CN112110924A - 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof - Google Patents
6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof Download PDFInfo
- Publication number
- CN112110924A CN112110924A CN201910542916.2A CN201910542916A CN112110924A CN 112110924 A CN112110924 A CN 112110924A CN 201910542916 A CN201910542916 A CN 201910542916A CN 112110924 A CN112110924 A CN 112110924A
- Authority
- CN
- China
- Prior art keywords
- obzl
- lys
- diacetyl
- mercaptopurine
- purine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/36—Sulfur atom
- C07D473/38—Sulfur atom attached in position 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
Description
Technical Field
The invention relates to 6-S,9-N- (diacetyl-Lys-OBzl-sulfhydryl) purine, a preparation method thereof and antitumor activity thereof. The invention thus relates to the use of this compound in the preparation of an anti-tumour medicament. The invention belongs to the field of biological medicine.
Background
6-mercaptopurine is a common medicine for clinically treating acute lymphoblastic leukemia of children. However, it is also used for the treatment of chorionic epithelial cancer. However, some toxic side effects limit the clinical use of 6-mercaptopurine. For example, 6-mercaptopurine has a more severe myelosuppressive effect, a shorter half-life, and a higher dose. Although there have been numerous studies over the past decades attempting to overcome these disadvantages of 6-mercaptopurine, there has been no apparent success. The inventor finds that CH is used after years of exploration2CO-Lys-OBzl modifies 6-SH and 9-N of 6-mercaptopurine, can eliminate the myelosuppression effect of 6-mercaptopurine, prolongs the half life and reduces the dosage. Based on these findings, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine.
A second aspect of the present invention provides a process for the preparation of 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, which process comprises:
1. synthesizing 6-S, 9-N-diacetyl-O-ethylmercaptopurine;
2. synthesizing 6-S, 9-N-dicarboxymethylmercaptopurine;
3. condensing 6-S,9-N- (dicarboxymethylmercapto) purine and Lys-OBzl by a liquid phase method using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to prepare 6-S, 9-N-diacetyl-Lys (Boc) -OBzl-mercaptopurine;
4. deprotecting 6-S, 9-N-diacetyl-Lys (Boc) -OBzl-mercaptopurine to produce 6-S, 9-N-diacetyl-Lys-OBzl-mercaptopurine;
the third aspect of the present invention is to evaluate the antitumor effect of 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine.
Drawings
FIG. 1. Synthesis of 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine route i) ethyl bromoacetate, dimethylformamide, K2CO3,65℃;ii)CH3OH,2N NaOH aqueous solution; iii) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine, dimethylformamide; iv)4N HCl/EA solution, 0 ℃.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of 6-S,9-N- (diacetyl-O-ethylmercapto) purine (1)
To 3.001g (19.70mmol) of 6-mercaptopurine was added 50mL of N, N-dimethylformamide, and the mixture was stirred at 65 ℃ until the 6-mercaptopurine was completely dissolved, whereby the solution was yellow, clear and transparent. 5.400g (39.50mmol) of potassium carbonate as a catalyst were added, activation was carried out for 30min, and 6.60mL (59.20mmol) of ethyl bromoacetate were added, and the reaction was continued at 65 ℃. TLC (petroleum ether/ethyl acetate 1/1) after 48h showed 6-mercaptopurine to disappear. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) to give 1.500g (23%) of the title compound as a colorless solid. ESI-MS (M/e):325[ M + H]+;1H-NMR(300MHz,DMSO-d6)/ppm=8.692(s,1H),8.489(s,1H),5.214(s,2H),4.260(s,2H),4.215~4.098(dq,J1=6.9Hz,J2=7.2Hz,4H),1.238~1.165(dt,J1=7.2Hz,J2=11.0Hz,6H);13C-NMR(75MHz,DMSO-d6):/ppm=167.93,167.55,166.54,150.30,147.67,137.81,132.98,61.00,60.64,53.03,31.11,14.16。
EXAMPLE 2 preparation of 6-S,9-N- (dicarboxymethylmercapto) purine (2)
