CN110772643A - α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug - Google Patents

α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug Download PDF

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CN110772643A
CN110772643A CN201910908191.4A CN201910908191A CN110772643A CN 110772643 A CN110772643 A CN 110772643A CN 201910908191 A CN201910908191 A CN 201910908191A CN 110772643 A CN110772643 A CN 110772643A
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cancer
polyethylene glycol
glycol succinate
tocopheryl polyethylene
cardiac glycoside
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殷军
韩娜
李怡雯
叶纯
刘志惠
翟健秀
李嗣凯
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to the technical field of medicines, and relates to α -Tocopheryl Polyethylene Glycol Succinate (TPGS) -modified cardiac glycoside compound prodrug, preparation and application thereof, in particular to TPGS prodrug of cardiac glycoside compound separated from streptocaulon juventas, a preparation method and anti-tumor application thereof, wherein the structure of the α -tocopheryl polyethylene glycol succinate-modified cardiac glycoside compound prodrug at least comprises one of the following general formulas, wherein R is shown in the specification 1、R 2、R 3、R 4As described in the claims and specification.

Description

α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug
Technical Field
The invention belongs to the technical field of medicines, and relates to α -Tocopherol Polyethylene Glycol Succinate (TPGS) -modified cardiac glycoside compound prodrug, preparation and application thereof, in particular to TPGS prodrug of cardiac glycoside compound separated from streptocaulon juventas, a preparation method and anti-tumor application thereof.
Background
The cardiac glycoside compound is separated from plant streptocaulon juventas (Schw.) Merr of saddle of Asclepiadaceae. Dark degummed rattan (streptaculon juventas (Lour.) Merr.) is a plant belonging to Asclepiadaceae (Asclepiadaceae) Ma Nelumbus (streptaculon) and is mainly produced in southeast Asia, China is mainly distributed in Yunnan and Guangxi, according to the record in the medicinal plant dictionary, the dark degummed rattan is a folk medicine with few stems, the roots play a role in tonifying the kidney and strengthening the body, the roots and the stems can strengthen the spleen and the stomach, milk has the effect of removing nebula, and is used for treating conjunctivitis.
In the previous research, a series of cardiac glycosides with good antitumor activity are separated from the streptocaulon juventas. However, the in vivo metabolism time of the series of cardiac glycoside compounds is too fast, and the water solubility and the lipid solubility are both lower, so that the wide clinical application of the series of cardiac glycoside compounds is greatly limited. Therefore, the water solubility of the series of cardiac glycoside compounds is enhanced, the in vivo circulation time of the series of cardiac glycoside compounds is prolonged, the bioavailability of the series of cardiac glycoside compounds is further improved, and the method has important significance for promoting the clinical application of the series of cardiac glycoside compounds.
At present, the widely applied polymer carriers mainly comprise polyethylene glycol (PEG), α -Tocopheryl Polyethylene Glycol Succinate (TPGS), hydroxyethyl starch and the like, and the polymer carriers can form stable chemical bonds with cardiac glycoside compounds, so that the in vivo half-life period of the medicine is prolonged, the metabolic rate of the medicine in the body circulation process is reduced, the proportion of the medicine reaching lesion sites can be improved through the high permeability and retention effect (EPR effect) of solid tumors, and the anti-tumor efficacy is further enhanced.
The TPGS has an amphiphilic structure, contains both lipophilic α -tocopherol and hydrophilic polyethylene glycol, has the property of a surfactant, and is widely applied to a solubilizer, an absorption promoter, an emulsifier, a plasticizer and a carrier of a fat-soluble drug delivery system in preparation research at home and abroad.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a series of α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrugs with anti-tumor activity, and the prodrugs have anti-tumor activity.
Specifically, the invention is realized by the following technical scheme:
the α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug at least comprises one of the following general formulas:
Figure BDA0002213903710000021
wherein,
R 1、R 2is H or OH;
R 3is A-X,
Figure BDA0002213903710000031
Or glucose or digitose or digitoxin orCanadian sesame candy;
R 4is H or OH or OAc;
R 5is A-X;
a is α -tocopheryl polyethylene glycol succinate containing polyethylene glycol segments with different molecular weights, and the molecular weight range of the contained polyethylene glycol is 2000-10000, preferably 2000-8000, and can be 2000, 4000, 8000, most preferably 4000;
x is a linker arm comprising-CH 2CH 2O-CO-or-CH 2CH 2O-CO-aa-, aa is an amino acid including glycine, alanine, phenylalanine, leucine and proline.
