Selenium phospholipid compound, synthesis method and liposome preparation

Abstract

The present invention discloses a selenium phospholipid compound, a synthesis method and a liposome preparation. The structural formula of the selenium phospholipid compound is shown in formula (I): The selenium phospholipid compound of the present invention uses selenium as the core of the antioxidant function, and natural phospholipid molecules serve as the main template, so that it can self-assemble in an aqueous solution to form a liposome structure, greatly improving the water solubility and stability. At the same time, its hydrophilic selenium-containing head is easily exposed on the surface of the liposome, and can quickly contact with the surrounding active oxygen free radicals, thereby achieving a highly efficient antioxidant effect.

Description

Technical Field

[0001] The invention relates to the pharmaceutical field, and in particular to a selenophospholipid compound, a synthesis method and a liposome preparation. Background Art

[0002] Oxidative stress is the result of reactive oxygen and reactive nitrogen produced during the metabolism of organisms exceeding the body's own antioxidant capacity, and oxidative damage caused by oxidative stress is the root cause of the occurrence or development of many diseases (including cardiovascular disease, tissue and organ damage, infection, and rejection reactions, etc.). Antioxidant therapy is the main means to maintain the body's antioxidant balance and treat oxidative damage. However, antioxidant small molecule drugs are irreversible compounds. Once oxidized, they lose the ability to continue to regulate oxidative stress; although natural antioxidant enzymes can remove reactive oxygen for a long time through catalytic cycles, their poor stability, high production and purification costs, and low cell membrane permeability seriously limit their application in biomedicine. Glutathione peroxidase (GPx) is an important component of the natural antioxidant defense system, and its catalytic center is the naturally occurring "twenty-first amino acid" - selenocysteine. The high catalytic activity of this organic selenium gives GPx a high antioxidant capacity. Therefore, the development of natural GPx biomimetic drugs containing selenium has aroused widespread interest among scientists, and a variety of selenium-containing organic compounds have been synthesized. However, these small molecule selenium compounds have unsatisfactory antioxidant efficiency, poor water solubility and low drugability. Therefore, the preparation of a selenium-containing drug with high antioxidant activity, good water solubility and drugability has become a research hotspot in the relevant field. Summary of the invention

[0003] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a selenophospholipid compound.

[0004] Another object of the present invention is to provide a method for synthesizing the above-mentioned selenophospholipid compound.

[0005] The third object of the present invention is to provide a liposome preparation of the above-mentioned selenium phospholipid compound.

[0006] The fourth object of the present invention is to provide a method for preparing the liposome preparation of the above-mentioned selenophospholipid compound.

[0007] The fifth object of the present invention is to provide the use of the liposome preparation of the above-mentioned selenophospholipid compound in the preparation of antioxidant drugs.

[0008] The technical solution of the present invention is summarized as follows:

[0009] The selenium phospholipid compound is characterized by a structural formula as shown in Formula I:

[0010]

[0011] in:

[0012] R1 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl;

[0013] R2 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl;

[0014] X is hydrogen, sodium, potassium, ammonium or calcium.

[0015] The synthesis method of the above-mentioned selenophospholipid compound comprises the following steps:

[0016] 1) Bromoacetic acid reacts with Na2Se2 to generate 2,2'-diselenodiacetic acid II;

[0017]

[0018] 2) dispersing 2,2'-diselenodiacetic acid (II) in an inert solvent, adding a condensing agent and 1-hydroxybenzotriazole (HOBT) under alkaline conditions, and then adding phosphatidylethanolamine (III) to undergo an acylation reaction to generate a selenophospholipid precursor IV;

[0019]

[0020] 3) oxidizing the selenophospholipid precursor IV with hydrogen peroxide to generate a selenophospholipid compound I;

[0021]

[0022] in:

[0023] R1 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl;

[0024] R2 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl;

[0025] X is hydrogen, sodium, potassium, ammonium or calcium.