0.170g (0.52mmol) of 6-S,9-N- (diacetyl-O-ethylmercapto) purine (1) was completely dissolved in 5mL of methanol, and the solution was clear and transparent. The reaction mixture was adjusted to pH 13 with 2N aqueous NaOH at 0 ℃, stirred for 4h at 0 ℃ and monitored for completion by TLC (petroleum ether/ethyl acetate ═ 1/2). Saturated KHSO is used for reaction liquid4The aqueous solution was adjusted to pH 7, concentrated under reduced pressure to precipitate a colorless salt solid, and 5mL of water was added to completely dissolve the solid. The solution is saturated with KHSO at 0 deg.C4The aqueous solution was adjusted to pH 2, extracted with ethyl acetate (20 mL. times.3), the ethyl acetate layers were combined and washed with saturated NaCl (15 mL. times.3), and the resulting ethyl acetate phase was dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave 0.138g (98%) of the title compound as a colorless solid. ESI-MS (M/e):267[ M-H]+;1H-NMR(300MHz,DMSO-d6)/ppm=13.011(s,2H),8.501(s,1H),8.078(s,1H),4.799(s,2H),4.026(s,2H);13C-NMR(75MHz,DMSO-d6):/ppm=174.90,171.01,159.64,158.52,151.60,140.33,122.48,54.85,32.01。
EXAMPLE 3 preparation of 6-S,9-N- [ diacetyl-Lys (Boc) -OBzl-mercapto ] purine (3a)
0.300g (1.12mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, 0.605g (2.24mmol) of 1-hydroxybenzotriazole was added at 0 ℃ and stirred for 10min, then 0.924g (4.48mmol) of dicyclohexylcarbodiimide was added and stirred for 30 min. 1.890g (4.48mmol) Lys (Boc) -OBzl was added to the reaction solution at 0 deg.C, the pH of the reaction mixture was adjusted to 9 with N-methylmorpholine, and the reaction was monitored for completion by TLC (dichloromethane/methanol 20/1) after stirring at room temperature for 12 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 50mL of ethyl acetate, the insoluble material was filtered off, and the filtrate was taken with saturated NaHCO3Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO4Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution3The ethyl acetate phase was dried over anhydrous sodium sulfate for 12 hours, after washing with an aqueous solution (30 mL. times.3) and saturated aqueous NaCl solution (30 mL. times.3). Filtration and concentration of the filtrate under reduced pressure gave a yellow oil which was purified by silica gel column chromatography (dichloromethane/methanol 40/1) to give 0.808g (80%) of the title compound. ESI-MS (M/e):904[ M-H]-;1H-NMR(300MHz,DMSO-d6):/ppm=8.883~8.855(d,J=8.4Hz,1H),8.677~8.651(d,J=7.8Hz,1H),8.634(s,1H),8.416(s,1H),7.340(s,10H),6.754(m,2H),5.114(m,4H),5.040(m,2H),4.297(m,2H),4.184(m,2H),2.875(m,4H),1.715~1.580(m,6H),1.495~1.160(m,28H);13C-NMR(75MHz,DMSO-d6):/ppm=172.14,172.00,167.92,166.68,158.77,156.03,151.69,149.23,146.16,136.37,136.29,130.60,128.85,128.51,128.44,128.26,128.18,77.83,66.48,66.36,52.93,52.80,45.43,32.21,31.17,31.06,29.84,29.50,28.73,25.99,23.00。
EXAMPLE 4 preparation of 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine (4a)
To 0.800g (0.88mmol) of compound 3a was added 8mL of a 4N ethyl acetate solution of hydrogen chloride at 0 ℃, and the completion of the reaction was monitored by TLC (dichloromethane/methanol ═ 20/1) after stirring for 1 h. Pumping out the reaction solution, adding 15mL of dry ethyl acetate, pumping out, and repeating for three times; 15mL of anhydrous ether was added, and the mixture was dried by suction and repeated 3 times. The resulting pale yellow solid was dissolved in 1mL of distilled water and RP-C was used18Purifying by column chromatography(40% aqueous methanol) and the fractions were freeze-dried. The resulting colorless solids were combined to give a total of 0.498g (72%) of the title compound. FT-MS (M/e) 705.32[ M + H]+;1H-NMR(300MHz,DMSO-d6):/ppm=9.023~8.997(d,J=7.8Hz,1H),8.773~8.748(d,J=7.5Hz,1H),8.664(s,1H),8.449(s,1H),7.390~7.310(m,10H),5.124(m,4H),5.072(s,2H),4.355~4.254(m,2H),4.202(s,2H),2.744~2.708(m,4H),1.785~1.655(m,4H),1.616~1.538(m,4H),1.487~1.406(m,4H);13C-NMR(75MHz,DMSO-d6):/ppm=172.03,171.89,168.00,166.76,158.75,151.72,149.23,146.20,136.33,136.26,130.60,128.89,128.56,128.50,128.29,128.21,66.57,66.45,52.69,52.58,45.49,38.93,32.17,30.79,26.83,22.59。
Example 5 evaluation of the antitumor Effect of 4a
6-mercaptopurine and sodium carboxymethylcellulose were purchased from national pharmaceutical group chemical reagents, Inc. Male mice (20 ± 2g) of the SPF grade ICR strain were purchased from experimental animal technology ltd, viton, beijing. The experiment was performed using a transplanted mouse S180 sarcoma model.