Specifically, the α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug has the following structure:
the invention also provides a preparation method of the α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug, wherein hydroxyl at the tail end of α -tocopheryl polyethylene glycol succinate is activated through a connecting arm and then is chemically connected with cardiac glycoside, and the preparation method of the α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug comprises the following steps:
A. active carbonate is introduced into the terminal hydroxyl of α -tocopheryl polyethylene glycol succinate, and then the active carbonate and cardiac glycoside are subjected to ester exchange reaction under the catalysis of organic base, and the synthetic route is as follows:
B. introducing amino acid into the terminal hydroxyl of α -tocopheryl polyethylene glycol succinate, and then carrying out esterification reaction with cardiac glycoside under the catalysis of a condensing agent and an organic base, wherein the synthetic route is as follows:
Figure BDA0002213903710000042
wherein the condensing agent is DCC, DIC, TBTU and EDC, and the most preferable condensing agent is DCC.
The organic base is triethylamine, DMAP and pyridine, preferably DMAP.
The reaction solvent is a mixed solvent of one of pyridine, DMF or DMAO and dichloromethane, and the best mixed solvent is dichloromethane and DMF.
The reaction temperature is 0-40 ℃, and the optimal temperature is 0-25 ℃; the reaction time is 1-6 days, and the optimal reaction time is 2-3 days.
The compound I-II (wherein the cardiac glycoside is acovogenin A- β -glucoside, hereinafter abbreviated as TXA 9; the compound I is-CH) 2CH 2O-CO-is a cardiac glycoside prodrug of the linker; the compound II is-CH 2CH 2O-CO-aa-a cardiac glycoside prodrug with a linker arm, aa is glycine) as an example to further illustrate the preparation method of each α -tocopheryl polyethylene glycol succinate-modified cardiac glycoside prodrug.
(1) Process for the preparation of compounds I
Reacting the terminal hydroxyl of α -tocopheryl polyethylene glycol succinate with p-nitrophenyl chloroformate, and then reacting with TXA9 in DCM/DMF solvent under the catalysis of DMAP and DCC to obtain the compound I.
Figure BDA0002213903710000051
(2) Process for preparing compounds II
α -tocopheryl polyethylene glycol succinate reacts with p-nitrophenyl chloroformate to enable the tail end of the p-nitrophenyl chloroformate to be active carbonate, then the p-nitrophenyl chloroformate reacts with glycine under an alkaline condition to enable the tail end of the p-nitrophenyl chloroformate to be glycine through an ester exchange reaction, and finally the tail end carboxyl of the glycine and the active hydroxyl of the cardiac glycoside compound undergo an esterification reaction in a DCM/DMF solvent under the catalytic action of EDCI/DMAP to obtain a compound II.
Figure BDA0002213903710000052
The invention further inspects the water solubility of the compounds I-II according to a method under a solubility experimental item in Chinese pharmacopoeia. The determination result shows that the compounds I-II can obviously increase the water solubility of cardiac glycoside compounds, and are easier to prepare into various medicinal preparations, and the result is shown in table 1.
The results of in vitro antitumor cell activity experiments on the compounds I-II show that the prodrug has good antitumor activity on human prostate cancer PC-3 cells, human cervical cancer Hela cells, human gastric cancer SGC7901 cells, human lung cancer A549 cells and human liver cancer SMMC-7721, wherein the tumor cell growth inhibition activity of the compound I and the original drug is equivalent, the inhibition effect of the compound II is superior to that of the original drug, and the results are shown in Table 2.
The in vivo pharmacokinetic properties of the compounds I-II were examined. The results show that compared with the prototype drug, the prodrug can increase the blood concentration of the original drug and prolong the in vivo half-life period, wherein the compound II shows longer in vivo half-life period and higher area under the time curve, and is more beneficial to enhancing the in vivo anti-tumor effect of the drug, and the results are shown in figure 1 and table 3.
As the compound II shows the strongest tumor cell inhibition effect and the best in vivo pharmacokinetic property in the experimental results, the invention further performs in vivo antitumor drug effect experiments on the compound II in nude mice. The experimental results (table 3) show that compared with the TXA9 group, the compound ii can significantly improve the in vivo antitumor effect of the original drug, and the tumor inhibition rate of the high-dose group of the compound ii can reach 52.46%, which is equivalent to the tumor inhibition rate (54.57%) of the positive control cisplatin, which indicates that the compound ii has a good tumor growth inhibition effect on the transplanted tumor of the human lung adenocarcinoma cell strain a549 inoculated in the nude mouse.