[0026] The inert solvent is at least one of dichloromethane, tetrahydrofuran, acetonitrile, toluene and N,N-dimethylformamide.

[0027] The alkaline condition is to add at least one of triethylamine, pyridine, 4-dimethylaminopyridine and N,N-diisopropylethylamine.

[0028] The condensing agent is a carbodiimide condensing agent, an onium salt condensing agent or an organic phosphorus condensing agent.

[0029] Liposomal formulations of selenophospholipid compounds.

[0030] The preparation method of the liposome preparation of the above-mentioned selenium phospholipid compound comprises the following steps:

[0031] 1) dissolving the selenium phospholipid compound (I), cholesterol and methoxy-polyethylene glycol 2000-distearoylphosphatidylethanolamine in a mixed solvent, wherein the mixed solvent is composed of chloroform and methanol in a volume ratio of 3:1;

[0032] 2) removing the solvent by evaporation under reduced pressure to form a uniform lipid film, and vacuum drying;

[0033] 3) Add water or phosphate buffer with pH=7-8 at 25-50°C to completely dissolve the vacuum-dried lipid membrane to generate a liposome preparation of the selenium phospholipid compound.

[0034] Application of the liposome preparation of the above-mentioned selenophospholipid compound in the preparation of antioxidant drugs.

[0035] The beneficial effects of the present invention are:

[0036] The selenium phospholipid compound of the present invention uses selenium as the core of the antioxidant function, and the natural phospholipid molecule acts as the main template, so that it can self-assemble in an aqueous solution to form a liposome structure, greatly improving the water solubility and stability. At the same time, its hydrophilic selenium-containing head is easily exposed on the surface of the liposome, and can quickly contact with the surrounding active oxygen free radicals, thereby achieving a highly efficient antioxidant effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 To detect and analyze the NMR spectrum of 2,2'-diselenodiacetic acid (II);

[0038] Figure 2 To detect and analyze the mass spectrum of 2,2'-diselenodiacetic acid (II);

[0039] Figure 3 To detect and analyze the mass spectrum of selenophospholipid precursor IV-1;

[0040] Figure 4 To detect and analyze the mass spectrum of selenophospholipid compound I-1;

[0041] Figure 5 To detect and analyze the mass spectrum of selenophospholipid compound I-2;

[0042] Figure 6 To detect and analyze the mass spectrum of selenophospholipid compound I-3;

[0043] Figure 7 The transmission electron microscopy characterization results of the liposome preparation of selenium phospholipid compound I-1;

[0044] Figure 8 The particle size distribution and surface potential measurement results of the liposome preparation of the selenium phospholipid compound I-1;

[0045] Fig. 9 The results of the antioxidant activity test of the liposome preparation of selenium phospholipid compound I-1;

[0046] Fig.10 The scavenging effect of the liposome preparation of selenium phospholipid compound I-1 on intracellular reactive oxygen species;

[0047] Fig.11 The protective effect of liposome preparation of selenium phospholipid compound I-1 on cells damaged by active oxygen;

[0048] Fig.12 The biological safety of liposome preparation of selenium phospholipid compound I-1. DETAILED DESCRIPTION

[0049] The present invention will be further described below by means of specific examples.

[0050] Selenium phospholipid compound, the structural formula is shown in Formula I:

[0051]

[0052] in:

[0053] R1 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl;

[0054] Saturated alkyl groups such as butyric acid (C4:0), pentanoic acid (C5:0), hexanoic acid (C6:0), heptanoic acid (C7:0), octanoic acid (C8:0), nonanoic acid (C9:0), decanoic acid (C10:0), undecanoic acid (C11:0), dodecanoic acid (C12:0), tridecanoic acid (C13:0), tetradecanoic acid (C14:0), pentadecanoic acid (C15:0), palmitic acid (C16:0), heptadecanoic acid (C17:0), stearic acid (C18:0);

[0055] Unsaturated alkyl groups such as palmitoleic acid (C16:1), oleic acid (C18:1), erucic acid (C22:1), etc.