The dose of compound 4a was 16. mu. mol/kg/day, the dose of positive control 6-mercaptopurine was 164. mu. mol/kg/day, and the negative control was CMCNa.
The tumor source for modeling the transplanted mouse S180 sarcoma model is S180 mouse sarcoma cells purchased from animal experiment center of department of medicine of Beijing university and self-passaged and reserved according to a suspension cell culture method. A male ICR mouse with the SPF level of S180 ascites tumor after one week of passage is taken, the neck is cut off after the anesthesia of a proper amount of ether, the mouse is soaked in 75% alcohol for disinfection for 1min, the abdominal cavity is cut open, ascites S180 tumor liquid is taken, the centrifugation is carried out for 1000r/min multiplied by 10min, the supernatant is discarded, the residues are washed by a small amount of cooled normal saline to remove non-cell fragments, tissues and floating blood, the cell activity is calibrated by a MUSE flow cytometer, and the result shows that the cell activity reaches 94.67%. Viable cell count, density 4X 107one/mL. The living cells were suspended in cooled physiological saline to a cell density of 2X 107one/mL, used for inoculation as soon as possible. During inoculation, the mouse is fixed by the left hand, a 1mL syringe is held by the right hand to pierce the right armpit of the mouse by about 2mm to the subcutaneous part, a small cavity is separated by slight blunting, and 0.2mL of living cell suspension is injected.
The mice are observed every day after detection and inoculation, until the majority of mice can see mung bean particle solid tumors under the armpit (average about 5 days of inoculation), the mice are grouped, 11 mice in each group are continuously administrated for 10 days, the mice in each group are weighed until 11 days, the mice are anesthetized by ether, cervical vertebra dislocation is killed, the growth parts of the solid tumors under the armpit of the mice are fixed, scissors are taken to cut the skin, the tumor bodies are fully exposed, and sarcomas are taken out and weighed by blunt separation of the upper limbs along the skin. The brain, heart, liver, spleen and kidney were dissected out in sequence and weighed, and the index of each organ was calculated.
The in-situ tumor weight of the data is represented by a mean value +/-SD g, the SD value is subjected to variance analysis through SPSS software, the homogeneity of the variance is detected, and statistical comparison among groups is performed by adopting t-test detection.
As a result, Compound 4a exhibited antitumor activity, and 4a had antitumor activity comparable to that of 6-mercaptopurine at a dose reduced by 9-fold compared to that of 6-mercaptopurine. This is the unexpected technical effect of this case.
S180 antitumor Activity of Compound 4a of Table 1
Compound (I) | Dosage (mu mol/kg/day) | Tumor weight (mean + -SD g) |
CMCNa | - | 2.34±0.67 |
6-mercaptopurine | 164 | 1.10±0.33 |
4a | 16 | 1.25±0.60a |
a) P <0.05 to CMCNa, p >0.05 to 6-mercaptopurine; n is 11.
Example 6 evaluation of myelosuppressive toxicity of 4a
The method comprises the steps of taking 20 mu L of eyeball blood before mice are sacrificed for 10 days after continuous administration treatment, placing the eyeball blood into a 0.5mL special EDTA blood collection tube, tightly covering the tube opening, shaking up and down uniformly, and detecting by using a full-automatic three-classification blood cell analyzer within 4 h. 4a is 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, control CMCNa.
