A metal complex with FTO inhibitory activity and its preparation method and application

Abstract

The present invention discloses a metal complex with FTO inhibitory activity, and also discloses a preparation method and application of the metal complex with FTO inhibitory activity. The metal complex of the present invention is obtained by CuAAC reaction of an alkynyl-modified FTO inhibitor and an azide-containing metal complex precursor, and the metal complex has good anticancer activity and FTO inhibitory activity, which can overcome the problem of poor target selectivity of a single FTO inhibitor, and can overcome the problem of large toxic side effects when a simple metal complex (precursor) is used as an antitumor drug or an antitumor drug component.

Description

Technical Field

[0001] The invention relates to a metal complex with FTO inhibition activity and also relates to a preparation method and application of the metal complex. Technical Background

[0002] Cancer is one of the most serious diseases threatening human life. Most platinum-based drugs and other drugs (such as cisplatin, carboplatin, oxaliplatin, etc.) currently used in clinical practice have the disadvantages of large toxic side effects, poor selectivity and drug resistance. With the in-depth study of the mechanism of action of anticancer drugs in tumor cells, many metal anti-tumor drugs with broad application prospects have emerged in recent years. At present, metal complexes such as aryl ruthenium, iridium, rhodium and osmium are considered to be the most promising metal anti-cancer drugs because of their high activity, selectivity, multiple targets, low drug resistance and other advantages. At present, many experts at home and abroad, such as Professor Peter Sadler of the University of Warwick in the UK, Professor Paul Dyson of the Swiss Federal Institute of Technology in Lausanne, and Professor Bernhard Keppler of the University of Vienna in Austria, have conducted in-depth research in this area.

[0003] In 2007, British scientists discovered the FTO gene (Fat mass and obesity-associated protein) related to obesity in a single nucleotide polymorphism (SNP) study related to type 2 diabetes. The protein encoded by the FTO gene is a member of the AlkB family and is dependent on divalent iron (Fe). 2+ FTO is an oxygenase that catalyzes the demethylation of nucleotides. Related studies have shown that FTO plays an oncogene role in the occurrence of acute myeloid leukemia and clearly revealed that FTO-mediated mRNA 6 A modification is involved in the occurrence of tumors. In 2012, researchers from the Shanghai Institute of Materia Medica screened out three compounds, including rhein, that could inhibit the activity of FTO. Among them, rhein had the best inhibitory effect and was more suitable as a candidate drug molecule. In 2014, American scientists accidentally discovered that the obtained chemical could not effectively inhibit the target protein PHD2 while studying anti-epileptic drugs, but could effectively inhibit FTO of its 2OG oxygenase family, and IC 50 The value is close to that of the broad-spectrum 2OG enzyme inhibitor NOG and stronger than the previously reported rhein. However, most of the FTO inhibitors reported so far are not suitable for clinical application due to poor target selectivity or poor pharmacokinetics. Summary of the invention

[0004] Purpose of the invention: The purpose of the present invention is to provide a metal complex with FTO inhibitory activity. The metal complex is obtained by reacting an alkynyl-modified FTO inhibitor with an azide-containing metal complex precursor through CuAAC. The metal complex has good anticancer activity and FTO inhibitory activity. On the one hand, it can overcome the problem of poor target selectivity of a single FTO inhibitor, and on the other hand, it can overcome the problem of large toxic side effects when a simple metal complex (precursor) is used as an antitumor drug or an antitumor drug component.

[0005] Technical solution: The metal complex with FTO inhibition activity described in the present invention has a general structural formula as shown below:

[0006]

[0007] Wherein, M is Ru, Ir, Rh or Os; for L is

[0008] The method for preparing the above-mentioned metal complex having FTO inhibition activity comprises the following steps:

[0009] (1) preparing a metal complex precursor containing an azide group: dissolving a metal ruthenium dimer, a metal iridium dimer, a metal rhodium dimer or a metal osmium dimer in methanol under an inert atmosphere, carrying out a coordination reaction with a chelating ligand, removing the solvent by rotary evaporation under reduced pressure after the reaction, adding a methanol solution of a saturated anion salt, freezing the mixture at low temperature, collecting the solid by centrifugation after freezing, and purifying the crude product by column chromatography to obtain a metal complex precursor;

[0010] (2) Preparing an alkynyl-modified organic active molecule ligand: Under an inert atmosphere, an organic active molecule, an alkynyl compound and a catalyst are placed in an organic solvent for reaction. After the reaction is completed, the solvent is removed by rotary evaporation to obtain a crude product, which is then purified by column chromatography to obtain an organic active molecule ligand;

[0011] (3) Under an inert atmosphere, a metal complex precursor, an organic active molecular ligand and a catalyst are subjected to a CuAAC reaction in an organic solvent. After the reaction is completed, the solvent is removed by rotary evaporation, and the crude product is purified by a chromatographic column to obtain a metal complex.

[0012] Wherein, in step (1), the dimer of metal ruthenium is p-cymene ruthenium dichloride (II) dimer (purchased from Shanghai MacLean Biochemical Technology Co., Ltd., CAS: 52462-29-0), the dimer of metal iridium is dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (purchased from Shanghai MacLean Biochemical Technology Co., Ltd., CAS: 12354-84-6), the dimer of metal rhodium is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (purchased from Shanghai MacLean Biochemical Technology Co., Ltd., CAS: 12354-85-7), and the dimer of metal osmium is p-cymene osmium dichloride (II) dimer (purchased from aablocks, CAS: 78615-08-4).

[0013] Wherein, in step (1), the molar ratio of the dimer of metal ruthenium to the chelating ligand is 8 to 9:1; the molar ratio of the dimer of metal iridium to the chelating ligand is 13 to 14:1; the molar ratio of the dimer of metal rhodium to the chelating ligand is 12 to 13:1; and the molar ratio of the dimer of metal osmium to the chelating ligand is 12 to 13:1.

[0014] Wherein, in step (1), the chelating ligand is 4-azidomethyl-4'-methyl-2,2'-bipyridine, and 4-azidomethyl-4'-methyl-2,2'-bipyridine is prepared by the method reported in the document "Artificial photosynthesis dendrimers integrating light-harvesting, electron delivery and hydrogen production".

