Amidoxime polydentate ligand as well as preparation method and application thereof

Abstract

The invention provides an amidoxime polydentate ligand as well as a preparation method and application thereof, and relates to the technical field of radionuclide discharge promotion. The amidoxime polydentate ligand provided by the invention has two amidoxime groups, and the amidoxime groups contain both a coordination atom N and a coordination atom O, so that a polydentate coordination mode can be formed, the amidoxime polydentate ligand can be combined with radionuclides such as actinide elements to form soluble chelates, and the amidoxime polydentate ligand has relatively high affinity and selectivity to the radionuclides such as the actinide elements; the excretion promoting effect on radionuclides such as actinide elements is excellent. The amidoxime polydentate ligand provided by the invention is small in molecular weight, good in cell membrane permeability and small in toxicity.

Description

Technical Field

[0001] The present invention relates to the technical field of radionuclide excretion promotion, and in particular to an amidoxime multidentate ligand and a preparation method and application thereof. Background Art

[0002] Radioactive actinide nuclides have high solubility and high transferability. Their radioactivity and chemical toxicity pose a long-term threat to biodiversity even at ultra-low concentrations. They cause irreversible damage to the human body through enrichment in the food chain, and even induce human cell mutations and carcinogenesis. Among them, actinide nuclides such as uranium and thorium have a long lifespan and are alpha emitters with both radiotoxicity and chemical toxicity. They can enter the blood circulation through the skin, inhalation, etc. and further deposit in the kidneys, bones, liver, etc., causing cancer, etc. The formation of stable and excretable actinide nuclide complexes is an important method to reduce the internal contamination of actinide nuclides such as uranium. Currently, most of the excretion promoters are organic ligands that can chelate with actinide nuclides. Most of the reported excretion promoters have many limitations and shortcomings. Among them, DTPA-CaNa3 is the only excretion promoter currently available on the market. It has a good excretion effect on actinide nuclides plutonium and americium. Studies have found that DTPA-CaNa3 has a good excretion effect on actinide nuclides plutonium and americium, but it still has many limitations and shortcomings.

[0003] The selection of coordinating atoms in the chelating agent is an important step in the combination of actinide nuclides and catalytic agents to form complexes. Selecting appropriate coordinating atoms can improve the selectivity and affinity of the chelating agent for actinide nuclides. Amidoxime compounds contain coordinating atoms N and O, which can form bidentate chelates with actinide nuclides uranium or η with NO bonds. 2 Chelation, and according to the theory of hard and soft acids and bases, functional groups containing harder coordinating atoms (such as O) usually have stronger coordination affinity for metal ions, but poor ion selectivity; while functional groups containing softer coordinating atoms (such as N) may have good selectivity for several metal ions. Amidoxime compounds contain both N and O atoms, making each coordinating atom "moderately soft and hard", thus showing good selectivity and high affinity for actinide nuclides such as uranium. Currently, a variety of amidoxime functionalized polymers are used to extract actinide nuclides from seawater, showing excellent affinity, and amidoxime-modified chitosan oligosaccharides have a good excretion-promoting effect on nuclides in vivo. However, due to the large molecular weight of amidoxime-modified chitosan oligosaccharides compared to small molecule ligands, and the formation of insoluble chelates with actinide nuclides, it is not easy to excrete. Summary of the invention

[0004] In view of this, the purpose of the present invention is to provide an amidoxime multidentate ligand and its preparation method and application. The amidoxime multidentate ligand provided by the present invention has a small molecular weight, strong cell membrane permeability, can combine with actinide nuclides to form soluble chelates, and is easy to be excreted from the body.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides an amidoxime multidentate ligand having a structure shown in Formula I:

[0007]

[0008] The present invention also provides a method for preparing the amidoxime multidentate ligand described in the above technical solution, comprising the following steps:

[0009] Compound 2 is subjected to an acid-amine condensation reaction with cyanoacetic acid to obtain an intermediate;

[0010] The intermediate is subjected to an oximation addition reaction with hydroxylamine to obtain the amidoxime multidentate ligand;

[0011] Compound 2 Intermediate.

