosilicate ion, an acetate ion, a sulfonate ion, a benzoate ion and a polyphosphate ion;

[0032] Preferably, the protonated dimer salt of phenanthroline has a structure of Formula II, wherein k=1 to 3, and X is at least one of hexafluorophosphate ion, hexafluorosilicate ion, chloride ion and sulfate ion;

[0033]

[0034] Preferably, k=1.

[0035] Preferably, the protonated dimer salt of phenanthroline has a structure of any one of Formulas III to VI:

[0036]

[0037] Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen;

[0038]

[0039] Among them, R 1 is hydrogen, R 2 Methyl, R 3 Methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 Methyl, R 7 Methyl, R8 is hydrogen, R 11 is hydrogen, R 12 Methyl, R 13 Methyl, R 14 is hydrogen, R 15 is hydrogen, R 16 Methyl, R 17 Methyl, R 18 is hydrogen;

[0040]

[0041] Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 Nitro, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 Nitro, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen;

[0042]

[0043] Among them, R 1 Methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 Methyl, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

[0044] Beneficial effects:

[0045] The present invention provides the use of a protonated dimer cation of phenanthroline or a protonated dimer salt of phenanthroline in the preparation of a drug for treating leukemia. Casein hydrolyzing proteinase P (CLpP) is a polyserine protease in mitochondria, and CLpP is essential for the survival, growth, resistance and metastasis of malignant tumors. The mechanism by which the protonated dimer salt of phenanthroline can achieve anti-leukemia is that the protonated dimer cation in the protonated dimer salt of phenanthroline can bind to isoleucine (Ile), leucine (Leu) and valine (Val) in casein hydrolyzing proteinase P (CLpP) through hydrogen bonds and hydrophobic bonds, thereby activating CLpP protein, reducing the activity of leukemia cells, achieving the effect of killing leukemia tumor cells, and providing compound basis and technical support for the research and development of new drugs for the treatment of leukemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required to be used in the embodiments are briefly introduced below.

[0047] Figure 1 is the mass spectrometry result of the protonated dimer salt of phenanthroline in Example 1, wherein a and b are 1 H nuclear magnetic resonance (NMR) spectrum and high performance liquid chromatography (HPLC) spectrum;

[0048] Figure 2 is the mass spectrometry result of the protonated dimer salt of phenanthroline in Example 2, wherein a, b, c, and d are FTIR spectra, 1 H NMR spectra, HRMS spectra and HPLC spectra;

[0049] Figure 3 is the mass spectrometry result of the protonated dimer salt of phenanthroline in Example 3, wherein a, b, c, and d are FTIR spectra, 1 H NMR spectra, HRMS spectra and HPLC spectra;

[0050] Figure 4 is the IC of the protonated dimer salt of phenanthroline against leukemia cells in Examples 1 to 4 50 Value result. DETAILED DESCRIPTION

[0051] The present invention provides the use of a phenanthroline protonated dimer cation or a phenanthroline protonated dimer salt in the preparation of a drug for treating leukemia, wherein the phenanthroline protonated dimer cation has a structure of formula I, wherein is a covalent bond or a non-covalent bond,

[0052]

[0053] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, methyl, phenyl, cyano, amino, nitro or chloro;

[0054] The protonated dimer salt of phenanthroline comprises a protonated dimer cation of phenanthroline and an anion, wherein the anion is at least one of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a sulfide ion, a nitrate ion, a sulfate ion, a sulfite ion, a thiosulfate ion, a persulfate ion, a selenate ion, a phosphate ion, a carbonate ion, a hexafluorophosphate ion, a hexafluorosilicate ion, an acetate ion, a sulfonate ion, a benzoate ion and a polyphosphate ion.

[0055] As an embodiment, the term "dimer" of the present invention refers to a complex formed by two molecules or ions, such as 1,10-phenanthroline or its derivatives or their protonated ions, through interaction, especially non-covalent interaction, for example, a complex formed by a 1,10-phenanthroline or its derivatives and a protonated ion of 1,10-phenanthroline or its derivatives.