[0015] Wherein, in step (1), the freezing temperature is -20 to 0°C and the freezing time is 8 to 14 hours.

[0016] Wherein, in step (2), the alkynyl compound is propargyl bromide, propargylamine or pentynoic acid; the catalyst is potassium carbonate or a catalyst is a composition of N-hydroxybenzotriazole and N,N-diisopropylethylamine in a molar ratio of 82 to 83:135.

[0017] Wherein, in step (2), the molar ratio of the organic active molecule to the alkynyl compound is 0.1 to 4:1.

[0018] Wherein, in step (3), the catalyst is a composition of copper sulfate pentahydrate and sodium ascorbate in a molar ratio of 3 to 3.5:4.

[0019] Wherein, in step (3), the reaction molar ratio of the metal complex precursor to the organic active molecule ligand is 3 to 25.5:1.

[0020] Application of the above-mentioned metal complex with FTO inhibitory activity in preparing antitumor drugs, antitumor drug components, FTO inhibitory drugs and FTO inhibitory drug components.

[0021] The reaction mechanism of the metal complex synthesis process of the present invention is:

[0022]

[0023] in: is a metal complex precursor, and the metal complex precursor has the structural formula; X is an azide group in the metal complex precursor;

[0024] Wherein: M is Ru, Ir, Rh or Os;

[0025] in: is p-cymene or pentamethylcyclopentadiene;

[0026] in: It is an organic active molecular ligand with the structural formula:

[0027] Y is an alkyne group in the organic active molecular ligand.

[0028] The aryl / metallocene complex of the present invention is obtained by a CuAAC reaction with a molecule having anti-FTO activity as the alkyne end and an aryl / metallocene as the azide end. The aryl / metallocene complex of the present invention has good lipid solubility, can increase the reactive oxygen species produced by cancer cells, induce the generation of mitochondrial membrane potential, and block the cell cycle.

[0029] Beneficial effects: The present invention modifies the FTO inhibitor with anti-tumor, antibacterial and anti-inflammatory effects with specific groups and coordinates it with cyclopentadienyl and aryl metals to obtain a complex with good inhibitory activity of obesity gene FTO, anticancer activity, antibacterial activity and anti-inflammatory activity. Therefore, the metal complex of the present invention has targeted anticancer, antibacterial, anti-inflammatory and FTO demethylase inhibitory effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the cellular localization map of the complex FTO-2-Ru / Ir / Rh in cells;

[0031] Figure 2 This is a diagram of the complex FTO-2-Ru / Ir / Rh and the organic active molecule ligand and the organic active molecule inducing cell apoptosis;

[0032] Figure 3Confocal fluorescence imaging and flow cytometry images of the complex FTO-2-Ru / Ir / Rh and the organic active molecule ligands and organic active molecules promoting the generation of intracellular reactive oxygen species;

[0033] Figure 4 The flow cytometric images and confocal fluorescence imaging images of the complex FTO-2-Ru / Ir / Rh and the organic active molecule ligands and organic active molecules inducing the decrease of mitochondrial membrane potential;

[0034] Figure 5 This is a diagram showing the effects of the complex FTO-2-Ru / Ir / Rh and the organic active molecule ligands and organic active molecules on cell cycle arrest.

[0035] Figure 6 Schematic diagram of the complex FTO-2-Ru / Ir / Rh and the inhibition of FTO activity by organic active molecule ligands and organic active molecules. DETAILED DESCRIPTION

[0036] The technical solution of the present invention is further described below in conjunction with specific embodiments.

[0037] Example 1

[0038] The preparation method of the metal complex FTO-2-Ru of the present invention comprises the following steps:

[0039]

[0040] Step 1, 6-(5-methylpyrazin-2-yl)naphthalen-2-ol (FTO-2) (0.13 g, 0.5 mmol), propargyl bromide (0.53 g, 4.5 mmol) and potassium carbonate (2.05 g, 15.2 mmol) were dissolved in DMF (N, N-dimethylformamide), stirred at 80 ° C for 12 h, added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to obtain a crude product. The crude product was separated and purified by column chromatography to obtain an organic compound FTO-2-alkyne with a yield of 85%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.06(s,2H),8.25(d,J=1.9Hz,1H),7.93(dd,J=8.8,6.7Hz,2H),7.86(dd,J=8.6,1.9Hz,1H),7.45(d ,J=2.6Hz,1H),7.26(dd,J=9.0,2.6Hz,1H),4.95(d,J=2.4Hz,2H),3.99(s,3H),3.64(t,J=2.4Hz,1H).

[0041] The above-mentioned FTO-2 is prepared by the synthesis method reported in the document "Broad spectrum anti-cancer compounds for treatment of cancer".

[0042] Step 2: At room temperature, the bridging ligand 4-azidomethyl-4'-methyl-2,2'-bipyridine (0.9 g, 4 mmol) and p-cymene dichloride ruthenium (II) dimer (1.96 g, 3.2 mmol) were reacted in a methanol solution for 48 h, the solvent was removed by rotary evaporation, and saturated (NH 4 )PF 6 The methanol solution was placed in a refrigerator at -20°C overnight, and the solid was collected by centrifugation after freezing. The crude product was purified by column chromatography to obtain a pure product with a yield of 85%, named Ru-N 3 . 1 H NMR (400 MHz, DMSO-d 6 )δ9.50(d,J=5.8Hz,1H),9.36(d,J=5.8Hz,1H),8.60–8.57(m,2H),7.74(dd,J=6.0,1.7Hz,1H),7.67–7.63(m,1H),6.22 –6.19(m,2H),5.98–5.94(m,2H),4.88(s,2H),2.58(s,3H),2.57–2.52(m,1H),2.18(s,3H),0.94(dd,J=7.0,2.0Hz,6H).

