A amidoxime multidentate ligand and its preparation method and application

Abstract

The present invention provides an amidoxime multidentate ligand and its preparation method and application, relating to the field of radionuclide facilitation technology. The amidoxime multidentate ligand provided by the present invention has two amidoxime groups, and the amidoxime group contains both a coordinating atom N and a coordinating atom O, so that a multidentate coordination mode can be formed, and it can be combined with radionuclides such as actinides to form a soluble chelate, and has a high affinity and selectivity for radionuclides such as actinides, and has an excellent facilitation effect on radionuclides such as actinides. The amidoxime multidentate ligand provided by the present invention has a small molecular weight, good cell membrane permeability, and low 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, a preparation method and application thereof. Background Art

[0002] Radioactive actinides are highly soluble and transferable. Their radioactivity and chemical toxicity, even at ultra-low concentrations, pose a long-term threat to biodiversity. Accumulation through the food chain can cause irreversible damage to the human body, even inducing mutations and carcinogenesis. Actinides such as uranium and thorium have long lifespans and are alpha emitters, exhibiting both radiotoxicity and chemical toxicity. They can enter the bloodstream through the skin or inhalation, and further deposit in the kidneys, bones, liver, and other organs, potentially causing cancer. Forming stable, excretable actinide complexes is an important method for reducing internal contamination with uranium and other actinide nuclides. Currently, most 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-promoting effect on actinide nuclides plutonium and americium. Studies have found that DTPA-CaNa3 has a good excretion-promoting 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 formation of complexes between actinide nuclides and catalytic agents. Choosing 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 actinides such as uranium. Currently, a variety of amidoxime functionalized polymers are used to extract actinides from seawater, showing excellent affinity, and amidoxime-modified chitosan oligosaccharides have a good excretion-promoting effect on in vivo nuclides. However, due to the large molecular weight of amidoxime-modified chitosan oligosaccharides compared to small molecule ligands, and the formation of insoluble chelates with actinides, they are not easy to excrete. Summary of the Invention

[0004] In view of this, the present invention aims 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 bind to actinide nuclides to form soluble chelates, and is easily 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-amide 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 chloroalkane 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 group contains both a coordinating atom N and a coordinating atom O, so that a multidentate coordination mode can be formed, and it can be combined with actinide nuclides to form a soluble chelate, and has a high affinity and selectivity for radionuclides such as actinides, and has an excellent effect on promoting the discharge of radionuclides such as actinides. The amidoxime multidentate ligand provided by the present invention has a small molecular weight, good cell membrane permeability, and low toxicity.

[0025] The preparation method of the amidoxime multidentate ligand provided by the present invention has high product yield, a simple and safe synthetic 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 the amidoxime multidentate ligand having the structure shown in Formula I under positive ion mode;

[0028] Figure 3 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 of each group after 1 hour and 3 hours of delayed administration;

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

[0031] Figure 6 Graph showing 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-amide 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-amide 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 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 (denoted as the first organic solvent). Specifically, the acid-amine condensation reaction preferably includes: 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 compound 2 to the catalyst is preferably 1:0.8-2.5, and in specific embodiments 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 a chlorinated alkane and / or an amide solvent, the chlorinated alkane preferably includes dichloromethane; the amide solvent preferably includes dimethylformamide (DMF). The amount of the first organic solvent is not particularly limited, and the amount can be sufficient to ensure uniform mixing of the raw materials and smooth progress of the acid-amine condensation reaction.

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

[0045] After completing the acid-amine condensation reaction, the present invention preferably further comprises: subjecting the reaction solution obtained from the acid-amine condensation reaction to silica gel column chromatography, concentrating the obtained eluate by vacuum 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 specific embodiments 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 1-3 hours, and in specific embodiments, it can be 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours.

[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 (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 an aqueous hydroxylamine solution, and the mass concentration of the aqueous hydroxylamine 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 (denoted 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 it can uniformly mix the raw materials and ensure smooth oximation addition reaction.