The invention also provides a pharmaceutical composition which comprises the α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug and a pharmaceutically acceptable carrier or excipient.
The invention also provides application of the α -tocopherol polyethylene glycol succinate modified cardiac glycoside compound prodrug and a pharmaceutical composition in preparing antitumor drugs, wherein the tumors are lung cancer, gastric cancer, liver cancer, cervical cancer, acute leukemia, colon cancer, breast cancer, sarcoma, nasopharyngeal cancer, ovarian cancer, skin cancer, prostatic cancer, bladder cancer, chorioepithelioma, kidney tumor, rectal cancer, oral cancer, esophageal cancer, biliary tract cancer, bile duct cancer, pancreatic cancer, bone cancer, laryngeal cancer, tongue cancer, thymus gland cancer, lymph cancer, malignant thyroid tumor, brain tumor, central nervous system tumor, mediastinal tumor and melanoma.
According to the invention, by utilizing the characteristic that α -tocopheryl polyethylene glycol succinate can prolong the internal circulation time of the medicine, α -tocopheryl polyethylene glycol succinate is used for carrying out structural modification on a series of cardiac glycoside compounds, and meanwhile, a carbonic ester bond which can be cracked in vivo and amino acid with strong water solubility are used as connecting arms, so that a series of cardiac glycoside compound prodrugs are designed and synthesized.
Drawings
FIG. 1 is a graph of the in vivo pharmacokinetics of compounds I-II.
Detailed Description
Example 1: preparation of Compound I
Accurately weighing TPGS 4000(1.20mmol), phenyl p-nitrochloroformate (5.80mmol) and DMAP (2.40mmol) were placed in a 100mL round-bottomed flask, and 25mL of anhydrous dichloromethane were added to conduct reaction for 12 hours. TLC detecting reaction, sequentially extracting reaction solution with equal volume of 10% citric acid water solution for 3 times, extracting saturated sodium chloride water solution for 3 times, drying organic layer with anhydrous sodium sulfate, filtering, concentrating, and purifying by silica gel column chromatography to obtain white powdery solid, i.e. TPGS 4000pNP, yield 58%.
1H NMR(600MHz,CDCl 3)δ8.29(d,J＝9.1Hz,2H),7.40(d,J＝9.1Hz,2H),4.47–4.41(m,2H),4.28–4.25(m,2H),3.82–3.81(m,2H),3.77–3.75(m,2H),3.65(br.s),2.93(t,J＝6.8Hz,2H),2.80(t,J＝6.8Hz,2H),2.58(t,J＝6.8Hz,2H),2.08(s,3H),2.01(s,3H),1.97(s,3H),1.81(d,J＝6.7Hz,1H),1.75(d,J＝6.6Hz,1H),1.56–1.49(m,3H),1.38–1.05(m,21H),0.87–0.84(m,12H).
Accurately weighing the TPGS prepared above 4000-pNP (0.25mmol), 30mL of toluene were added, stirred, refluxed at 115 ℃ for 2h, and the solvent was evaporated at 72 ℃ under reduced pressure and redissolved with 30mL of anhydrous dichloromethane. TXA9(0.30mmol) was weighed out accurately into a 5mL round-bottomed flask, dissolved in 1.3mL anhydrous DMF, and added dropwise slowly to the reaction system, triethylamine (0.27mmol) was added thereto and reacted at room temperature for 48 hours. TLC detection shows that the product is not increased any more, the reaction solution is extracted with distilled water for 5 times, 10% citric acid water solution is extracted for 3 times, saturated sodium chloride water solution is extracted for 3 times, the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated, the product is separated out by anhydrous ether, and the white powdery solid, namely the compound I, is obtained by suction filtration, and the yield is 77%.
1H-NMR(600MHz,CDCl 3)δ5.88(s,1H),4.99(dd,J＝18.2,1.9Hz,1H),4.81(dd,J＝18.1,1.7Hz,1H),4.78(d,J＝9.4Hz,1H),4.71(t,J＝9.5Hz,1H),4.45-4.41(m,8H),4.27-4.26(m,8H),4.04(d,J＝11.1Hz,1H),3.88(dd,J＝11.7,3.6Hz,1H),3.77-3.75(m,8H),3.74-3.71(m,8H),3.65(br.s),2.94(d,J＝6.5Hz,8H),2.79(d,J＝6.6Hz,8H),2.58(t,J＝6.8Hz,8H),2.08(s,3H),2.01(s,3H),1.97(s,3H),0.95-0.92(m,3H),0.87-0.84(m,47H).