[0043] The above-mentioned bridging ligand 4-azidomethyl-4'-methyl-2,2'-bipyridine is prepared by the synthesis method reported in the literature "Artificial photosynthesis dendrimers integrating light-harvesting, electron delivery and hydrogen production", specifically:

[0044] Take 4,4'-dimethyl-2,2'-bipyridine (8.0 g, 4.3 mmol) and 1,4-dioxane (50-250 mL) to prepare a suspension, then add SeO 2(8.0 g, 7.1 mmol) was heated to reflux for 48 h, filtered to obtain a filtrate, and the filtrate was decompressed to remove the solvent to obtain a solid substance; the solid substance was dissolved in chloroform, filtered, and the filtrate was decompressed to remove the solid substance, and the above steps were repeated three times to finally obtain a crude product; sodium borohydride (2.8 g) was dissolved in sodium hydroxide solution (0.2 mol, 20 mL), and the solution was added dropwise to a methanol suspension (50 mL) containing the crude product, cooled and stirred for 1 h, and then methanol was removed under reduced pressure, and 80 mL of saturated Na 2 CO 3 The solution was diluted, the organic phase was extracted and dried, the solvent was evaporated, and purified by column chromatography to obtain 4-hydroxymethyl-4'-methyl-2,2'-bipyridine; 4-hydroxymethyl-4'-methyl-2,2'-bipyridine (3.2 g, 5.3 mmol) was dissolved in HBr (48%, 40 mL), and concentrated sulfuric acid (10 mL) was added and heated to reflux overnight, and the pH was adjusted to 8 after cooling, and extracted with chloroform until the organic layer was colorless, and the organic layer was dried to remove chloroform to obtain 4-bromomethyl-4'-methyl-2,2'-bipyridine; 4-bromomethyl-4'-methyl-2,2'-bipyridine (2.8 g, 10.7 mmol) and NaN 3 (1.2 g, 18.5 mmol) was dissolved in an aqueous solution of N,N-dimethylformamide (55 mL, v / v = 10:1) and stirred at 70 °C for 12 h. The crude product was obtained after removing the solvent and then purified by CH 2 Cl 2 The organic layer obtained by extraction was washed with water, dried and then the solvent was removed, and purified by column chromatography to obtain 4-azidomethyl-4'-methyl-2,2'-bipyridine. 1 H NMR (400 MHz, DMSO-d 6 )δ8.68(dd,J=4.9,0.8Hz,1H),8.55(dd,J=5.0,0.8Hz,1H),8.38(dd,J=1.7,0.9Hz,1H),8.26(dt,J=1. 7,0.9Hz,1H),7.44–7.41(m,1H),7.31(ddd,J=5.0,1.8,0.8Hz,1H),4.70(s,2H),2.42(d,J=0.7Hz,3H).

[0045] Step 3: Under argon atmosphere, FTO-2-alkyne (0.52 g, 1.8 mmol) and Ru-N 3(1.49 g, 3 mmol), copper sulfate pentahydrate (0.34 g, 1.50 mmol) and sodium ascorbate (0.40 g, 2.0 mmol) were dissolved in DMF and stirred for 10 h. After the reaction, the solvent was removed by rotary evaporation and the orange-yellow product FTO-2-Ru was separated by column chromatography with a yield of 83.3%. 1 HNMR (400 MHz, DMSO-d 6 )δ9.50(d,J=5.9Hz,1H),9.37(d,J=5.8Hz,1H),9.06(s,2H),8.64(s,1H),8.54(s,1H),8.48(s, 1H),8.25(s,1H),7.97–7.90(m,2H),7.89–7.83(m,1H),7.66(d,J=5.9Hz,1H),7.58(d,J=2.5Hz, 1H),7.49(d,J=5.9Hz,1H),7.26(dd,J=8.9,2.5Hz,1H),6.19(dd,J=14.8,6.1Hz,2H),6.00–5.91 (m,4H),5.35(s,2H),3.99(s,3H),2.58(s,3H),2.55(s,1H),2.16(s,3H),0.94(t,J=7.0Hz,6H).

[0046] Example 2

[0047] The preparation method of the metal complex FTO-2-Ir of the present invention comprises the following steps:

[0048]

[0049] Step 1: At room temperature, the bridging ligand 4-azidomethyl-4'-methyl-2,2'-bipyridine (0.9 g, 4 mmol) and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (2.54 g, 3.2 mmol) were reacted in a methanol solution for 10 h, the solvent was removed by rotary evaporation, and saturated (NH 4 )PF 6 The methanol solution was placed in a refrigerator at -20°C overnight, and the solid was collected by centrifugation after freezing. The crude product was purified by column chromatography to obtain a pure product with a yield of 87.6%, named Ir-N 3 . 1 H NMR (400 MHz, DMSO-d 6)δ8.95(d,J=5.8Hz,1H),8.81(d,J=5.8Hz,1H),8.72(t,J=2.3Hz,2H),7.79(dd,J=6 .0,1.7Hz,1H),7.70(dd,J=6.0,1.7Hz,1H),4.94(s,2H),2.64(s,3H),1.65(s,15H).

[0050] Step 2: Under argon atmosphere, FTO-2-alkyne (0.52 g, 1.8 mmol) and Ir-N 3 (2.17 g, 3.0 mmol), copper sulfate pentahydrate (0.34 g, 1.50 mmol) and sodium ascorbate (0.40 g, 2.0 mmol) were dissolved in DMF and stirred for 10 h. After the reaction, the solvent was removed by rotary evaporation and the orange-yellow product FTO-2-Ir was separated by column chromatography with a yield of 85.3%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.06(s,2H),8.95(d,J=5.9Hz,1H),8.84–8.78(m,2H),8.62(s,1H),8.55(s,1 H),8.25(d,J=1.8Hz,1H),7.96–7.91(m,2H),7.86(dd,J=8.6,1.9Hz,1H),7.71(d ,J=5.8Hz,1H),7.59(d,J=2.6Hz,1H),7.49(dd,J=5.9,1.8Hz,1H),7.27(dd,J=8. 9,2.5Hz,1H),6.00(s,2H),5.36(s,2H),3.99(s,3H),2.64(s,3H),1.64(s,15H).