[0056] As an embodiment, the term "covalent bond" of the present invention includes but is not limited to: peptide bond, glycosidic bond, ester bond, phosphodiester bond, and especially includes coordinate covalent bond; the term "non-covalent bond" includes any bond or interaction between two or more parts that does not contain or involve electron sharing; the non-covalent bond includes but is not limited to electrostatic, π-π effect, van der Waals force, hydrogen bond and hydrophobic effect.

[0057] As an embodiment, in the formula I of the present invention It can be a covalent bond.

[0058] As an embodiment, the protonated dimer salt of phenanthroline described in the present invention has a structure of Formula II,

[0059]

[0060] As another implementation manner, the k may be 1-3; in a specific embodiment, the k may be 1, 2 or 3.

[0061] As an embodiment, the X may be at least one of hexafluorophosphate ion, hexafluorosilicate ion, chloride ion and sulfate ion; as another embodiment, the X may be hexafluorophosphate ion, hexafluorosilicate ion, chloride ion or sulfate ion; in a specific embodiment, the X may be hexafluorophosphate ion.

[0062] As an embodiment, the protonated dimer salt of phenanthroline of the present invention has a structure of any one of Formulas III to VI:

[0063]

[0064] Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen;

[0065]

[0066] Among them, R 1 is hydrogen, R 2 Methyl, R 3 Methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 Methyl, R 7 Methyl, R 8 is hydrogen, R 11 is hydrogen, R 12 Methyl, R 13 Methyl, R 14 is hydrogen, R 15 is hydrogen, R 16 Methyl, R 17 Methyl, R 18 is hydrogen;

[0067]

[0068] Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 Nitro, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 Nitro, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen;

[0069]

[0070] Among them, R 1 Methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 Methyl, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

[0071] As an embodiment, the leukemia described in the present invention may be acute leukemia; as another embodiment, the acute leukemia described in the present invention may be acute myeloid leukemia (AML) and / or acute lymphocytic leukemia (ALL); as another embodiment, the acute leukemia described in the present invention may be acute myeloid leukemia and acute lymphocytic leukemia. As an embodiment, the acute myeloid leukemia described in the present invention may be one or more of acute undifferentiated lineage leukemia (M0), acute minimally differentiated myeloblastic leukemia (M1), acute partially differentiated myeloblastic leukemia (M2), acute promyelocytic leukemia (M3), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), erythroleukemia (M6) and acute megakaryocytic leukemia (M8).

[0072] As one embodiment, the acute lymphocytic leukemia described in the present invention can be B-lineage acute lymphocytic leukemia and / or T-lineage acute lymphocytic leukemia; as another embodiment, the acute lymphocytic leukemia described in the present invention can be B-lineage acute lymphocytic leukemia and T-lineage acute lymphocytic leukemia.

[0073] In a specific embodiment, the phenanthroline protonated dimer salt containing the phenanthroline protonated dimer cation is used to act on different types of leukemia cells to illustrate the resistance effect of the phenanthroline protonated dimer salt on leukemias of different types; the different types of leukemia cells may be KG-1 human acute myeloid leukemia cells, KG-1A human acute myeloid leukemia cells, HEL human erythroleukemia cells, Kasumi-1 human erythroleukemia cells, THP-1 human monocytic leukemia cells, MOLT-4 human acute lymphoblastic leukemia cells, Jurkat human T lymphocyte leukemia cells, Reh human acute non-B non-T lymphocytes and MEG-01 human megakaryoblastic leukemia cells, but the above 9 types of leukemia cells cannot be used as the entire protection scope of the present invention.

[0074] As an embodiment, the effective concentration of the phenanthroline protonated dimer cation or the phenanthroline protonated dimer salt of the present invention can be at least 0.00625; in a specific embodiment, the concentration of the phenanthroline protonated dimer salt can be but is not limited to 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.4 mg / mL or 0.8 mg / mL.