[0056] R2 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl;

[0057] Saturated alkyl groups such as butyric acid (C4:0), pentanoic acid (C5:0), hexanoic acid (C6:0), heptanoic acid (C7:0), octanoic acid (C8:0), nonanoic acid (C9:0), decanoic acid (C10:0), undecanoic acid (C11:0), dodecanoic acid (C12:0), tridecanoic acid (C13:0), tetradecanoic acid (C14:0), pentadecanoic acid (C15:0), palmitic acid (C16:0), heptadecanoic acid (C17:0), stearic acid (C18:0);

[0058] Unsaturated alkyl groups such as palmitoleic acid (C16:1), oleic acid (C18:1), erucic acid (C22:1), etc.

[0059] X is hydrogen, sodium, potassium, ammonium or calcium.

[0060] Example 1

[0061] The preparation of sodium diselenide (Na2Se2) comprises the following steps:

[0062] Under argon protection, add 20 mL of 1,4-dioxane to the mixture of selenium powder (0.79 g, 1.0 eq.) and sodium borohydride (0.76 g, 2.0 eq.), place in an ice-water bath, slowly add 10 mL of deionized water with a syringe, and slowly turn it into a suspension. Remove the ice-water bath, and then add 10 mL of deionized water to form a transparent solution. React for 1 h, quickly add selenium powder (0.79 g, 1.0 eq.) and stir evenly. The solution turns brown-red. React at 50°C for 3 h to obtain Na2Se2 solution for use.

[0063] Example 2

[0064] The synthesis method of the selenophospholipid compound I-1 (R1 and R2 in the compound shown in Formula I are both oleic acid, and X is hydrogen) comprises the following steps:

[0065] 1) Dissolve bromoacetic acid (2.92 g, 2.1 eq.) in 40 mL of water, neutralize with sodium bicarbonate (1.85 g, 2.2 eq.), heat to 50°C, add the Na2Se2 solution prepared in Example 1 to the reaction bottle, keep warm and react overnight (>4 h), the solution turns golden yellow, cool to room temperature, adjust pH to 2 (or any value between 2 and 3) with 1 M HCl, extract twice with 50 mL of ethyl acetate, combine the organic phases, wash with 50 mL of saturated brine, dry with anhydrous sodium sulfate, and the yellow sample will turn red during the filtration process; concentrate to obtain a yellow oily liquid, wash with a little petroleum ether 3 times (or 4 times) to remove the boric acid ester and the remaining ethyl acetate. Recrystallize with a mixed solvent of ethyl acetate and n-pentane in a volume ratio of 8:1 (to remove the monoselenoic acid molecule, because the monoselenoic acid has a large solubility in the mixed solution), and continue to drain for 4 hours to obtain the product, which is a yellow solid 2,2'-diselenodiacetic acid (II); see Figure 1 and Figure 2 .

[0066]

[0067] 2) Disperse 2,2'-diselenodiacetic acid (II) (14 mg, 1.0 eq.) in 20 mL of dichloromethane, add N,N-diisopropylethylamine (46 mg, 7.0 eq.), carbodiimide condensation agent (EDC·HCl, 22 mg, 2.2 eq.) and 1-hydroxybenzotriazole (HOBT, 15 mg, 2.2 eq.) used in combination therewith, add phosphatidylethanolamine III-1 (i.e., R1 and R2 in the compound shown in formula III are both oleic acid, X is hydrogen, 74 mg, 2.0 eq.), react at room temperature for 48 h, add 20 mL of dichloromethane and 40 mL of deionized water successively, extract and wash, let stand, separate the organic phase, and repeat twice. There is obvious emulsification. The organic phase can be separated by adding 40 mL of deionized water again, adjusting the pH to 2 (or any value between 2 and 3) with 1 M HCl, and then repeatedly washing with 40 mL of saturated brine until there is basically no emulsification; drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and drying the residue to obtain the product selenophospholipid precursor (IV-1) (i.e., R1 and R2 in the compound shown in formula IV are both oleic acid, and X is hydrogen), see Figure 3 .