[0051] Example 3

[0052] The preparation method of the metal complex FTO-2-Rh of the present invention comprises the following steps:

[0053]

[0054] Step 1: At room temperature, the bridging ligand 4-azidomethyl-4'-methyl-2,2'-bipyridine (0.9 g, 4 mmol) and dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (2.26 g, 3.2 mmol) were reacted in a methanol solution for 10 h, the solvent was removed by rotary evaporation, and saturated (NH 4 )PF 6The methanol solution was placed in a refrigerator at -20°C overnight, and the solid was collected by centrifugation after freezing. The crude product was purified by column chromatography to obtain a pure product with a yield of 78.5%, named Rh-N 3 . 1 H NMR (400 MHz, DMSO-d 6 )δ8.95(d,J=5.7Hz,1H),8.81(d,J=5.7Hz,1H),8.62(t,J=1.9Hz,2H),7.82(dd ,J=5.8,1.7Hz,1H),7.75–7.69(m,1H),4.89(s,2H),2.59(s,3H),1.66(s,15H).

[0055] Step 2: Under argon atmosphere, FTO-2-alkyne (0.52 g, 1.8 mmol) and Rh-N 3 (1.91 g, 3 mmol), copper sulfate pentahydrate (0.34 g, 1.50 mmol) and sodium ascorbate (0.40 g, 2.0 mmol) were dissolved in DMF and stirred for 10 h. After the reaction, the solvent was removed by rotary evaporation and the orange-yellow product FTO-2-Rh was separated by column chromatography with a yield of 86.5%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.06(s,2H),8.95(d,J=5.8Hz,1H),8.82(d,J=5.7Hz,1H),8.72(s,1H),8.54( d,J=4.8Hz,2H),8.25(s,1H),7.98–7.91(m,2H),7.88–7.84(m,1H),7.73(d,J=5 .8Hz,1H),7.59(d,J=2.5Hz,1H),7.52(d,J=5.8Hz,1H),7.27(dd,J=8.9,2.4Hz, 1H),5.96(s,2H),5.36(s,2H),3.99(d,J=1.1Hz,3H),2.59(s,3H),1.65(s,15H).

[0056] Example 4

[0057] The preparation method of the metal complex FTO-2-Os of the present invention comprises the following steps:

[0058]

[0059] Step 1: At room temperature, the bridging ligand 4-azidomethyl-4'-methyl-2,2'-bipyridine (0.9 g, .4 mmol) and p-cymene dichloride osmium (II) dimer (2.25 g, 3.2 mmol) were reacted in a methanol solution for 10 h, the solvent was removed by rotary evaporation, and saturated (NH 4 )PF 6 The methanol solution was placed in a refrigerator at -20°C overnight, and the solid was collected by centrifugation after freezing. The crude product was purified by column chromatography to obtain a pure product with a yield of 86.3%, named Os-N 3 . 1 H NMR (400 MHz, CD 3 OD)δ9.21(d,J=5.9Hz,1H),9.02(d,J=5.8Hz,1H),8.33(d,J=19.1Hz,2H),7.52(ddd,J=44.9,5.9,1.4Hz,2H ),6.31-6.15(m,2H),5.74-5.59(m,2H),4.81(s,2H),2.58(m,4H),2.23(s,3H),1.11(dd,J=6.9,1.0Hz,6H).

[0060] Step 2: Under argon atmosphere, FTO-2-alkyne (0.52 g, 1.8 mmol) and Os-N 3 (1.76 g, 3 mmol), copper sulfate pentahydrate (0.34 g, 1.50 mmol) and sodium ascorbate (0.40 g, 2.0 mmol) were dissolved in DMF and stirred for 10 h. After the reaction, the solvent was removed by rotary evaporation and the orange-yellow product FTO-2-Os was separated by column chromatography with a yield of 84.2%. 1 H NMR (400 MHz, DMSO-d 6)δ9.52(d,J=5.9Hz,1H),9.38(d,J=5.8Hz,1H),9.07(s,2H),8.63(s,1H),8.52(s,1H),8.46(s, 1H),8.26(s,1H),7.97–7.91(m,2H),7.89–7.85(m,1H),7.63(d,J=5.9Hz,1H),7.57(d,J=2.5Hz, 1H),7.45(d,J=5.9Hz,1H),7.26(dd,J=8.9,2.5Hz,1H),6.18(dd,J=14.8,6.1Hz,2H),6.02–5.90 (m,4H),5.32(s,2H),3.95(s,3H),2.59(s,3H),2.56(s,1H),2.26(s,3H),1.14(t,J=7.0Hz,6H).

[0061] Example 5

[0062] The preparation method of the metal complex FTO-4-Ru of the present invention comprises the following steps:

[0063]

[0064] Step 1, under argon atmosphere, pentynoic acid (29.4 mg, 0.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.3 mmol) and triethylamine (50 μL) were dissolved in DMF, and reacted for 30 min under ice bath conditions. N-hydroxybenzotriazole (32.4 mg, 0.24 mmol) was dissolved in DMF and added dropwise to the above mixture, and reacted for 15 min under ice bath conditions. 6-(5-methoxypyridin-3-yl)benzothiazole-2-amine (FTO-4) (129.2 mg, 0.5 mmol) was then added dropwise to the mixed solution. The reaction mass was warmed to room temperature, stirred overnight, and the organic solvent was removed. The white solid FTO-4-alkyne was purified by column chromatography with a yield of 65.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.91(s,2H),8.09(d,J=1.8Hz,1H),7.61(dd,J=8.3,1.8Hz,1H),7.45(d,J=8.3Hz,1H),3.96(s,3H),2.35=4(td,J=7.1,2.7Hz,4H),2.05(s,1H).

[0065] The above-mentioned FTO-4 is prepared by the synthesis method reported in the document “Broad spectrum anti-cancer compounds for treatment of cancer”.