Example 2: preparation of Compound II
Accurately weighing TPGS 4000-pNP (0.37mmol), glycine (2.80mmol) in a 100mL round-bottomed flask, 30mL 2/3 acetonitrile water was added, stirred, and after the reaction mass was completely dissolved, 200. mu.l triethylamine (1.40mmol) was added and reacted at 25 ℃ for 5 hours. TLC detecting reaction, adjusting pH to 2 with dilute hydrochloric acid, diluting reaction solution with appropriate amount of water, extracting with equal volume of diethyl ether for 3 times, extracting with dichloromethane for 5 times, mixing organic layers, drying with anhydrous sodium sulfate for 4 hr, filtering, concentrating to a small amount, precipitating product with anhydrous diethyl ether, and vacuum filtering to obtain white powdery solid, i.e. TPGS 4000Gly yield 83%.
1H NMR(600MHz,CDCl 3)δ5.64(s,1H),4.28-4.25(m,2H),4.23(d,J＝4.9Hz,1H),3.96(d,J＝5.2Hz,1H),3.77-3.75(m,2H),3.71-3.70(m,2H),3.65(br.s),3.11(qd,J＝7.3,4.9Hz,2H),2.93(t,J＝6.8Hz,2H),2.79(t,J＝6.8Hz,2H),2.58(t,J＝6.7Hz,2H),2.08(s,3H),2.01(s,3H),1.97(s,3H),1.80(d,J＝6.8Hz,1H),1.75(d,J＝6.7Hz,1H),1.59-1.50(m,3H),1.38-1.03(m,21H),0.88-0.83(m,12H).
Accurately weighing the TPGS prepared above 4000To a 100mL round-bottom flask, was added-Gly (0.25mmol) and DCC (0.50mmol), followed by stirring and dissolving in anhydrous dichloromethane, followed by reaction at 0 ℃ for 30 min. TXA9(0.31mmol) was weighed out accurately, dissolved in 1.3mL of anhydrous DMF, added dropwise slowly to the reaction system, and triethylamine (0.25mmol) was added thereto, and the reaction was carried out at 25 ℃ for 48 hours after completion of the dropwise addition. TLC detection reaction is complete, the reaction solution is extracted by distilled water for 5 times, 10% citric acid aqueous solution is extracted for 3 times, saturated sodium chloride aqueous solution is extracted for 3 times, an organic layer is dried by anhydrous sodium sulfate, filtered and concentrated, a product is separated out by anhydrous ether, and the product is filtered and filtered to obtain white powdery solid, namely a compound II, with the yield of 71%.
1H NMR(600MHz,CDCl 3)δ5.88(s,1H),5.61-5.57(m,2H),5.05-5.02(m,1H),4.99(d,J＝17.2Hz,1H),4.94-4.87(m,1H),4.81(d,J＝17.8Hz,1H),4.50-4.31(m,4H),4.28-4.26(m,2H),4.25-4.23(m,2H),4.07-4.04(m,1H),4.03-3.97(m,2H),3.88(m,1H),3.77-3.75(m,4H),3.71-3.69(m,4H),3.65(br.s),2.93(t,J＝6.8Hz,4H),2.79(t,J＝6.9Hz,4H),2.58(t,J＝6.8Hz,4H),2.08(s,6H),2.01(s,6H),1.97(s,6H),0.93(d,J＝7.5Hz,3H),0.87-0.83(m,32H).
Example 3: determination of Water solubility of Compounds I-II
According to the method under the solubility experimental item in Chinese pharmacopoeia, a certain amount of compounds I-II which are ground into fine powder are respectively and precisely weighed, a certain amount of normal saline is added in batches at the temperature of 25 +/-2 ℃, strong shaking is carried out for 30s every 5min, the dissolution condition is observed within 30min, and the solute particles which are not visible visually are regarded as complete dissolution. The volume of physiological saline in which the drug fine powder was completely dissolved was recorded, and the solubility of compounds i to ii in water was calculated.