[0012] Preferably, the molar ratio of the compound 2 to cyanoacetic acid is 1:1.3-2.5.

[0013] Preferably, the acid-amine condensation reaction is carried out in the presence of a catalyst and an organic solvent.

[0014] Preferably, the catalyst comprises one or more of 1-hydroxybenzotriazole, 1-n-propyl phosphoric anhydride, N-hydroxysuccinimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexyldiimide, carbodiimide, O-benzotriazole-N,N,N,N-tetramethyluronium tetrafluoroboric acid, 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate;

[0015] The molar ratio of the compound 2 to the catalyst is 1:0.8-2.5;

[0016] The organic solvent includes chlorinated alkane and / or amide solvent.

[0017] Preferably, the temperature of the acid-amine condensation reaction is 40-60° C. and the time is 24-48 hours.

[0018] Preferably, the molar ratio of the intermediate to hydroxylamine is 1:2-4;

[0019] The hydroxylamine is used in the form of an aqueous hydroxylamine solution.

[0020] Preferably, the oximation addition reaction is carried out in the presence of an organic solvent, and the organic solvent includes an alcohol solvent;

[0021] The temperature of the oximation addition reaction is 25-60° C. and the time is 24-48 hours.

[0022] The present invention also provides the use of the amidoxime multidentate ligand described in the above technical solution in promoting the excretion of radionuclides.

[0023] Preferably, the radionuclide comprises an actinide.

[0024] The amidoxime multidentate ligand provided by the present invention has two amidoxime groups, and the amidoxime groups contain both coordinating atoms N and coordinating atoms O, so that a multidentate coordination mode can be formed, and it can be combined with actinide nuclides to form soluble chelates, and has a high affinity and selectivity for radionuclides such as actinide elements, and has an excellent effect on promoting the discharge of radionuclides such as actinide elements. The amidoxime multidentate ligand provided by the present invention has a small molecular weight, good cell membrane permeability, and low toxicity.

[0025] The method for preparing the amidoxime multidentate ligand provided by the invention has high product yield, simple and safe synthesis route, is green and environmentally friendly, has low cost and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is a hydrogen spectrum of an amidoxime multidentate ligand having a structure shown in Formula I;

[0027] Figure 2 is a mass spectrum of an amidoxime multidentate ligand having a structure shown in Formula I under positive ion mode;

[0028] Figure 3 It is a bar graph showing the accumulation of uranium in the kidney and femur in each group immediately after administration;

[0029] Figure 4 The bar graphs show the accumulation of uranium in the kidney and femur in each group after delayed administration for 1 hour and 3 hours;

[0030] Figure 5 Graph showing the effect of amidoxime multidentate ligands having a structure shown in Formula I on cell activity;

[0031] Figure 6 The figure shows the effect of amidoxime multidentate ligands having the structure shown in Formula I on the activity of uranium-damaged cells. DETAILED DESCRIPTION

[0032] The present invention provides an amidoxime multidentate ligand having a structure shown in Formula I:

[0033]

[0034] The present invention also provides a method for preparing the amidoxime multidentate ligand described in the above technical solution, comprising the following steps:

[0035] Compound 2 is subjected to an acid-amine condensation reaction with cyanoacetic acid to obtain an intermediate;

[0036] The intermediate is subjected to an oximation addition reaction with hydroxylamine to obtain the amidoxime multidentate ligand;

[0037] Compound 2 Intermediate.

[0038] Unless otherwise specified, the materials used in the present invention are all commercially available products in the art.

[0039] In the present invention, compound 2 is subjected to an acid-amine condensation reaction with cyanoacetic acid to obtain an intermediate.