[0066] Step 2: Under argon atmosphere, FTO-4-alkyne (0.61 g, 1.8 mmol) and Ru-N 3 (1.49 g, 3 mmol), copper sulfate pentahydrate (0.34 g, 1.50 mmol) and sodium ascorbate (0.40 g, 2.0 mmol) were dissolved in DMF and stirred for 10 h. After the reaction, the solvent was removed by rotary evaporation and the orange-yellow product FTO-4-Ru was separated by column chromatography with a yield of 75.2%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.50(d,J=5.9Hz,1H),9.08(s,2H),8.91(s,2H),8.63(s,1H),8.52(s ,1H),8.23(s,1H),8.09(d,J=1.8Hz,1H),8.02(dd,J=8.0,1.7Hz,1H),7. 98–7.90(m,2H),7.89–7.2(m,1H),7.64(d,J=5.9Hz,1H),7.61(dd,J=8. 3,1.8Hz,1H),7.45(d,J=8.3Hz,1H),7.42(d,J=8.3Hz,1H),7.31–7.24(m ,2H),7.18(d,J=2.1Hz,2H),6.94(s,1H),6.61(d,J=2.4Hz,1H),6.78(d dd,J=8.2,7.1,1.1Hz,1H),6.00–5.93(m,4H),5.34(s,2H),3.96(s,3H), 2.78(td,J=7.1,2.7Hz,4H),2.54(s,1H),2.43(d,J=0.7Hz,3H),2.35=4 (td,J=7.1,2.7Hz,4H),2.13(s,3H),2.05(s,1H),0.95(t,J=7.0Hz,6H).

[0067] Example 6

[0068] The preparation method of the metal complex FL1-Ru of the present invention comprises the following steps:

[0069]

[0070] Step 1, under argon atmosphere, pentynoic acid (29.4 mg, 0.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.3 mmol) and triethylamine (50 μL) were dissolved in DMF, and reacted for 30 min under ice bath condition, N-hydroxybenzotriazole (32.4 mg, 0.24 mmol) was dissolved in DMF and added dropwise to the above mixture, and reacted for 15 min under ice bath condition, and 5-aminofluorescein (FL1) (0.42 g, 1.2 mmol) was added to the mixture, and the reaction mass was warmed to room temperature. After stirring overnight, the organic solvent was removed and purified by column chromatography to obtain a white solid FL1-alkyne with a yield of 69.5%. 1 H NMR (400 MHz, Methanol-d 4 )δ7.16(d,J=2.1Hz,2H),7.10(d,J=2.2Hz,1H),7.08(d,J=2.2Hz,1H),6.93(s,1H),6.91(s,1H),6 .67(s,1H),6.61(d,J=2.4Hz,1H),6.58(d,J=2.4Hz,1H),2.63(td,J=7.1,2.7Hz,4H),2.05(s,1H).

[0071] Step 2: Under argon atmosphere, FL1-alkyne (0.77 g, 1.8 mmol) and Ru-N 3 (1.49 g, 3 mmol), copper sulfate pentahydrate (0.34 g, 1.50 mmol) and sodium ascorbate (0.40 g, 2.0 mmol) were dissolved in DMF and stirred for 10 h. After the reaction, the solvent was removed by rotary evaporation and the orange-yellow product FL1-Ru was separated by column chromatography with a yield of 85.2%. 1 H NMR (400 MHz, DMSO-d 6)δ9.50(d,J=5.9Hz,1H),9.08(s,2H),8.63(s,1H),8.52(s,1H),8.23(s,1H),8.02(dd,J=8.0,1.7Hz,1H),7 .98–7.90(m,2H),7.89–7.2(m,1H),7.64(d,J=5.9Hz,1H),7.42(d,J=8.3Hz,1H),7.31–7.24(m,2H),7.18(d, J=2.1Hz,2H),6.94(s,1H),6.61(d,J=2.4Hz,1H),6.78(ddd,J=8.2,7.1,1.1Hz,1H),6.00–5.93(m,4H),5.34 (s,2H),2.78(td,J=7.1,2.7Hz,4H),2.54(s,1H),2.43(d,J=0.7Hz,3H),2.13(s,3H),0.96(t,J=7.0Hz,6H).

[0072] Example 7

[0073] The preparation method of the metal complex FL2-Ru of the present invention comprises the following steps:

[0074]

[0075] Step 1. Under an argon atmosphere, 2',7'-dichlorofluorescein (FL2) (0.48 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.3 mmol) and triethylamine (50 μL) were dissolved in DMF and reacted in an ice bath for 30 min. N-hydroxybenzotriazole (32.4 mg, 0.24 mmol) was dissolved in DMF and added dropwise to the above mixture, and reacted in an ice bath for 15 min. Propylamine (82.6 mg, 1.5 mmol) was then added dropwise to the mixture. The reaction mass was allowed to warm to room temperature overnight. After stirring overnight, the organic solvent was removed and purified by column chromatography to obtain a white solid FL2-alkyne with a yield of 77.8%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.38(s,2H),8.04–8.00(m,1H),7.83(td,J=7.5,1.2Hz,1H),7.76(td,J=7.5,1. 0Hz,1H),7.35(d,J=7.7Hz,1H),7.07(s,2H),6.63(s,2H),4.88(s,2H),2.05(s,1H).

[0076] Step 2: Under argon atmosphere, FL2-alkyne (0.79 g, 1.8 mmol) and Ru-N 3 (1.49 g, 3 mmol), copper sulfate pentahydrate (0.34 g, 1.50 mmol) and sodium ascorbate (0.40 g, 2.0 mmol) were dissolved in DMF and stirred for 10 h. After the reaction, the solvent was removed by rotary evaporation and the orange-yellow product FL2-Ru was separated by column chromatography with a yield of 78.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.38(s,2H),9.50(d,J=5.9Hz,1H),8.63(s,1H),8.09(d,J=1.8Hz,1H),8.04–8.0 0(m,1H),7.98–7.90(m,2H),7.64(d,J=5.9Hz,1H),7.61(dd,J=8.3,1.8Hz,1H),7.31– 7.24(m,2H),7.07(s,2H),6.00–5.93(m,4H),4.88(s,2H),2.78(td,J=7.1,2.7Hz,4H) ,2.54(s,1H),2.43(d,J=0.7Hz,3H),2.13(s,3H),2.05(s,1H),0.95(t,J=7.0Hz,6H).