The method for measuring the water solubility of TXA9 comprises the following steps: taking a certain amount of TXA9 ground into fine powder, placing the mixture into a ground test tube, adding a certain amount of normal saline to prepare a TXA9 supersaturated solution, placing the solution into a constant-temperature oscillator (180 revolutions per minute) at 37 ℃ for 24 hours, centrifuging the solution at 12000rpm for 15 minutes, taking the supernatant, passing through a 0.45 mu m water film, detecting the solution by HPLC, recording the peak area, and calculating the solubility of the TXA9 in water.
The results are shown in Table 1. The results show that compared with original drug TXA9, the water solubility of the compounds I-II is improved by 10-19 times, and the compounds I-II can obviously improve the water solubility of TXA9 and can be prepared into various pharmaceutical preparations more easily.
TABLE 1 results of water solubility measurement of Compounds I-II
Figure BDA0002213903710000091
*Ratio of Water solubility of Compound to Water solubility of TXA9
Example 4: determination of growth inhibitory Activity of Compounds I-II on tumor cells
The experiment investigates the growth inhibition effect of the compounds I-II on five tumor cells of human prostate cancer PC-3 cells, human cervical carcinoma Hela cells, human gastric cancer SGC7901 cells, human lung cancer A549 cells and human liver cancer SMMC-7721. Selecting tumor cells in logarithmic growth phase, digesting with pancreatin, and preparing into 5 × 10 with culture medium containing 10% calf serum 4The cell suspension/mL, seeded in 96-well plates at 100. mu.l/well, 37 ℃ 5% CO 2And culturing for 24 h. The experimental group was replaced with a new culture medium containing compounds I-II at different concentrations, the control group was replaced with a culture medium containing an equal volume of solvent, each group had 3 parallel wells, 37 deg.C, 5% CO 2Culturing for 48 h. The supernatant was discarded, carefully washed 2 times with PBS, 100. mu.l of freshly prepared medium containing 0.5mg/ml MTT was added to each well, and incubation was continued for 4h at 37 ℃. The supernatant was carefully discarded, 150. mu.l DMSO was added, and after mixing for 10min with a micro shaker, the optical density was measured at 492nm using a microplate reader. The inhibition rate of the drug on the growth of tumor cells was calculated according to the following formula:
Figure BDA0002213903710000101
thereby determining the half Inhibitory Concentration (IC) of the sample 50)。
The results of in vitro anti-tumor cell experiments are shown in Table 2, and the results show that the compounds I-II have good activity of inhibiting the growth of tumor cells, wherein the growth inhibition effect of the compound II on the tumor cells is better than that of TXA 9.
TABLE 2 IC of Compounds I-II on five tumor cells 50Values (nM, TXA9 equivalent)
Figure BDA0002213903710000102
Example 5: in vivo pharmacokinetic investigation of Compounds I-II
18 rats were randomly divided into 3 groups, and administered TXA9(5mg/kg), compound I-II (5mg/kg TXA9 equivalent) by single dose injection into the tail vein, 0.5mL was collected at 5min, 15min, 30min, 1h, 1.5h, 2h and 3h after administration, blood samples were centrifuged to collect plasma, plasma proteins were precipitated with methanol, supernatants were centrifuged to collect supernatant, the amount of TXA9 in plasma was measured by HPLC, pharmaceutical time curves were plotted, the results are shown in FIG. 1, and pharmacokinetic parameters were calculated by DAS 2.0 software, and the results are shown in Table 3. The experimental result shows that compared with the original drug TXA9, the compounds I and II can increase the blood concentration of TXA9 and prolong the half-life period in vivo, wherein the compound II shows longer half-life period in vivo and higher area under the curve of drug time, and is more beneficial to enhancing the in vivo antitumor effect of the drug.
TABLE 3 in vivo pharmacokinetic parameters of Compound TXA9 and Compounds I-II
Figure BDA0002213903710000111
Compared with the compound TXA9 group, *p<0.05, ***p<0.001。
example 6: in vivo antitumor drug efficacy experiment of Compound II
As the compound II shows better water solubility and stronger tumor cell growth inhibition effect in the experimental results, the compound II is subjected to an in-vivo anti-tumor drug effect experiment on nude mice. Compared with other cell lines, the sensitivity of A549 cells to TXA9 and prodrugs thereof is highest, so the cells are selected for in vivo anti-tumor experiments.