[0068] EDC·HCl is the abbreviation of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0069] HOBt is the abbreviation for 1-hydroxybenzotriazole.

[0070]

[0071] 3) The selenophospholipid precursor IV-1 (51 mg, 1.0 eq.) was dissolved in 30 mL of tetrahydrofuran, 30 μL of H2O2 was added, the reaction was continued for 5 h, the mixture was directly concentrated under reduced pressure, and the selenophospholipid compound I-1 (i.e., R1 and R2 in the compound shown in formula I are both oleic acid, and X is hydrogen) was obtained. Figure 4 .

[0072]

[0073] Experiments have shown that selenophospholipid compounds can be obtained by replacing X with sodium, potassium, ammonium or calcium, respectively, instead of hydrogen in the compound represented by Formula III in this embodiment, while the other parts are the same as in this embodiment.

[0074] Experimental results show that tetrahydrofuran, acetonitrile or a mixed solvent consisting of toluene and N,N-dimethylformamide in a volume ratio of 1:1 is used to replace the dichloromethane in this example, while the other conditions are the same as in this example to obtain selenophospholipid compounds I-1.

[0075] Experimental results show that: triethylamine, pyridine and 4-dimethylaminopyridine are used to replace N,N-diisopropylethylamine in this example, and the other conditions are the same as in this example to obtain selenophospholipid compound I-1.

[0076] Experiments have shown that 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, onium salt condensing agent), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, onium salt condensing agent) or diphenylphosphoryl chloride (DPP-Cl, organophosphorus condensing agent), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl, organophosphorus condensing agent) are used to replace the carbodiimide condensing agent EDC·HCl in this example, and the other conditions are the same as in this example to obtain selenophospholipid compounds I-1 respectively.

[0077] Reference: J.Org.Chem.1994,59,4805, discloses a general method for synthesizing phosphatidylethanolamine compounds (Formula III), which illustrates that the C4-C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl groups can be synthesized; Reference: SN Appl.Sci.2020,2,1229, discloses that the reaction of the amino group on phosphatidylethanolamine is not affected by the alkyl groups of R1 and R2, and its reaction of connecting with carboxylic acid molecules to form amides is a mature process.

[0078] Embodiment 3:

[0079] Synthesis method of selenophospholipid compound I-2 (R1 and R2 in the compound shown in formula I are both stearic acid, and X is hydrogen):

[0080] Phosphatidylethanolamine III-1 in Example 2 was replaced by phosphatidylethanolamine III-2 (i.e., R1 and R2 in the compound shown in Formula III are both stearic acid, and X is hydrogen) (2.0 eq.), and the rest was the same as in Example 2 to obtain selenium phospholipid compound I-2, see Figure 5 .

[0081] Embodiment 4:

[0082] Synthesis method of selenophospholipid compound I-3 (R1 and R2 in the compound shown in formula I are both tetradecanoic acid, and X is hydrogen):

[0083] Phosphatidylethanolamine III-3 (i.e., R1 and R2 in the compound shown in formula III are both tetradecanoic acid, and X is hydrogen) (2.0 eq.) was used to replace the phosphatidylethanolamine III-1 in Example 2, and the rest was the same as in Example 2 to obtain the selenium phospholipid compound I-3, see Figure 6 .

[0084] Embodiment 5:

[0085] Synthesis method of selenophospholipid compound I-4 (R1 and R2 in the compound shown in formula I are both butyric acid, and X is hydrogen):

[0086] The phosphatidylethanolamine III-1 in Example 2 is replaced by phosphatidylethanolamine III-4 (i.e., R1 and R2 in the compound represented by Formula III are both butyric acid, and X is hydrogen) (2.0 eq.), and the rest is the same as in Example 2 to obtain the selenophospholipid compound I-4.