[0077] Example 8

[0078] The preparation method of the metal complex MA-Ru of the present invention comprises the following steps:

[0079]

[0080] Step 1, under argon atmosphere, meclofenamic acid (MA) (0.36 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.3 mmol) and triethylamine (50 μL) were dissolved in DMF, and reacted for 30 min under ice bath conditions, N-hydroxybenzotriazole (32.4 mg, 0.24 mmol) was dissolved in DMF and added dropwise to the above mixture, and reacted for 15 min under ice bath conditions, and propargylamine (82.6 mg, 1.5 mmol) was added dropwise to the mixed solution, and the reaction mass was warmed to room temperature overnight. After stirring overnight, the organic solvent was removed and purified by column chromatography to obtain a white solid MA-alkyne with a yield of 72.5%. 1 H NMR (400 MHz, Methanol-d 4)δ8.00(dd,J=8.0,1.7Hz,1H),7.41(d,J=8.3Hz,1H),7.31–7.23(m,2H),6.76(ddd,J=8.2,7 .1,1.1Hz,1H),6.25(dd,J=8.4,1.0Hz,1H),4.88(s,2H),3.08(s,1H),2.43(d,J=0.7Hz,3H).

[0081] Step 2: Under argon atmosphere, MA-alkyne (0.60 g, 1.8 mmol) and Ru-N 3 (1.49 g, 3 mmol), copper sulfate pentahydrate (0.34 g, 1.50 mmol) and sodium ascorbate (0.40 g, 2.0 mmol) were dissolved in DMF and stirred for 10 h. After the reaction, the solvent was removed by rotary evaporation and the orange-yellow product MA-Ru was separated by column chromatography with a yield of 80.2%. 1 H NMR (400 MHz, DMSO-d 6 ))δ9.50(d,J=5.9Hz,1H),9.37(d,J=5.8Hz,1H),9.06(s,2H),8.64(s,1H),8.54(s,1H),8.48(s,1H),8.25 (s,1H),8.00(dd,J=8.0,1.7Hz,1H),7.97–7.90(m,2H),7.89–7.83(m,1H),7.66(d,J=5.9Hz,1H),7.41(d, J=8.3Hz,1H),7.31–7.23(m,2H),6.76(ddd,J=8.2,7.1,1.1Hz,1H),6.25(dd,J=8.4,1.0Hz,1H),6.00–5.9 1(m,4H),5.35(s,2H),4.88(s,2H),3.08(s,1H),2.43(d,J=0.7Hz,3H),2.16(s,3H),0.95(t,J=7.0Hz,6H).

[0082] The metal complex of the invention is used in the treatment of tumor cells.

[0083] Methods: MTT colorimetric method, CCK-8 colorimetric method. This experiment measured the anticancer activity of the human cancer cell lines such as human breast cancer cells (MCF-7), mouse glioma cells (A261), human chronic myeloid leukemia cells (K562), human acute promyelocytic leukemia cells (NB-4) and human normal liver cells (LO2) in vitro. MCF-7, MDA-MB-231 and LO2 cells were cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution, and K562 and NB-4 cells were cultured in 1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution at 37°C and 5% CO. 2 Cultured in a cell culture incubator. The cells were inoculated into 96-well cell culture plates at an initial density of 5000 cells / well. After culturing for 24 hours, different concentration gradients of drug culture medium were added. After culturing for 48 hours, 20 μL of MTT aqueous solution (5 mg / mL) was added to each well of the well plates with MCF-7, A261 and LO2 cells, and incubated for 4 hours. The culture medium was removed, and 150 μL of DMSO was added. The well plates were shaken until the purple crystals were completely dissolved, and the plate was shaken for 1 minute using a microplate reader (model: Tecan Infinite M1000 Pro) and the absorbance at 490 nm was read. For the well plates with K562 and NB-4 cells, 10 μL of CCK-8 was added to each well plate, and the plate was incubated for 3 hours. The plate was directly shaken for 1 minute using a microplate reader (model: Tecan Infinite M1000 Pro) and the absorbance at 450 nm was read.

[0084] The anticancer activities of the FTO-2 ruthenium / iridium / rhodium complexes prepared in Examples 1 to 3 are shown in Table 1.

[0085] Table 1 shows the IC values ​​of the complexes FTO-2-Ru, FTO-2-Ir, FTO-2-Rh, FTO-2, FTO-2-alkyne and cisplatin (CDDP) 50 (μM) value

[0086]

[0087]

[0088] The results showed that the organic active molecules FTO-2 and FTO-2-alkyne had little activity against several cell types (IC 50>100μM), FTO-2-Ru showed low toxicity to several cells, but showed excellent selectivity to NB-4 cells, FTO-2-Ir and FTO-2-Rh showed low toxicity to adherent cells, but had good selectivity to leukemia cells, especially NB-4 cells, and had very poor activity to normal human liver cells (LO2), which showed that the aryl and cyclopentadienyl metal complexes based on FTO-2 had high selectivity to leukemia cells. Therefore, FTO-2-Ru, FTO-2-Ir, and FTO-2-Rh all help to reduce the side effects of drugs and have good anti-cancer activity. The complex of the present invention has a certain selectivity to leukemia and can achieve targeted treatment of leukemia cells.

[0089] Example 9

[0090] The localization of the FTO-2-Ru / Ir / Rh complexes prepared in Examples 1 to 3 of the present invention in cells.

[0091] Methods: NB-4 cells were inoculated into 10 cm culture dishes. After 24 h of culture, 1640 culture medium containing FTO-2-Ru (3 μM), FTO-2-Ir (5 μM) and FTO-2-Rh (5 μM) was added and cultured for 12 h. The cells were collected and washed twice with PBS (4 °C). The nuclei, mitochondria and cytoplasm were removed using a mitochondrial / nucleus preparation kit. Then, each sample was digested with concentrated nitric acid (100 μL, 95 °C) for 2 h, hydrogen peroxide (50 μL, 95 °C) for 1 h and concentrated hydrochloric acid (100 μL, 95 °C) for 2 h. After cooling, the obtained liquid was diluted to 2 mL with ultrapure water. The metal content in the sample was determined by ICP-MS, and the intracellular metal content was normalized by the number of cells in each sample.