[0050] In the present invention, the temperature of the oximation addition reaction is preferably 25 to 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 to 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 recrystallizing the obtained solid component 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 at room temperature and static 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 3 hours, and in specific embodiments it can be 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours.

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

[0053] The present invention also provides the application of the amidoxime multidentate ligand described in the above technical solutions in the promotion of radionuclide discharge. In the present invention, the radionuclide preferably includes actinides; The actinides preferably include one or more of uranium (U), thorium (Th) and curium (Am). The amidoxime multidentate ligand provided by the present invention has 2 amidoxime groups, and the amidoxime group contains both coordinating atoms N and coordinating atoms O, so it is possible to form a multidentate coordination mode, can be combined with actinides to form a soluble chelate, has a higher affinity and selectivity to radionuclides such as actinides, and is excellent in promoting the discharge of radionuclides such as actinides. The molecular weight of the amidoxime multidentate ligand provided by the present invention is small, cell membrane permeability is good, and toxicity is low.

[0054] To further illustrate the present invention, the amidoxime multidentate ligands provided by the present invention, their preparation methods and applications are described in detail below with reference to the examples. However, these examples 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 a solvent (dichloromethane) were stirred and activated for 30 minutes. 2,2'-Oxybisdiethylamine was then added and allowed to react at 40°C for 12 hours. After completion of the reaction, the product was separated by column chromatography (dichloromethane:ethyl acetate volume ratio = 25:1). Dissolved in ethyl acetate at 70°C, the product was allowed to stand at room temperature for 2.5 hours, and recrystallized to obtain the intermediate in a 45% yield. The molar ratio of cyanoacetic acid, 1-hydroxybenzotriazole, EDCI, and 2,2'-Oxybisdiethylamine was 10:5:5.8:4.8, and the ratio of cyanoacetic acid to dichloromethane was 1 mmol:10 mL.

[0058] The intermediate, a 50 wt% aqueous hydroxylamine solution, and an ethanol solvent were mixed and subjected to an oximation addition reaction at 40°C for 48 hours. The mixture was filtered, and the resulting solid component was dissolved in anhydrous ethanol at 60°C and allowed to stand at room temperature for 3 hours for recrystallization to obtain an amidoxime-based multidentate ligand having the structure of Formula I in a 50% yield. The molar ratio of the intermediate to hydroxylamine was 1:2.1, and the ratio of the intermediate to the ethanol solvent was 1 mmol:50 mL.

[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 there was precipitation after the small molecule amidoxime A6 excretion promoter was mixed with uranyl acetate, indicating that compared with the small molecule amidoxime A6, the chelate formed after the amidoxime multidentate ligand provided by the present invention and the uranium nuclide chelate has better solubility and may be more easily discharged from the body.

[0063]

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

[0065] Thirty mice were randomly divided into five groups, each containing six mice: a blank group (NG), a model group (MG), a positive control group (PG, ZnNa3-DTPA), a 0.21 mmol / kg amidoxime group (CN), and a 0.42 mmol / kg amidoxime group (EN). After a week of adaptive feeding before the experiment, drug administration began on the eighth day. Mice in the amidoxime group received a tail vein injection of uranyl acetate (0.5 mg / kg) immediately followed by a tail vein injection of varying doses of amidoxime-based polydentate ligands. Mice in the positive control group received a tail vein injection of uranyl acetate (0.5 mg / kg) immediately followed by a tail vein injection of ZnNa3-DTPA (0.42 mmol / kg). Mice in the blank group received a tail vein injection of normal saline immediately followed by a tail vein injection of normal saline. Mice in the model group received a tail vein injection of uranyl acetate (0.5 mg / kg) immediately followed by an equal volume of normal saline. Twenty-four hours after drug administration, blood was collected from the eyeballs, and the mice were sacrificed by cervical dislocation. The kidneys and femurs were removed, weighed, and cryopreserved. 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. The samples were placed in a microwave digester 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 removing 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 3 .Depend on Figure 3 It can be seen that compared with the model group, amidoxime multidentate ligands can effectively remove uranium from the kidneys and femurs and the effect is better than that of Xincuopailing.