[0040] In the present invention, the molar ratio of compound 2 to cyanoacetic acid is preferably 1:1.3-2.5, and in specific embodiments it can be 1:1.3, 1:1.33, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4 or 1:2.5.

[0041] In the present invention, the acid-amine condensation reaction is carried out in the presence of a catalyst and an organic solvent (referred to as the first organic solvent). Specifically, the acid-amine condensation reaction preferably comprises: mixing compound 2, cyanoacetic acid, a catalyst and the first organic solvent to carry out the acid-amine condensation reaction.

[0042] In the present invention, the catalyst preferably includes one or more of 1-hydroxybenzotriazole (HOBT), 1-n-propyl phosphoric anhydride, N-hydroxysuccinimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), dicyclohexyldiimide, carbodiimide, O-benzotriazole-N,N,N,N-tetramethyluronium tetrafluoroborate, 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate. In the present invention, the molar ratio of the compound 2 to the catalyst is preferably 1:0.8-2.5, and in specific embodiments it can be 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4 or 1:2.5.

[0043] In the present invention, the first organic solvent preferably includes chloroalkane and / or amide solvent, the chloroalkane preferably includes dichloromethane; the amide solvent preferably includes dimethylformamide (DMF). The present invention has no particular limitation on the amount of the first organic solvent, as long as the raw materials are mixed evenly and the acid-amine condensation reaction is carried out smoothly.

[0044] In the present invention, the temperature of the acid amine condensation reaction is preferably 40-60°C, and in a specific embodiment, it can be 40°C, 45°C, 50°C, 55°C or 60°C; the time of the acid amine condensation reaction is preferably 24-48h, and in a specific embodiment, it can be 24h, 25h, 26h, 27h, 28h, 29h, 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h, 41h, 42h, 43h, 44h, 45h, 46h, 47h or 48h; in the acid amine condensation reaction, under the action of a catalyst, the carboxyl group and the amine group condense to remove a water molecule to form an amide bond.

[0045] After the acid-amine condensation reaction is completed, the present invention preferably further comprises: subjecting the reaction solution obtained by the acid-amine condensation reaction to silica gel column chromatography, concentrating the obtained eluent by reduced pressure distillation, and then recrystallizing to obtain an intermediate. In the present invention, the eluent used in the silica gel column chromatography preferably comprises a dichloromethane-methanol mixed solvent, and the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is preferably 20-30:1-1.5, and in a specific embodiment can be 20:1, 25:1, 30:1, 20:1.1, 25:1.1, 30:1.1, 20:1.2, 25:1.2, 20:1.3, 25:1.3, 30:1.3, 20:1.4, 25:1.4, 30:1.4 or 20:1.5. In the present invention, the recrystallization preferably comprises: adding a recrystallization solvent, dissolving under heating conditions, and then recrystallizing at room temperature and static conditions. In the present invention, the heating temperature is preferably 50-80°C, and in specific embodiments, it can be 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C. In the present invention, the recrystallization solvent preferably includes ethyl acetate. In the present invention, the recrystallization time is preferably 1-3h, and in specific embodiments, it can be 1h, 1.5h, 2h, 2.5h or 3h.

[0046] After obtaining the intermediate, the present invention conducts an oximation addition reaction between the intermediate and hydroxylamine to obtain the amidoxime multidentate ligand.

[0047] In the present invention, the molar ratio of the intermediate to hydroxylamine (Hydroxylamine, chemical formula NH2OH) is 1:2-4, and in specific embodiments, it can be 1:2, 1:2.5, 1:3, 1:3.5 or 1:4. In the present invention, the hydroxylamine is preferably used in the form of a hydroxylamine aqueous solution, and the mass concentration of the hydroxylamine aqueous solution is preferably 40-60%, and in specific embodiments, it can be 40%, 45%, 50%, 55% or 60%.