Human lung cancer A549 cells are treated according to the proportion of 1 × 10 8cells/mL, 50 nude mice were inoculated with 0.2mL of subcutaneous axillary vaccine per mouse. After 10 days, the mean tumor volume was greater than 100mm 3And randomly dividing into 5 groups: the model group, the cisplatin positive drug group (4mg/kg), the TXA9 group (5mg/kg), the compound II low dose group (5mg/kg TXA9 equivalent) and the compound II high dose group (10mg/kg TXA9 equivalent) are continuously administrated for 28 days, the tumor growth condition is observed, and the tumor inhibition rate is calculated.
The results of in vivo antitumor drug efficacy experiments on the compound II (Table 3) show that compared with the original drug TXA9 (tumor inhibition rate is 25.26%), the tumor inhibition rate of the compound II can reach 43.81% (low dose group) and 52.46% (high dose group), which indicates that the compound II can significantly improve the in vivo antitumor drug efficacy of the original drug; the tumor inhibition rate of the high-dose group of the compound II is equivalent to that of a cisplatin positive drug (54.57%), which shows that the compound II has good tumor growth inhibition effect on human lung adenocarcinoma cell strain A549 transplantation tumor inoculated by nude mice.
TABLE 4 test results of in vivo antitumor effect of Compound II
Figure BDA0002213903710000121

Claims (10)

  1. α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug, characterized in that it comprises at least one of the following general formulas:
    Figure FDA0002213903700000011
    wherein,
    R 1、R 2is H or OH;
    R 3is A-X, Or glucose or digitose or digitoxose or canada biose;
    R 4is H or OH or OAc;
    R 5is A-X;
    a is α -tocopheryl polyethylene glycol succinate, and the molecular weight range of contained polyethylene glycol is 2000-10000;
    x is a linker arm comprising-CH 2CH 2O-CO-or-CH 2CH 2O-CO-aa-, aa is an amino acid.
  2. 2. The α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug of claim 1, wherein:
    R 1is OH;
    R 2is H;
    R 3is A-X,
    R 5Is A-X;
    a is α -tocopheryl polyethylene glycol succinate, and the molecular weight range of contained polyethylene glycol is 2000-8000;
    x is a linker arm comprising-CH 2CH 2O-CO-or-CH 2CH 2O-CO-aa-, aa is glycine, alanine, phenylalanine, leucine, proline.
  3. 3. The α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug of claim 1 or 2, wherein:
    R 1is OH;
    R 2is H;
    R 3is composed of
    R 5Is A-X;
    a is α -tocopheryl polyethylene glycol succinate, and the molecular weight range of contained polyethylene glycol is 2000-8000;
    x is a linker arm comprising-CH 2CH 2O-CO-or-CH 2CH 2O-CO-aa-, aa is glycine, alanine, phenylalanine, leucine, proline.
  4. 4. The α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound pro-drug of any one of claims 1 to 3, wherein α -tocopheryl polyethylene glycol succinate is chemically linked to a series of cardiac glycosides or aglycones via a carbonate linker or an amino acid linker.
  5. 5, α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound prodrug, which has the following structure:
    Figure FDA0002213903700000031
  6. 6. the method of claim 1, wherein the terminal hydroxyl group of α -tocopheryl polyethylene glycol succinate is activated via a linker and chemically linked to the cardiac glycoside.
  7. 7. A pharmaceutical composition comprising the α -tocopheryl polyethylene glycol succinate modified cardiac glycoside compound pro-drug of any one of claims 1-5 and a pharmaceutically acceptable carrier or excipient.
  8. 8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is formulated with a pharmaceutically acceptable carrier into a clinically acceptable nanosuspension, micelle, nanoparticle, nanoemulsion or liposome.
  9. 9. Use of the α -tocopheryl polyethylene glycol succinate modified cardiac glycoside prodrug of any one of claims 1 to 5 or the pharmaceutical composition of any one of claims 7 to 8 for the preparation of an anti-neoplastic drug.
  10. 10. The use of claim 9, wherein the neoplasm is lung cancer, gastric cancer, liver cancer, cervical cancer, acute leukemia, colon cancer, breast cancer, sarcoma, nasopharyngeal cancer, ovarian cancer, skin cancer, prostate cancer, bladder cancer, chorioepithelial cancer, kidney cancer, rectal cancer, oral cancer, esophageal cancer, biliary tract cancer, pancreatic cancer, bone cancer, laryngeal cancer, tongue cancer, thymus cancer, lymphoid cancer, malignant thyroid cancer, brain tumor, central nervous system tumor, mediastinal tumor, melanoma.
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