[0075] Casein hydrolyzing proteinase P (CLpP) is a polyserine protease in mitochondria. CLpP is essential for the survival, growth, resistance and metastasis of malignant tumors. The mechanism by which the protonated dimer salt of phenanthroline can achieve anti-leukemia is that the protonated dimer cation in the protonated dimer salt of phenanthroline can bind to isoleucine (Ile), leucine (Leu) and valine (Val) in casein hydrolyzing proteinase P (CLpP) through hydrogen bonds and hydrophobic bonds, thereby activating CLpP protein, reducing the activity of leukemia cells, and achieving the effect of killing leukemia tumor cells. In addition, by acting the protonated dimer salt of phenanthroline on the mitochondria of human monocytic leukemia cells (THP-1) at a concentration of 0.05 mg / mL for 2 hours, it can be clearly found that the complete double-layer membrane structure of the mitochondria of THP-1 cells is destroyed, the number of cristae is reduced, there is no complete structure, and even a large number of cavities appear. In summary, it can be seen that the protonated dimer salt of phenanthroline can effectively destroy the structure of leukemia cells and inhibit the activity of leukemia cells.

[0076] The present invention also provides a drug for treating leukemia, wherein the active ingredient of the drug comprises a protonated phenanthroline dimer cation or a protonated phenanthroline dimer salt; the protonated phenanthroline dimer cation has a structure of formula I, wherein is a covalent bond or a non-covalent bond,

[0077]

[0078] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, methyl, phenyl, cyano, amino, nitro or chloro;

[0079] The protonated dimer salt of phenanthroline comprises a protonated dimer cation of phenanthroline and an anion, wherein the anion is at least one of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a sulfide ion, a nitrate ion, a sulfate ion, a sulfite ion, a thiosulfate ion, a persulfate ion, a selenate ion, a phosphate ion, a carbonate ion, a hexafluorophosphate ion, a hexafluorosilicate ion, an acetate ion, a sulfonate ion, a benzoate ion and a polyphosphate ion.

[0080] The preferred embodiment of the dimer cation or the protonated dimer salt of phenanthroline according to the present invention has been described in the above technical scheme and will not be described in detail.

[0081] As an embodiment, the protonated dimer salt of phenanthroline of the present invention has a structure of any one of Formulas III to VI:

[0082]

[0083] Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen;

[0084]

[0085] Among them, R 1 is hydrogen, R 2 Methyl, R 3 Methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 Methyl, R 7 Methyl, R 8 is hydrogen, R 11 is hydrogen, R 12 Methyl, R 13 Methyl, R 14 is hydrogen, R 15 is hydrogen, R 16 Methyl, R 17 Methyl, R 18 is hydrogen;

[0086]

[0087] Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 Nitro, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 Nitro, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen;

[0088]

[0089] Among them, R 1 Methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R8 Methyl, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

[0090] As an embodiment, the drug of the present invention includes pharmaceutically acceptable excipients. The present invention has no special restrictions on the type of the excipients, which can be selected and limited according to the actual dosage form prepared.

[0091] In order to further illustrate the present invention, the technical solution provided by the present invention is described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0092] Example 1

[0093] The protonated dimer salt of phenanthroline in Example 1 is specifically shown in Formula II. That is, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

[0094]

[0095] Preparation method

[0096] The preparation method of the protonated dimer salt of phenanthroline in this embodiment is as follows.

[0097] - The first reactant is 1,10-phenanthroline;

[0098] - the second reactant is 1,10-phenanthroline; and

[0099] - The first salt is ammonium hexafluorophosphate, that is, the anion is the hexafluorophosphate ion.

[0100] At 25°C, place 1g of the first reactant in 10mL of 2M hydrochloric acid and stir vigorously until completely dissolved. Heat to 85°C for 30 minutes and concentrate under reduced pressure to 2mL. After cooling, crystals precipitate. Wash the crystals with ethanol solution 3 times and dry to obtain the hydrochloride of the first reactant.

[0101] 0.8 g of the first reactant hydrochloride was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.

[0102] 0.8 g of the second reactant was added to the first aqueous solution at 25° C. and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment. The solution was fully dialyzed using a dialysis bag with a molecular weight cutoff of 200 Da and dried to obtain a first intermediate product.

[0103] The first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia water was added to adjust the pH value to 9 to precipitate a large amount of white precipitate. The precipitate was filtered and the filter cake was washed twice with water and dried to obtain the product, i.e., the salt of this example.

[0104] Detection of products or intermediates

[0105] The hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.

[0106] The salt yield in this example is about 1.6 g, with a yield of about 85%.

[0107] The protonated dimer salt of phenanthroline of this embodiment is subjected to high-resolution mass spectrometry to obtain the cation of this embodiment, (C 24 H 17 N4) + m / z = 361.4.