[0087] Embodiment 6:

[0088] Synthesis method of selenophospholipid compound I-5 (R1 and R2 in the compound shown in formula I are both palmitoleic acid, and X is hydrogen):

[0089] The phosphatidylethanolamine III-1 in Example 2 is replaced by phosphatidylethanolamine III-5 (i.e., R1 and R2 in the compound represented by Formula III are both palmitoleic acid, and X is hydrogen) (2.0 eq.), and the rest is the same as in Example 2 to obtain selenophospholipid compound I-5.

[0090] Embodiment 7:

[0091] Synthesis method of selenophospholipid compound I-6 (R1 and R2 in the compound shown in formula I are both erucic acid, and X is hydrogen):

[0092] Phosphatidylethanolamine III-1 in Example 2 is replaced by phosphatidylethanolamine III-6 (i.e., R1 and R2 in the compound represented by formula III are both erucic acid, and X is hydrogen) (2.0 eq.), and the rest is the same as in Example 2 to obtain selenophospholipid compound I-6.

[0093] Embodiment 8:

[0094] The preparation method of the liposome preparation of the selenium phospholipid compound comprises the following steps:

[0095] 1) dissolving the selenophospholipid compound I-1 prepared in Example 2, cholesterol and methoxy-polyethylene glycol 2000-distearoylphosphatidylethanolamine in a mixed solvent at a molar ratio of 20:4:1, wherein the mixed solvent is composed of chloroform and methanol at a volume ratio of 3:1;

[0096] 2) evaporating the mixed solvent under reduced pressure to form a uniform film in a round-bottom flask, and vacuum drying to remove the mixed solvent;

[0097] 3) Add 10 mL of water (10 mL of phosphate buffer with pH = 7.5, phosphate buffer with pH = 7 or phosphate buffer with pH = 8 can also be used), shake at 37°C for 2 h (any value between 25-50°C can also be used, such as 25°C, 30°C, 35°C, 40°C, 45°C, 50°C) to completely dissolve the vacuum-dried lipid film, perform short-term ultrasonic treatment for 30 seconds, completely suspend and filter with a 0.45-micron filter membrane to obtain a liposome preparation of selenophospholipid compound I-1.

[0098] The selenophospholipid compounds prepared in Examples 3 to 7 were prepared according to the methods of these Examples to obtain liposome preparations of selenophospholipid compounds.

[0099] Example 9

[0100] Physicochemical properties of selenophospholipid compound I-1 liposome preparation (obtained in Example 8)

[0101] The microscopic morphology of selenophospholipid compound (I-1) liposome preparation was analyzed by transmission electron microscopy. Figure 7 As shown, its diameter is 40-100nm; dynamic light scattering was used to further analyze the liposome preparation of selenium phospholipid compound I-1. Figure 8 As shown, its surface potential is about -30mV, and the particle size distribution is 40-100nm. Figure 7 The characterization results are consistent.

[0102] Experiments have shown that the microscopic morphology, particle size distribution and surface potential of the liposome preparations of selenium phospholipid compounds I-2 to I-6 are similar to those of the liposome preparations of selenium phospholipid compounds I-1.

[0103] Example 10

[0104] Antioxidant activity test of liposome preparation of selenium phospholipid compound I-1

[0105] The antioxidant activity of selenophospholipid compound I-1 liposomal preparation was evaluated by using an indirect enzyme assay.