[0048] In the present invention, the oximation addition reaction is carried out in the presence of an organic solvent (referred to as the second organic solvent). Specifically, the intermediate, the hydroxylamine aqueous solution and the second organic solvent are mixed to carry out the oximation addition reaction.

[0049] In the present invention, the second organic solvent preferably includes an alcohol solvent, more preferably methanol and / or ethanol. The present invention has no particular limitation on the amount of the second organic solvent, as long as the raw materials can be mixed evenly and the oximation addition reaction can proceed smoothly.

[0050] In the present invention, the temperature of the oximation addition reaction is preferably 25-60°C, and in specific embodiments it can be 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C or 60°C; the time of the oximation addition reaction is 24-48h, and in specific embodiments it can be 24h, 25h, 26h, 27h, 28h, 29h, 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h, 41h, 42h, 43h, 44h, 45h, 46h, 47h or 48h.

[0051] After completing the oximation addition reaction, the present invention preferably further comprises: subjecting the reaction solution obtained by the oximation addition reaction to solid-liquid separation, and subjecting the obtained solid component to recrystallization to obtain the amidoxime multidentate ligand. In the present invention, the solid-liquid separation preferably comprises filtration, suction filtration or centrifugal separation. In the present invention, the recrystallization preferably comprises: adding a recrystallization solvent, dissolving under heating conditions, and then recrystallizing under room temperature and standing conditions. In the present invention, the recrystallization solvent preferably comprises anhydrous ethanol. In the present invention, the heating temperature is preferably 50 to 80°C, and in specific embodiments, it can be 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C. In the present invention, the recrystallization time is preferably 1 to 3h, and in specific embodiments, it can be 1h, 1.5h, 2h, 2.5h or 3h.

[0052] The method for preparing the amidoxime multidentate ligand provided by the invention has high product yield, simple and safe synthesis route, is green and environmentally friendly, has low cost and is suitable for industrial production.

[0053] The present invention also provides the application of amidoxime multidentate ligands described in the above technical solution in promoting the discharge of radionuclides. In the present invention, the radionuclides preferably include actinides; the actinides preferably include one or more of uranium (U), thorium (Th) and curium (Am). The amidoxime multidentate ligands provided by the present invention have 2 amidoxime groups, and the amidoxime groups contain both coordinating atoms N and coordinating atoms O, so that a multidentate coordination mode can be formed, and it can be combined with actinide nuclides to form soluble chelates, and has a higher affinity and selectivity for radionuclides such as actinides, and has excellent effects on promoting the discharge of radionuclides such as actinides. The amidoxime multidentate ligands provided by the present invention have a small molecular weight, good cell membrane permeability, and low toxicity.

[0054] In order to further illustrate the present invention, the amidoxime multidentate ligands provided by the present invention and their preparation methods and applications are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0055] Example 1

[0056]

[0057] Cyanoacetic acid, 1-hydroxybenzotriazole, EDCI and solvent (dichloromethane) were stirred and activated for 30 minutes, 2,2'-oxybisdiethylamine was added, and the reaction was carried out at 40°C for 12 hours. After the reaction was completed, column chromatography was performed (dichloromethane: ethyl acetate volume ratio = 25:1), and the intermediate was obtained by dissolving it in ethyl acetate under heating conditions (70°C) and standing at room temperature for 2.5 hours for recrystallization, and the yield was 45%. Among them, the molar ratio of cyanoacetic acid, 1-hydroxybenzotriazole, EDCI and 2,2'-oxybisdiethylamine was 10:5:5.8:4.8; the amount ratio of cyanoacetic acid to solvent dichloromethane was 1mmol:10mL.

[0058] The intermediate, 50wt% hydroxylamine aqueous solution and solvent (ethanol) were mixed, and oximation addition reaction was carried out at 40°C for 48h, filtered, and the obtained solid component was dissolved in anhydrous ethanol under heating conditions (60°C) and then allowed to stand at room temperature for 3h for recrystallization to obtain an amidoxime multidentate ligand having a structure shown in formula I, with a yield of 50%. The molar ratio of the intermediate to hydroxylamine was 1:2.1; the amount ratio of the intermediate to the solvent ethanol was 1mmol:50mL.