[0108] The protonated dimer salt of phenanthroline in this example 1 H-NMR spectrum and HPLC spectrum are shown in Figure 1 HPLC conditions: stationary phase: Shim-pack Scepter C18-120 column (4.6×250 mm, 5 μm); mobile phase: acetonitrile / 20 mM ammonium acetate buffer 25:75 (v / v); flow rate: 1.0 mL / min; detection wavelength: 273 nm; column temperature: 25°C; injection volume: 10 μL.

[0109] Example 2

[0110] The protonated dimer salt of phenanthroline of Example 2 is specifically shown in Formula III. That is, R 1 is hydrogen, R 2Methyl, R 3 Methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 Methyl, R 7 Methyl, R 8 is hydrogen, R 11 is hydrogen, R 12 Methyl, R 13 Methyl, R 14 is hydrogen, R 15 is hydrogen, R 16 Methyl, R 17 Methyl, R 18 For hydrogen.

[0111]

[0112] Preparation method

[0113] The preparation method of the protonated dimer salt of phenanthroline in this embodiment is as follows.

[0114] - The first reactant is 3,4,7,8-tetramethyl-1,10-phenanthroline;

[0115] - the second reactant is 3,4,7,8-tetramethyl-1,10-phenanthroline; and

[0116] - The first salt is ammonium hexafluorophosphate, that is, the anion is the hexafluorophosphate ion.

[0117] At 25°C, place 1g of the first reactant in 10mL of 2M hydrochloric acid and stir vigorously until completely dissolved. Heat to 85°C for 30 minutes and concentrate under reduced pressure to 2mL. After cooling, crystals precipitate. Wash the crystals with ethanol solution 3 times and dry to obtain the hydrochloride of the first reactant.

[0118] 0.8 g of the first reactant hydrochloride was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.

[0119] 0.8 g of the second reactant was added to the first aqueous solution at 25° C. and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment. The solution was fully dialyzed using a dialysis bag with a molecular weight cutoff of 200 Da and dried to obtain a first intermediate product.

[0120] The first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia water was added to adjust the pH value to 9 to precipitate a large amount of white precipitate. The precipitate was filtered and the filter cake was washed twice with water and dried to obtain the product, i.e., the salt of this example.

[0121] Detection of products or intermediates

[0122] The hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.

[0123] The salt yield in this example is about 1.6 g, with a yield of about 85%.

[0124] The salt of this example is subjected to high-resolution mass spectrometry to obtain the cation of this example, (C 32 H 33 N4) + m / z = 473.6.

[0125] The FTIR spectrum of the salt of this example, 1 H NMR spectra, HRMS spectra and HPLC spectra are shown in Figure 2 HPLC conditions: stationary phase is Shim-pack Scepter C18-120 column (4.6×250 mm, 5 μm); mobile phase is acetonitrile, pH 6.0; flow rate is 1.0 mL / min; detection wavelength is 273 nm; column temperature is 25°C; injection volume is 10 μL.

[0126] Example 3

[0127] The protonated dimer salt of phenanthroline of Example 3 is specifically shown in Formula IV. That is, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 Nitro, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 Nitro, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

[0128]

[0129] Preparation method

[0130] The preparation method of the protonated dimer salt of phenanthroline in this embodiment is as follows.

[0131] - The first reactant is 5-nitro-1,10-phenanthroline;

[0132] - the second reactant is 5-nitro-1,10-phenanthroline; and

[0133] - The first salt is ammonium hexafluorophosphate, that is, the anion is the hexafluorophosphate ion.

[0134] At 25°C, place 1g of the first reactant in 10mL of 2M hydrochloric acid and stir vigorously until completely dissolved. Heat to 85°C for 30 minutes and concentrate under reduced pressure to 2mL. After cooling, crystals precipitate. Wash the crystals with ethanol solution 3 times and dry to obtain the hydrochloride of the first reactant.

[0135] 0.8 g of the first reactant hydrochloride was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.

[0136] 0.8 g of the second reactant was added to the first aqueous solution at 25° C. and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment. The solution was fully dialyzed using a dialysis bag with a molecular weight cutoff of 200 Da and dried to obtain a first intermediate product.