[0092] The intracellular localization of the FTO-2-Ru complex of Example 1 is as follows Figure 1 As shown in Figure A, after the complex FTO-2-Ru (3 μM) was co-incubated with NB-4 cells for 12 hours, the cell organelles were extracted and the content of metal Ru in the samples in different cell organelles was determined by inductively coupled plasma mass spectrometry ICP-MS. The data in the figure show that the complex FTO-2-Ru is mainly distributed in the nucleus and mitochondria, and partially distributed in the cytoplasm. Example 2 Intracellular localization of FTO-2-Ir complex Figure 1 As shown in Figure B, after the complex FTO-2-Ir (5 μM) was co-incubated with NB-4 cells for 12 hours, the organelles were extracted and the content of metal Ir in the samples in different organelles was determined by inductively coupled plasma mass spectrometry ICP-MS. The data in the figure show that the complex FTO-2-Ir is mainly distributed in the mitochondria. Example 3 Intracellular localization of FTO-2-Rh complex Figure 1As shown in Figure C, after the complex FTO-2-Rh (5 μM) was incubated with NB-4 cells for 12 hours, the organelles were extracted and the content of metal Rh in the samples in different organelles was determined by inductively coupled plasma mass spectrometry ICP-MS. The data in the figure show that the complex FTO-2-Rh is mainly distributed in the cell nucleus.

[0093] The results showed that the complex FTO-2-Ru / Ir / Rh could be taken up by NB-4 cells through the cell membrane in a large amount in a short time. FTO-2-Ru was mainly distributed in the nucleus and mitochondria, FTO-2-Ir was mainly distributed in the mitochondria, and FTO-2-Rh was mainly distributed in the nucleus.

[0094] Example 10

[0095] The FTO-2-Ru / Ir / Rh prepared in Examples 1 to 3 of the present invention induces cell apoptosis.

[0096] Methods: NB-4 cells were seeded into six-well plates and grown for 18 hours. Different concentrations of complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh were added. After incubation for 24 hours, the cells were washed twice with PBS, and the cells were collected and resuspended in 500μL Bindingbuffer. 5μL Annexin V-FITC was added and mixed. After 5 minutes, 5μL Propidium Iodide was added and mixed. Incubated for 15 minutes in the dark, the samples were analyzed by BD FACSverse flow cytometer, and the data were analyzed by FlowJo7.6 software.

[0097] The complexes FTO-2-Ru of Example 1, FTO-2-Ir of Example 2 and FTO-2-Rh of Example 3 induced cell apoptosis as shown in Figure 2 As shown, 24 hours after administration, the flow cytometer graphs of the complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh at different concentration gradients inducing apoptosis of NB-4 cells and the percentage graphs of each stage of cell apoptosis. It can be seen from the data in the figure that the complex FTO-2-Ru cannot induce cell apoptosis, and the cells gradually undergo apoptosis as the administration concentration of the complexes FTO-2-Ir and FTO-2-Rh increases.

[0098] The results showed that the complex FTO-2-Ru could not induce cell apoptosis, while the complexes FTO-2-Ir and FTO-2-Rh could induce cell apoptosis to varying degrees.

[0099] Embodiment 11

[0100] The FTO-2-Ru / Ir / Rh prepared in Examples 1 to 3 of the present invention promotes the generation of reactive oxygen species in cells;

[0101] Methods: Confocal microscopy was used to detect ROS generation: NB-4 cells were seeded in confocal cuvettes and incubated at 37°C for 12 h. 50 After incubation of FTO-2-Ru, FTO-2-Ir and FTO-2-Rh for 24 h, the cells were washed twice with PBS. The cells were exposed to the fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA, 10 μM) for 20 min at 37°C. The cells were then washed twice with PBS and imaged under a laser confocal microscope.

[0102] Flow cytometry detection of ROS generation: NB-4 cells were seeded in 6-well plates and incubated at 37°C for 12 h. 50 After incubation with FTO-2-Ru, FTO-2-Ir and FTO-2-Rh for 24 hours, the cells were washed twice with PBS. At 37°C, the cells were exposed to the fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA, 10μM) for 20 minutes. After washing with PBS twice, the cells were collected and resuspended with PBS. The cells were then immediately detected using a BD FACSverse flow cytometer with an excitation wavelength of 488nm and an emission wavelength of 510-540nm. The data were processed using FlowJo 7.6 software.

[0103] The complexes FTO-2-Ru of Example 1, FTO-2-Ir of Example 2, and FTO-2-Rh of Example 3 can promote the generation of active oxygen to varying degrees, such as Figure 3 As shown, NB-4 cells were treated with 2IC 50 After incubation of FTO-2-Ru, FTO-2-Ir and FTO-2-Rh with different concentrations for 24 hours, the production of intracellular reactive oxygen species induced by the complexes was detected by flow cytometry and laser confocal microscopy. As can be seen from the data in the figure, reactive oxygen species were produced in the cells after the complexes were added for 24 hours.

[0104] The results showed that FTO-2-Ru, FTO-2-Ir and FTO-2-Rh could promote the generation of reactive oxygen species to varying degrees.

[0105] Example 12

[0106] The FTO-2-Ru, FTO-2-Ir and FTO-2-Rh prepared in Examples 1 to 3 of the present invention induce a decrease in mitochondrial membrane potential;

[0107] Methods: NB-4 cells were seeded into 6-well plates and grown for 12 hours. Different concentration gradients of complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh were added. After incubation for 24 hours, the culture medium was aspirated, trypsin digested, cells were collected, washed three times with PBS, and then the prepared JC-1 working solution was added for staining for 30 minutes. Washed twice with JC-1 staining buffer, and finally resuspended with JC-1 staining buffer, and the samples were immediately detected using a BD FACSverse flow cytometer, with two channels set to FL1 and FL2, and the data were processed and analyzed using FlowJo 7.6 software.

[0108] The complexes FTO-2-Ru of Example 1, FTO-2-Ir of Example 2, and FTO-2-Rh of Example 3 induced a decrease in mitochondrial membrane potential. Figure 4 As shown in the figure, the changes in mitochondrial membrane potential of NB-4 cells after incubation in different concentrations of complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh for 24 hours. It can be seen that with the increase of drug concentration, the mitochondrial membrane potential showed a downward trend, indicating that the complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh can induce the decrease of mitochondrial membrane potential of NB-4 cells to varying degrees.

[0109] The results showed that the complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh could induce the decrease of mitochondrial membrane potential to different extents.