[0059] The hydrogen spectrum of amidoxime multidentate ligands is shown in Figure 1 , mass spectrum in positive ion mode is shown in Figure 2 , characterization results: 1H NMR (600MHz, DMSO) δ8.97(s,1H),7.95(t,1H),5.36(s,2H),3.41(t,2H),3.21(q,2H),2.85(s,2H); ESI + -MS: [M+Na + ]m / z:327.14, [M+H + ]m / z:305.16.

[0060] Test Example 1

[0061] 1. Solubility of the chelate formed by the amidoxime multidentate ligand having the structure shown in Formula I and the nuclide

[0062] Experimental group: 1.1 mg of uranyl acetate was mixed with 7 mL of Hepes buffer solution to prepare a 0.143 mg / mL uranyl acetate solution. 1 mg of amidoxime multidentate ligand was mixed with 1 mL of Hepes buffer solution to obtain an amidoxime multidentate ligand solution. The uranyl acetate solution was mixed with the amidoxime multidentate ligand solution to observe its solubility. Control group: The amidoxime multidentate ligand in the experimental group was replaced with a small molecule amidoxime A6 (structural formula as shown in Formula II). The results showed that there was no precipitation after the amidoxime multidentate ligand was mixed with uranyl acetate, while the small molecule amidoxime A6 excretion promoter was mixed with uranyl acetate. Precipitation showed that compared with the small molecule amidoxime A6, the amidoxime multidentate ligand provided by the present invention and the chelate formed after chelation with uranium nuclides had better solubility and may be easier to discharge from the body.

[0063]

[0064] 2. Immediate administration of amidoxime multidentate ligands having the structure shown in Formula I to promote excretion

[0065] Thirty mice were randomly divided into five groups, namely, blank group (NG), model group (MG), positive control group (PG, ZnNa3-DTPA group), 0.21mmol / kg amidoxime group (CN), and 0.42mmol / kg amidoxime group (EN), with 6 mice in each group. After one week of adaptive feeding before the experiment, the drugs were administered on the eighth day. The mice in the amidoxime group were injected with uranyl acetate (0.5mg / kg) through the tail vein, and then immediately injected with different doses of amidoxime multidentate ligands; the mice in the positive control group were injected with uranyl acetate (0.5mg / kg) through the tail vein, and then immediately injected with ZnNa3-DTPA (0.42mmol / kg); the mice in the blank group were first injected with normal saline through the tail vein, and then immediately injected with normal saline; the mice in the model group were injected with uranyl acetate (0.5mg / kg) through the tail vein, and then immediately injected with an equal amount of normal saline. 24h after administration, blood was collected from the eyeballs and the mice were killed by cervical dislocation. The kidneys and femurs on both sides were weighed and stored at low temperature. Mouse kidney and femur samples were placed in digestion tubes, 6 mL of 1 v / v% nitric acid aqueous solution was added to each sample, and the samples were preheated at 120°C for 30 min. After cooling, 2 mL of 30 wt% H2O2 aqueous solution was added, and the samples were placed in a microwave digestion instrument for programmed temperature digestion (maintained at 80°C for 3 min, increased to 120°C for 3 min, increased to 150°C for 3 min, increased to 180°C for 3 min, and increased to 190°C for 20 min). After cooling and taking out the digestion tube, the solution was transferred to a beaker, heated to evaporate the sample solvent, and diluted to 8 mL with 1 v / v% nitric acid aqueous solution. The accumulation of uranium in the organs was determined by ICP-MS. The results are shown in Table 1. Figure 3 .Depend on Figure 3 It can be seen that compared with the model group, amidoxime multidentate ligands can effectively remove uranium from the kidney and femur and the effect is better than that of Xinchuopailing.