[0137] The first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia water was added to adjust the pH value to 9 to precipitate a large amount of white precipitate. The precipitate was filtered and the filter cake was washed twice with water and dried to obtain the product, i.e., the salt of this example.

[0138] Detection of products or intermediates

[0139] The hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.

[0140] The salt yield in this example is about 1.6 g, with a yield of about 85%.

[0141] The salt of this example is subjected to high-resolution mass spectrometry to obtain the cation of this example, (C 24 H 15 O4N6) + m / z = 451.4.

[0142] The FTIR spectrum of the salt of this example, 1 H NMR spectra, HRMS spectra and HPLC spectra are shown in Figure 3 HPLC conditions: stationary phase is Shim-pack Scepter C18-120 column (4.6×250 mm, 5 μm); mobile phase is acetonitrile, pH 6.0; flow rate is 1.0 mL / min; detection wavelength is 273 nm; column temperature is 25°C; injection volume is 10 μL.

[0143] Example 4

[0144] The protonated dimer salt of phenanthroline of Example 4 is specifically shown in Formula V. That is, R 1 Methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 Methyl, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

[0145]

[0146] Preparation method

[0147] The preparation method of the salt of this embodiment is as follows.

[0148] - The first reactant is 2,9-dimethyl-1,10-phenanthroline;

[0149] - the second reactant is 1,10-phenanthroline; and

[0150] - The first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.

[0151] At 25°C, place 1g of the first reactant in 10mL of 2M hydrochloric acid and stir vigorously until completely dissolved. Heat to 85°C for 30 minutes and concentrate under reduced pressure to 2mL. After cooling, crystals precipitate. Wash the crystals with ethanol solution 3 times and dry to obtain the hydrochloride of the first reactant.

[0152] 0.8 g of the first reactant hydrochloride was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.

[0153] 0.8 g of the second reactant was added to the first aqueous solution at 25° C. and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment. The solution was fully dialyzed using a dialysis bag with a molecular weight cutoff of 200 Da and dried to obtain a first intermediate product.

[0154] The first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia water was added to adjust the pH value to 9 to precipitate a large amount of white precipitate. The precipitate was filtered and the filter cake was washed twice with water and dried to obtain the product, i.e., the salt of this example.

[0155] Detection of products or intermediates

[0156] The hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.

[0157] The salt yield in this example is about 1.6 g, with a yield of about 85%.

[0158] The salt of this example is subjected to high-resolution mass spectrometry to obtain the cation of this example, (C 26 H 21 N4) + m / z = 389.5.

[0159] Example 5

[0160] The anti-leukemia effect of different concentrations of protonated dimer salt of phenanthroline was studied as follows:

[0161] 1. Anti-KG-1 human acute myeloid leukemia cells

[0162] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0163] KG-1 human acute myeloid leukemia cells were uniformly inoculated into 96-well plates, with about 5000 cells per well. The cells were cultured in IMDM complete medium for 2 hours. Different concentrations of the example solutions (solvent was saline, the same as in the following examples) were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL, respectively.

[0164] After 24 hours of culture, 10 μL CCK-8 was added to each well to detect cell activity. After 1 hour of incubation, the absorbance at 450 nm was measured to calculate the IC 50 Value, the result is Figure 4As shown, H310, H311, H312 and H313 represent the protonated dimer salt of phenanthroline in Example 1, Example 2, Example 3 and Example 4 respectively; the ordinate represents the cell proliferation, and the abscissa represents the final concentration of the protonated dimer salt of phenanthroline, which are 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL from left to right, respectively, which are converted into the logarithmic value of 0.0125 mg / mL with respect to e for display, the same below.

[0165] Depend on Figure 4 It can be seen that after the protonated dimer salt of phenanthroline in Examples 1 to 4 was added to the cell culture medium, the activity of KG-1 human acute myeloid leukemia cells decreased with the increase of concentration.

[0166] 2. Anti-KG-1A human acute myeloid leukemia cells

[0167] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0168] KG-1A human acute myeloid leukemia cells were uniformly inoculated into 96-well plates, with about 5000 cells per well. The cells were cultured in IMDM complete medium for 2 hours. Different concentrations of the example solution were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL, respectively.