[0106] Glutathione (GSH 1 mM), reduced coenzyme II (NADPH 0.4 mM), and glutathione reductase (1.7 U) were added to the cuvette respectively;

[0107] Then, the selenophospholipid compound I-1 liposome preparation was added to the above-mentioned cuvette to prepare final concentrations of 0.36 μM, 3.6 μM and 7.2 μM, respectively, and the solvent was 1×PBS (pH=7.4) as the sample group; the blank control group did not add the selenophospholipid compound I-1 liposome preparation;

[0108] Incubate at 37°C for 3 minutes, then add 50 μL of hydrogen peroxide (0.5 mM) to the sample group and the blank control group (total volume of 0.5 mL) to start the reaction. After the reaction, a decrease in the NADPH absorbance at 340 nm was observed. The activity was corrected according to the value recorded in the control experiment. One unit of enzyme activity (U) is defined as the simulated amount of 1 μmol NADPH consumed per minute. The molar extinction coefficient of NADPH is ε = 6220M -1 cm -1 .

[0109] Test results see Fig. 9 In the figure, the black curve is the blank control group without the selenophospholipid compound I-1 liposome preparation; the red, blue and green curves are the sample groups with 0.36 μM, 3.6 μM and 7.2 μM selenophospholipid liposomes added, respectively.

[0110] according to Fig. 9 It can be seen that the consumption rate of NADPH in the sample group is significantly increased compared with the blank control group, and the increase rate is positively correlated with the concentration of the added selenophospholipid compound I-1 liposome preparation. Calculated by the slope value obtained by fitting the curve, the antioxidant activity of the selenophospholipid compound I-1 liposome preparation reached about 16.5U / μmol. This activity is more than 16 times the activity of the currently commercialized selenium-containing drug ebselen (about 0.99U / μmol).

[0111] Experiments have shown that the antioxidant activity of selenophospholipid compound I-2 liposome preparation to selenophospholipid compound I-6 liposome preparation is similar to the results of selenophospholipid compound I-1 liposome preparation.

[0112] Example 11: Effect of selenophospholipid compound (I-1) liposome preparation on the removal of active oxygen in fibroblasts (L929) (commercial product)

[0113] The experiment was divided into 5 groups, namely normal cells (negative control), cells + H2O2 (positive control), cells + H2O2 + 30 μM sample, cells + H2O2 + 45 μM sample, and cells + H2O2 + 60 μM sample. The sample was the prepared liposome preparation of selenophospholipid compound (I-1).

[0114] After the cells were plated, they were cultured for 48 h, and the liposome preparation of selenophospholipid compound (I-1) was added and cultured for another 30 min. H2O2 (300 μM) was added and cultured for another 3 h. Finally, active oxygen probe staining was performed and the results were observed using a laser confocal microscope.

[0115] according to Fig.10As shown, the green fluorescence in the cells of the negative control group is very weak, indicating that the content of reactive oxygen in the cells is very low. The green fluorescence in the cells of the positive control group is very strong, indicating that there is a large amount of reactive oxygen. The sample group added with the liposome preparation of the selenium phospholipid compound (I-1) can reduce the content of reactive oxygen in the cells, and the degree of reduction is positively correlated with the added concentration.

[0116] Experiments have shown that the antioxidant activity of selenophospholipid compound I-2 liposome preparation to selenophospholipid compound I-6 liposome preparation is similar to the results of selenophospholipid compound I-1 liposome preparation.

[0117] Example 12: Protective effect of phospholipid compound (I-1) liposome preparation on fibroblasts (L929) damaged by reactive oxygen species

[0118] The experiment was divided into 5 groups, namely normal cells (negative control), cells + H2O2 (positive control), cells + H2O2 + 30 μM sample, cells + H2O2 + 45 μM sample, and cells + H2O2 + 60 μM sample. The samples were prepared phospholipid compound (I-1) liposome preparations.

[0119] After the cells were plated, they were cultured for 48 h, and the liposome preparation of selenophospholipid compound (I-1) was added and cultured for another 30 min. H2O2 (300 μM) was added and cultured for another 3 h. Finally, the cells were stained for viability and death and the results were observed using a laser confocal microscope.