[0066] 3. The effect of delayed administration of amidoxime polydentate ligands for 1h and 3h on promoting ovulation

[0067] 48 mice were randomly divided into 6 groups, namely blank group (NG), model group (MG), 1h delayed positive control group (PG-1h), 3h delayed positive control group (PG-3h), 1h delayed administration group (EN-1h), and 3h delayed administration group (EN-3h), with 8 mice in each group. After one week of adaptive feeding before the experiment, administration began on the eighth day. The mice in the 1h delayed administration group were injected with uranyl acetate (0.5mg / kg) through the tail vein, and 1h later, amidoxime multidentate ligands (0.42mmol / kg) were injected into the tail vein; the mice in the 3h delayed administration group were injected with uranyl acetate (0.5mg / kg) through the tail vein, and 3h later, amidoxime multidentate ligands (0.42mmol / kg) were injected into the tail vein. The positive control group was injected with uranyl acetate (0.5 mg / kg) in the tail vein after 1 hour delay, and then injected with Xincuopailing (0.42 mmol / kg) in the tail vein immediately after 1 hour delay; the positive control group was injected with uranyl acetate (0.5 mg / kg) in the tail vein after 3 hours delay, and then injected with Xincuopailing (0.42 mmol / kg) in the tail vein immediately after 3 hours; the blank group mice were injected with normal saline in the tail vein for 3 hours and then immediately injected with an equal amount of normal saline; the model group was injected with uranyl acetate (0.5 mg / kg) in the tail vein for 3 hours and then immediately injected with an equal amount of normal saline. 24 hours after administration, blood was collected from the eyeballs and the mice were killed by dislocation of the neck, and the kidneys and femurs on both sides were weighed and stored at low temperature. Mouse kidney and femur samples were placed in digestion tubes, 6 mL of 1 v / v% nitric acid aqueous solution was added to each sample, preheated at 120°C for 30 min, and after cooling, 2 mL of 30 wt% H2O2 aqueous solution was added. The samples were placed in a microwave digestion instrument for programmed temperature digestion (maintained at 80°C for 3 min, raised to 120°C for 3 min, raised to 150°C for 3 min, raised to 180°C for 3 min, and raised to 190°C for 20 min). After cooling and taking out the digestion tube, the solution was transferred to a beaker, heated to evaporate the sample solvent, and diluted to 8 mL with 1 v / v% nitric acid aqueous solution. The uranium accumulation in the organs was determined by ICP-MS. The results are shown in Table 1. Figure 4 .Depend on Figure 4 It can be seen that compared with the model group, the amidoxime multidentate ligands can still effectively remove uranium from the kidney and femur after delayed administration for 1h and 3h, and the effect is better than that of Xinchuopailing.

[0068] 4. Effects of amidoxime polydentate ligands on HK-2 cell activity

[0069] HK-2 cells in the logarithmic growth phase were taken and the cell concentration was adjusted to 5×10 in DMEM medium containing 10% Gibco fetal bovine serum and 1% double-antibody. 4 / mL, inoculated in a 96-well plate, divided into a positive control group, a drug-treated group, and a blank group. Each group had 6 parallel wells, 100μL per well, and cultured in a 37°C, 5% CO2 incubator for 24 hours; after the cells adhered to the wall, the culture medium was removed, and the drug-treated group was added with culture media containing 30μmol / L, 70μmol / L, 150μmol / L, 300μmol / L and 600μmol / L amidoxime multidentate ligands, respectively, and the positive control group was added with culture media containing 70μmol / L of new promotion spirit; the blank group was added with drug-free culture media. After culturing in the incubator for 24 hours, the old culture media was discarded and culture media containing 10% CCK-8 was added. After culturing in the incubator for 2 hours, the absorbance of each well was measured at 450nm with an enzyme reader to calculate the cell survival rate (%). Cell survival rate = (OD value of the experimental group - OD value of the blank group) / (OD value of the control group - OD value of the blank group) × 100%. Results are shown in Figure 5 It can be seen that the cell survival rate reaches about 80% when the dosage concentration ranges from 30 to 600 μmol / L, indicating that the amidoxime multidentate ligand has little effect on the cell survival rate and has low toxicity.