[0169] After 24 hours of culture, 10 μL CCK-8 was added to each well to detect cell activity. After 1 hour of incubation, the absorbance at 450 nm was measured to calculate the IC 50 Value, the result is Figure 4 As shown, H310, H311, H312 and H313 represent the protonated dimer salt of phenanthroline in Example 1, Example 2, Example 3 and Example 4, respectively; the ordinate represents the cell proliferation, and the abscissa represents the final concentration of the protonated dimer salt of phenanthroline, which are 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL from left to right, respectively.

[0170] Depend on Figure 4It can be seen that after the protonated dimer salt of phenanthroline in Examples 1 to 4 was added to the cell culture medium, the activity of KG-1A human acute myeloid leukemia cells decreased with the increase of concentration.

[0171] 3. Anti-HEL human erythroleukemia cells

[0172] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0173] HEL human erythroleukemia cells were uniformly inoculated into 96-well plates, with about 5000 cells per well. The cells were cultured in IMDM complete medium for 2 hours. Different concentrations of the example solutions were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL, respectively.

[0174] After 24 hours of culture, 10 μL CCK-8 was added to each well to detect cell activity. After 1 hour of incubation, the absorbance at 450 nm was measured to calculate the IC 50 Value, the result is Figure 4 As shown, H310, H311, H312 and H313 represent the protonated dimer salt of phenanthroline in Example 1, Example 2, Example 3 and Example 4, respectively; the ordinate represents the cell proliferation, and the abscissa represents the final concentration of the protonated dimer salt of phenanthroline, which are 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL from left to right, respectively.

[0175] Depend on Figure 4 It can be seen that after the protonated dimer salt of phenanthroline in Examples 1 to 4 is added to the cell culture medium, the activity of HEL human erythroleukemia cells decreases with the increase of concentration.

[0176] 4. Anti-Kasumi-1 human erythroleukemia cells

[0177] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0178] Kasumi-1 human erythroleukemia cells were uniformly inoculated into 96-well plates, with about 5000 cells per well. The cells were cultured in IMDM complete medium for 2 hours. Different concentrations of the example solution were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL, respectively.

[0179] After 24 hours of culture, 10 μL CCK-8 was added to each well to detect cell activity. After 1 hour of incubation, the absorbance at 450 nm was measured to calculate the IC 50 Value, the result is Figure 4 As shown, H310, H311, H312 and H313 represent the protonated dimer salt of phenanthroline in Example 1, Example 2, Example 3 and Example 4, respectively; the ordinate represents the cell proliferation, and the abscissa represents the final concentration of the protonated dimer salt of phenanthroline, which are 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL from left to right, respectively.

[0180] Depend on Figure 4 It can be seen that after the protonated dimer salt of phenanthroline in Examples 1 to 4 was added to the cell culture medium, the activity of Kasumi-1 human erythroleukemia cells decreased with the increase of concentration.

[0181] 5. Anti-THP-1 human monocytic leukemia cells

[0182] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0183] THP-1 human monocytic leukemia cells were uniformly inoculated into 96-well plates, with about 5000 cells per well. The cells were cultured in RPMI 1640 complete medium for 2 hours. Different concentrations of the example solution were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.4 mg / mL and 0.8 mg / mL, respectively.

[0184] After culturing for 24 hours, 10 μL of CCK-8 was added to each well to detect cell activity. After incubation for 1 hour, the absorbance at a wavelength of 450 nm was measured to calculate the cell survival rate. The results are shown in Table 1.

[0185] Table 1 Results of the anti-THP-1 human monocytic leukemia cells of the protonated dimer salt of phenanthroline in Examples 1 to 4

[0186]

[0187]

[0188] It can be seen from Table 1 that after the protonated dimer salt of phenanthroline in Examples 1 to 4 was added to the cell culture medium, the activity of THP-1 human monocytic leukemia cells decreased with the increase of concentration.

[0189] 6. Anti-MOLT-4 human acute lymphoblastic leukemia cells

[0190] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0191] MOLT-4 human acute lymphoblastic leukemia cells were uniformly inoculated into 96-well plates, with about 5000 cells per well. The cells were cultured in RPMI 1640 complete medium for 2 hours. Different concentrations of the example solutions were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.4 mg / mL and 0.8 mg / mL, respectively.