[0120] according to Fig.11 As shown, the cells in the negative control group were green, indicating that the cells survived normally. Most of the cells in the positive control group were red, indicating that H2O2 induced a large number of cell death. The sample group with the addition of phospholipid compound (I-1) liposome preparation can reduce the cell death rate, and the survival rate is positively correlated with the added concentration.

[0121] Experiments have shown that the protective effects of selenophospholipid compound I-2 liposome preparations to selenophospholipid compound I-6 liposome preparations on fibroblasts (L929) damaged by reactive oxygen species are similar to the results of selenophospholipid compound I-1 liposome preparations.

[0122] Example 13: Biosafety of phospholipid compound (I-1) liposome preparation

[0123] 0.8×10 4L929 cells were seeded in 48-well plates at a concentration of 10 cells. After incubation for 24 hours, different concentrations (0, 10, 20, 30, 40, 50, 60 μM) of phospholipid compound (I-1) liposome preparations were dispersed in the cell culture medium and incubated for another 72 hours. The cells were washed with sterile PBS, and then treated with 200 μL of cell culture medium containing CCK-8 (10%) and incubated for another 2 hours. Cell viability was quantified by measuring the absorbance value at 450 nm. The results showed that the phospholipid compound (I-1) liposome preparation did not show cytotoxicity, indicating that it has very good biosafety. See Fig.12 .

[0124] Experiments have shown that the biosafety of selenophospholipid compound I-2 liposome preparations to selenophospholipid compound I-6 liposome preparations is similar to that of selenophospholipid compound I-1 liposome preparations.

Claims

1. A selenium phospholipid compound, characterized in that the structural formula is as shown in formula (I): in: R1 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl; R2 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl; X is hydrogen, sodium, potassium or ammonium.

2. The method for synthesizing the selenophospholipid compound of claim 1, characterized in that The steps include: 1) Bromoacetic acid reacts with Na2Se2 to generate 2,2'-diselenodiacetic acid (II) 2) Dispersing 2,2'-diselenodiacetic acid (II) in an inert solvent, adding a condensing agent and 1-hydroxybenzotriazole under alkaline conditions, and then adding compound (III) to undergo an acylation reaction to generate a selenophospholipid precursor (IV) 3) oxidizing the selenophospholipid precursor (IV) with hydrogen peroxide to generate a selenophospholipid compound (I) in: R1 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl; R2 is C4~C 18 Saturated alkyl or C 16 ~C 22 Unsaturated alkyl; X is hydrogen, sodium, potassium or ammonium.

3. The synthetic method according to claim 2, characterized in that The inert solvent is at least one of dichloromethane, tetrahydrofuran, acetonitrile, toluene and N,N-dimethylformamide.

4. The synthesis method according to claim 2, characterized in that The alkaline condition is to add at least one of triethylamine, pyridine, 4-dimethylaminopyridine and N,N-diisopropylethylamine.

5. The synthesis method according to claim 3, characterized in that The condensing agent is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, diphenyl phosphoryl chloride, di(2-oxo-3-oxazolidinyl) phosphoryl chloride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

6. A liposome preparation comprising the selenophospholipid compound of claim 1.

7. The method for preparing the liposome preparation containing the selenophospholipid compound according to claim 6, characterized in that The steps include: 1) dissolving the selenium phospholipid compound (I), cholesterol and methoxy-polyethylene glycol 2000-distearoylphosphatidylethanolamine in a mixed solvent, wherein the mixed solvent is composed of chloroform and methanol in a volume ratio of 3:1; 2) removing the solvent by evaporation under reduced pressure to form a uniform lipid film, and vacuum drying; 3) Add water or phosphate buffer with pH=7-8 at 25-50°C to completely dissolve the vacuum-dried lipid membrane to generate a liposome preparation of the selenium phospholipid compound.

8. Use of the liposome preparation containing selenophospholipid compounds according to claim 6 in the preparation of antioxidant drugs.

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