[0070] 5. Effects of amidoxime-based multidentate ligands on the activity of uranium-damaged cells

[0071] HK-2 cells in the logarithmic growth phase were taken and the cell concentration was adjusted to 5×10 in DMEM medium containing 10% Gibco fetal bovine serum and 1% double-antibody. 4 / mL, inoculated in 96-well plates, divided into model group, drug administration group and positive group. Each group has 6 parallel wells, 100μL per well, and cultured in a 37℃, 5% CO2 incubator for 24h; after the cells adhere to the wall, the culture medium is removed, and the model group is added with a culture medium containing 70μmol / L uranyl acetate; each group of the drug administration group is added with a culture medium containing 70μmol / L uranyl acetate mixed with 30μmol / L, 70μmol / L, 150μmol / L, and 300μmol / L amidoxime multidentate ligands; each group of the positive group is added with a culture medium containing 70μmol / L uranyl acetate mixed with 70μmol / L new promotion spirit. After culturing in the incubator for 24h, the old culture medium is discarded and a culture medium containing 10% CCK-8 is added. After culturing in the incubator for 2h, the absorbance value of each well is measured at 450nm with an enzyme reader to calculate the cell survival rate. Cell survival rate = (OD value of experimental group - OD value of blank group) / (OD value of control group - OD value of blank group) × 100%. Figure 6 It can be seen that compared with the model group, both amidoxime multidentate ligands and xinchuopailing can improve cell survival rate, and amidoxime multidentate ligands are slightly better than xinchuopailing, indicating that the compound formed by the amidoxime compound chelating with uranium has little effect on cell survival rate and low toxicity.

[0072] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An amidoxime multidentate ligand having a structure shown in Formula I:

2. The method for preparing the amidoxime multidentate ligand according to claim 1, comprising the following steps: Compound 2 is subjected to an acid-amine condensation reaction with cyanoacetic acid to obtain an intermediate; The intermediate is subjected to an oximation addition reaction with hydroxylamine to obtain the amidoxime multidentate ligand; Compound 2 Intermediate.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the compound 2 to cyanoacetic acid is 1:1.3-2.

5.

4. The preparation method according to claim 2, characterized in that: The acid-amine condensation reaction is carried out in the presence of a catalyst and an organic solvent.

5. The preparation method according to claim 4, characterized in that: The catalyst comprises one or more of 1-hydroxybenzotriazole, 1-n-propyl phosphoric anhydride, N-hydroxysuccinimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexyldiimide, carbodiimide, O-benzotriazole-N,N,N,N-tetramethyluronium tetrafluoroboric acid, 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate; The molar ratio of the compound 2 to the catalyst is 1:0.8-2.5; The organic solvent includes chlorinated alkane and / or amide solvent.

6. The preparation method according to any one of claims 2 to 5, characterized in that: The temperature of the acid-amine condensation reaction is 40-60° C. and the time is 24-48 hours.

7. The preparation method according to claim 2, characterized in that: The molar ratio of the intermediate to hydroxylamine is 1:2-4; The hydroxylamine is used in the form of an aqueous hydroxylamine solution.

8. The preparation method according to claim 2 or 7, characterized in that: The oximation addition reaction is carried out in the presence of an organic solvent, wherein the organic solvent includes an alcohol solvent; The temperature of the oximation addition reaction is 25-60° C. and the time is 24-48 hours.

9. Use of the amidoxime multidentate ligand according to claim 1 in promoting the excretion of radionuclides.

10. The use according to claim 9, characterized in that: The radionuclides include actinides.

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