[0192] After culturing for 24 hours, 10 μL of CCK-8 was added to each well to detect cell activity. After incubation for 1 hour, the absorbance at a wavelength of 450 nm was measured to calculate the cell survival rate. The results are shown in Table 2.

[0193] Table 2 Results of the protonated dimer salt of phenanthroline against MOLT-4 human acute lymphoblastic leukemia cells in Examples 1 to 4

[0194]

[0195] It can be seen from Table 2 that after the protonated dimer salts of phenanthroline in Examples 1 to 4 were added to the cell culture medium, the activity of MOLT-4 human acute lymphoblastic leukemia cells decreased with the increase of concentration.

[0196] 7. Anti-Jurkat human T lymphocyte leukemia cells

[0197] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0198] Jurkat human T lymphocyte leukemia cells were uniformly inoculated into 96-well plates, with about 5000 cells per well. The cells were cultured in RPMI 1640 complete medium for 2 hours. Different concentrations of the example solutions were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.4 mg / mL and 0.8 mg / mL, respectively.

[0199] After culturing for 24 hours, 10 μL of CCK-8 was added to each well to detect cell activity. After incubation for 1 hour, the absorbance at 450 nm was measured to calculate the cell survival rate. The results are shown in Table 3.

[0200] Table 3 Results of the protonated dimer salt of phenanthroline against Jurkat human T lymphocyte leukemia cells in Examples 1 to 4

[0201]

[0202] It can be seen from Table 3 that after the protonated dimer salt of phenanthroline in Examples 1 to 4 was added to the cell culture medium, the activity of Jurkat human T lymphocyte leukemia cells decreased with the increase of concentration.

[0203] 8. Anti-Reh human acute non-B non-T lymphocytes

[0204] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0205] Reh human acute non-B non-T lymphocytes were uniformly inoculated into a 96-well plate, with about 5000 cells per well. The cells were cultured in RPMI1640 complete medium for 2 hours. Different concentrations of the example solution were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.4 mg / mL and 0.8 mg / mL, respectively.

[0206] After culturing for 24 hours, 10 μL of CCK-8 was added to each well to detect cell activity. After incubation for 1 hour, the absorbance at 450 nm was measured to calculate the cell survival rate. The results are shown in Table 4.

[0207] Table 4 Results of the anti-Reh human acute non-B non-T lymphocytes of the protonated dimer salt of phenanthroline in Examples 1 to 4

[0208]

[0209] It can be seen from Table 4 that after the protonated dimer salt of phenanthroline in Examples 1 to 4 was added to the cell culture medium, the activity of Reh human acute non-B non-T lymphocytes decreased with the increase of concentration.

[0210] 9. Anti-MEG-01 human megakaryoblastic leukemia cells

[0211] The protonated dimer salts of phenanthroline in Examples 1 to 4 were used as experimental group compounds, and a blank control group (without adding drugs) was set up. Two biological replicates were set up for each experimental group and blank control group to detect the anti-leukemia ability of the protonated dimer salts of phenanthroline in Examples 1 to 4 at the cellular level.

[0212] MEG-01 human megakaryoblast leukemia cells were uniformly inoculated into 96-well plates, with approximately 5,000 cells per well. The cells were cultured in RPMI 1640 complete medium for 2 hours. Different concentrations of the example solution were added to each well according to the group, so that the final concentrations of each experimental group were 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.4 mg / mL and 0.8 mg / mL, respectively.

[0213] After culturing for 24 hours, 10 μL of CCK-8 was added to each well to detect cell activity. After incubation for 1 hour, the absorbance at a wavelength of 450 nm was measured to calculate the cell survival rate. The results are shown in Table 5.

[0214] Table 5 Results of the protonated dimer salt of phenanthroline against MEG-01 human megakaryoblastic leukemia cells in Examples 1 to 4

[0215]

[0216]

[0217] It can be seen from Table 5 that after the protonated dimer salt of phenanthroline in Examples 1 to 4 was added to the cell culture medium, the activity of MEG-01 human megakaryoblastic leukemia cells decreased with the increase of concentration.

[0218] It can be concluded from the above examples that the protonated dimer salt of phenanthroline described in the present invention can effectively inhibit the activity of leukemia cells in a concentration-dependent manner, thereby achieving an anti-leukemia effect.