[0110] Example 13

[0111] The cell cycle arrest phenomenon of FTO-2-Ru, FTO-2-Ir and FTO-2-Rh prepared in Examples 1 to 3 of the present invention.

[0112] Methods: NB-4 cells were seeded in 6-well cell plates and cultured in an atmosphere of 5% CO. 2 After incubation at 37°C for 18 hours in an atmosphere of 4% CO, different concentration gradients of complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh were added. After treatment at 37°C for 24 hours, the cells were collected, washed twice with cold PBS, and fixed with 70% ethanol at 4°C overnight. The fixed mixture was washed twice with PBS, pretreated with RNase A (100 μg / mL) for 10 minutes, incubated with propidium iodide (PI, 50 μg / mL) for 30 minutes, washed twice with PBS, and then analyzed by flow cytometry to evaluate the effect of NB-4 on cell cycle arrest.

[0113] The complexes FTO-2-Ru of Example 1, FTO-2-Ir of Example 2, and FTO-2-Rh of Example 3 arrest the cell cycle at the G1 / G2 phase. Figure 5 As shown, 24 hours after administration, the flow cytometer graphs of the cell cycle arrest effects of the complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh at different concentration gradients on NB-4 cells show that the complex FTO-2-Ru cannot arrest the cell cycle. As the concentrations of the complexes FTO-2-Ir and FTO-2-Rh increase, the number of cells in the G1 / G2 phase increases. It can be concluded that the complexes FTO-2-Ir and FTO-2-Rh can arrest NB-4 cells in the G1 / G2 phase.

[0114] The results showed that the complex FTO-2-Ru could not block the cell cycle, while FTO-2-Ir and FTO-2-Rh could block the cell cycle at the G1 / G2 phase.

[0115] Embodiment 14

[0116] Application of organic active molecules FTO-2, FTO-2-alkyne, complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh to inhibit FTO activity.

[0117] Method: 0.1 nmol of m 6 A ssDNA, 0.1 nmol FTO, 300 μM 2OG, 280 μM (NH 4 ) 2 Fe(SO 4 ) 2 , 2mM L-ascorbic acid and 100μM FTO-2, FTO-2-alkyne, complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh were dissolved in 100μL Tris-HCl (50mM, PH=7.5) buffer solution, incubated at room temperature for 2h, boiled at 90℃ for 5min and then annealed, added with 20% non-reducing PAGE, and stained with nucleic acid dye GelRed after electrophoresis. The band intensities were compared. The stronger the intensity, the more obvious the inhibition effect.

[0118] The FTO inhibitory activities of FTO-2, FTO-2-alkyne, complexes FTO-2-Ru, FTO-2-Ir and FTO-2-Rh are shown in Figure 6 As shown in the figure, it can be seen that FTO-2 and FTO-2-alkyne have no inhibitory activity, the complex FTO-2-Ru has the effect of degrading DNA, and FTO-2-Ir and FTO-2-Rh both have FTO inhibitory activity.

[0119] The results showed that FTO-2-Ir and FTO-2-Rh had FTO inhibitory activity.

Claims

1. A metal complex having FTO inhibitory activity, characterized in that: The general structural formula of the complex is shown below: Wherein, M is Ru, Ir or Rh; for L is 2. The method for preparing the metal complex having FTO inhibition activity according to claim 1, characterized in that: The steps include: (1) Preparing a metal complex precursor containing an azide group: dissolving a metal ruthenium dimer, a metal iridium dimer or a metal rhodium dimer in methanol under an inert atmosphere, and carrying out a coordination reaction with a chelating ligand, removing the solvent by rotary evaporation under reduced pressure after the reaction, adding a methanol solution of a saturated anion salt, freezing at low temperature, collecting solids by centrifugation after freezing, and purifying the crude product by column chromatography to obtain a metal complex precursor; the chelating ligand is 4-azidomethyl-4'-methyl-2,2'-bipyridine; (2) Preparing an alkynyl-modified organic active molecule ligand: Under an inert atmosphere, an organic active molecule, an alkynyl compound and a catalyst are placed in an organic solvent for reaction. After the reaction is completed, the solvent is removed by rotary evaporation to obtain a crude product, which is then purified by column chromatography to obtain an organic active molecule ligand; (3) Under an inert atmosphere, a metal complex precursor, an organic active molecular ligand and a catalyst are reacted in an organic solvent. After the reaction is completed, the solvent is removed by rotary evaporation, and the crude product is purified by a chromatographic column to obtain a metal complex.

3. The method for preparing a metal complex having FTO inhibition activity according to claim 2, characterized in that: In step (1), the molar ratio of the dimer of metal ruthenium to the chelating ligand is 8-9:1; the molar ratio of the dimer of metal iridium to the chelating ligand is 13-14:1; and the molar ratio of the dimer of metal rhodium to the chelating ligand is 12-13:

1.

4. The method for preparing a metal complex having FTO inhibition activity according to claim 2, characterized in that: In step (1), the freezing temperature is -20 to 0°C and the freezing time is 8 to 14 hours.

5. The method for preparing a metal complex having FTO inhibition activity according to claim 2, characterized in that: In step (2), the alkynyl compound is propargyl bromide, propargylamine or pentynoic acid; the catalyst is potassium carbonate or a composition of N-hydroxybenzotriazole and N,N-diisopropylethylamine in a molar ratio of 82 to 83:

135.

6. The method for preparing a metal complex having FTO inhibition activity according to claim 2, characterized in that: In step (2), the molar ratio of the organic active molecule to the alkynyl compound is 0.1 to 4:

1.

7. The method for preparing a metal complex having FTO inhibition activity according to claim 2, characterized in that: In step (3), the catalyst is a composition of copper sulfate pentahydrate and sodium ascorbate in a molar ratio of 3 to 3.5:

4.

8. The method for preparing a metal complex having FTO inhibition activity according to claim 2, characterized in that: In step (3), the reaction molar ratio of the metal complex precursor to the organic active molecule ligand is 3 to 25.5:

1.

9. Use of the metal complex having FTO inhibitory activity according to claim 1 for preparing anti-tumor drugs or FTO inhibitory drugs; wherein, The tumor is one of human breast cancer, brain glioma, human chronic myeloid leukemia or human acute promyelocytic leukemia.

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