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

[0067] Forty-eight mice were randomly divided into six groups, namely, blank group (NG), model group (MG), 1-hour delayed positive control group (PG-1h), 3-hour delayed positive control group (PG-3h), 1-hour delayed administration group (EN-1h), and 3-hour 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. Mice in the 1-hour delayed administration group were injected with uranyl acetate (0.5 mg / kg) via the tail vein, followed by an injection of amidoxime polydentate ligand (0.42 mmol / kg) 1 hour later. Mice in the 3-hour delayed administration group were injected with uranyl acetate (0.5 mg / kg) via the tail vein, followed by an injection of amidoxime polydentate ligand (0.42 mmol / kg) 3 hours later. The positive control group received a 1-hour delayed injection of uranyl acetate (0.5 mg / kg) into the tail vein, followed by an immediate injection of xincuopailing (0.42 mmol / kg) into the tail vein. The positive control group received a 3-hour delayed injection of uranyl acetate (0.5 mg / kg) into the tail vein, followed by an immediate injection of xincuopailing (0.42 mmol / kg) into the tail vein. The blank group received a 3-hour injection of normal saline into the tail vein, followed by an immediate injection of an equal volume of normal saline. The model group received a 3-hour injection of uranyl acetate (0.5 mg / kg) into the tail vein, followed by an immediate injection of an equal volume of normal saline. Blood was collected from the eyeballs 24 hours after administration, and the mice were sacrificed by cervical dislocation. The kidneys and femurs on both sides were weighed and stored at low temperatures. 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. The samples were placed in a microwave digester 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 removing 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, amidoxime multidentate ligands can still effectively clear uranium from the kidney and femur after delayed administration for 1h and 3h, and the effect is better than that of Xincuopailing.

[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 density was adjusted to 5×10 cells using DMEM medium containing 10% Gibco fetal bovine serum and 1% double-antibody. 4 / mL, inoculated in a 96-well plate, and 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℃, 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 medium containing 30μmol / L, 70μmol / L, 150μmol / L, 300μmol / L and 600μmol / L amidoxime multidentate ligands, respectively. The positive control group was added with culture medium containing 70μmol / L of Xinchuocuiling; the blank group was added with drug-free culture medium. After culturing in the incubator for 24 hours, the old culture medium was discarded and culture medium containing 10% CCK-8 was added. After culturing in the incubator for 2 hours, the absorbance of each well was measured at 450nm using a microplate 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%. See the results. 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 cell survival rate and 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 density was adjusted to 5×10 cells using DMEM medium containing 10% Gibco fetal bovine serum and 1% double-antibody. 4 Cells were seeded in 96-well plates at 40 μg / mL and divided into model, drug, and positive groups. Six replicate wells were plated in each group, with 100 μL per well, and incubated in a 37°C, 5% CO2 incubator for 24 hours. After cell attachment, the culture medium was removed, and the model group was treated with culture medium containing 70 μmol / L uranyl acetate. The drug groups were treated with culture medium containing 70 μmol / L uranyl acetate mixed with 30 μmol / L, 70 μmol / L, 150 μmol / L, or 300 μmol / L amidoxime-based multidentate ligands. The positive groups were treated with culture medium containing 70 μmol / L uranyl acetate mixed with 70 μmol / L xinchuopailing. After 24 hours of incubation, the old culture medium was discarded and replaced with culture medium containing 10% CCK-8. After 2 hours of incubation, the absorbance of each well was measured at 450 nm using a microplate reader to calculate cell viability. 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 principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. An amidoxime multidentate ligand having the 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-amide 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 chloroalkane 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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