[0219] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. Use of a protonated dimer cation of phenanthroline or a protonated dimer salt of phenanthroline in the preparation of a drug for treating leukemia, wherein the protonated dimer cation of phenanthroline has a structure of formula I, wherein is a covalent bond or a non-covalent bond, in, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, methyl, phenyl, cyano, amino, nitro or chloro; The protonated dimer salt of phenanthroline comprises a protonated dimer cation of phenanthroline and an anion, wherein the anion is at least one of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a sulfide ion, a nitrate ion, a sulfate ion, a sulfite ion, a thiosulfate ion, a persulfate ion, a selenate ion, a phosphate ion, a carbonate ion, a hexafluorophosphate ion, a hexafluorosilicate ion, an acetate ion, a sulfonate ion, a benzoate ion and a polyphosphate ion.

2. The use according to claim 1, characterized in that: The protonated dimer salt of phenanthroline has a structure of formula II, wherein k=1-3, and X is at least one of hexafluorophosphate ion, hexafluorosilicate ion, chloride ion and sulfate ion; 3. The use according to claim 2, characterized in that: The protonated dimer salt of phenanthroline has a structure of any one of Formulas III to VI: Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen; Among them, R 1 is hydrogen, R 2 Methyl, R 3 Methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 Methyl, R 7 Methyl, R 8 is hydrogen, R 11 is hydrogen, R 12 Methyl, R 13 Methyl, R 14 is hydrogen, R 15 is hydrogen, R 16 Methyl, R 17 Methyl, R 18 is hydrogen; Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 Nitro, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 Nitro, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen; Among them, R 1 Methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 Methyl, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

4. The use according to any one of claims 1 to 3, characterized in that: The leukemia includes acute leukemia.

5. The use according to claim 4, characterized in that: The acute leukemia includes acute myeloid leukemia and / or acute lymphocytic leukemia.

6. The use according to claim 5, characterized in that: The acute myeloid leukemia includes one or more of acute undifferentiated lineage leukemia, acute minimally differentiated myeloblastic leukemia, acute partially differentiated myeloblastic leukemia, acute promyelocytic leukemia, acute myelo-monocytic leukemia, acute monocytic leukemia, erythroleukemia and acute megakaryocytic leukemia.

7. The use according to claim 5, characterized in that: The acute lymphoblastic leukemia includes B-lineage acute lymphoblastic leukemia and / or T-lineage acute lymphoblastic leukemia.

8. The use according to any one of claims 1 to 3, characterized in that: The effective concentration of the phenanthroline protonated dimer cation or the phenanthroline protonated dimer salt is at least 0.00625 mg / mL, respectively.

9. A drug for treating leukemia, characterized in that: The active ingredient of the drug includes a phenanthroline protonated dimer cation or a phenanthroline protonated dimer salt; the phenanthroline protonated dimer cation has a structure of formula I, wherein is a covalent bond or a non-covalent bond, Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, methyl, phenyl, cyano, amino, nitro or chloro; The protonated dimer salt of phenanthroline comprises a protonated dimer cation of phenanthroline and an anion, wherein the anion is at least one of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a sulfide ion, a nitrate ion, a sulfate ion, a sulfite ion, a thiosulfate ion, a persulfate ion, a selenate ion, a phosphate ion, a carbonate ion, a hexafluorophosphate ion, a hexafluorosilicate ion, an acetate ion, a sulfonate ion, a benzoate ion and a polyphosphate ion.

10. The drug according to claim 9, characterized in that The protonated dimer salt of phenanthroline has a structure of any one of Formulas III to VI: Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen; Among them, R 1 is hydrogen, R 2 Methyl, R 3 Methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 Methyl, R 7 Methyl, R 8 is hydrogen, R 11 is hydrogen, R 12 Methyl, R 13 Methyl, R 14 is hydrogen, R 15 is hydrogen, R 16 Methyl, R 17 Methyl, R 18 is hydrogen; Among them, R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, R 4 Nitro, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 Nitro, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen; Among them, R 1 Methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 Methyl, R 11 is hydrogen, R 12 is hydrogen, R 13 is hydrogen, R 14 is hydrogen, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 For hydrogen.

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