Results table 2 shows that the white blood cell count and platelet count of the 6-mercaptopurine group mice were significantly lower than those of the CMCNa group mice, and the red blood cell count did not significantly decrease. This indicates that myelosuppressive toxicity caused by 6-mercaptopurine is mainly manifested by inhibition of leukocytes and platelets. The white blood cell number and the platelet number of the 4a group of mice are obviously higher than those of the 6-mercaptopurine group of mice, and are very close to those of the CMCNa group of mice, namely, the acetyl-Lys-OBzl modified 6-S,9-N can reduce the bone marrow suppression side effect of the 6-mercaptopurine. This is the unexpected technical effect of this case.
TABLE 24A group of mice myelosuppressive toxicity assay results
Compound (I) | Number of leukocytes (. times.10)9/L) | Number of platelets (. times.10)11/L) | Number of erythrocytes (. times.10)12/L) |
CMCNa | 18.39 | 13.75 | 6.54 |
6-mercaptopurine | 10.06 | 7.46 | 6.25 |
4a | 16.94 | 13.11 | 6.77 |
Example 7 evaluation of plasma half-life of 4a
Under the anesthesia state, the plasma of the mouse is taken out, centrifuged at 3000r/min for 10min, and the serum is taken out. 6-mercaptopurine and 4a were dissolved in 1mL of serum to give a concentration of 1 mg/mL. Incubating 100 μ L of sample at 37 deg.C, sampling at 0min,10min,30min,1h,2h, etc., precipitating protein with methanol, concentrating to obtain sample with the same concentration, and measuring ultraviolet absorption of 4a with ultraviolet spectrophotometer.
The absorbance value at 0min is taken as A0Calculating the content of the compound at different time points according to the formula, wherein the content is A0and/A. The data are shown in Table 3. The results show that the half-life of 4a in mouse plasma is 59.5min, which is significantly longer than the half-life of 6-mercaptopurine in mouse plasma (19.2 min). This is the unexpected technical effect of this case.
Table 34 a half-life in mouse plasma
Compound (I) | Half-life period (min) |
6-mercaptopurine | 19.2 |
4a | 59.5 |
Claims (3)
2. a process for the preparation of 6-S, 9-N-diacetyl-Lys-OBzl-mercaptopurine of claim 1 which comprises:
2.1. synthesizing 6-S, 9-N-diacetyl-O-ethylmercaptopurine;
2.2. synthesizing 6-S, 9-N-dicarboxymethylmercaptopurine;
2.3. condensing 6-S,9-N- (dicarboxymethylmercapto) purine and Lys (Boc) -OBzl by a liquid phase method using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to prepare 6-S, 9-N-diacetyl-Lys (Boc) -OBzl-mercaptopurine;
2.4. 6-S, 9-N-diacetyl-Lys-OBzl-mercaptopurine was deprotected to produce 6-S, 9-N-diacetyl-Lys-OBzl-mercaptopurine.
3. Use of 6-S, 9-N-diacetyl-Lys-OBzl-mercaptopurine according to claim 1 for the preparation of an anti-tumor medicament.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910542916.2A CN112110924B (en) | 2019-06-21 | 2019-06-21 | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910542916.2A CN112110924B (en) | 2019-06-21 | 2019-06-21 | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112110924A true CN112110924A (en) | 2020-12-22 |
CN112110924B CN112110924B (en) | 2023-01-13 |
Family
ID=73796356
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910542916.2A Active CN112110924B (en) | 2019-06-21 | 2019-06-21 | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112110924B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112125905A (en) * | 2019-06-24 | 2020-12-25 | 首都医科大学 | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015135659A1 (en) * | 2014-03-14 | 2015-09-17 | Ontochem Gmbh | Receptor ligand linked cytotoxic molecules |
CN105283201A (en) * | 2013-03-14 | 2016-01-27 | 加州生物医学研究所 | Targeting agent antibody conjugates and uses thereof |
CN109081801A (en) * | 2017-06-13 | 2018-12-25 | 首都医科大学 | The indoles alcohol derivative of acidic amino acid modification, synthesis, activity and application |
CN109081803A (en) * | 2017-06-13 | 2018-12-25 | 首都医科大学 | The indoles alcohol derivative of polar amino acid modification, synthesis, activity and application |
CN109111501A (en) * | 2017-06-23 | 2019-01-01 | 首都医科大学 | The indoles alcohol derivative of fatty acid/amino acid modification, synthesis, activity and application |
-
2019
- 2019-06-21 CN CN201910542916.2A patent/CN112110924B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105283201A (en) * | 2013-03-14 | 2016-01-27 | 加州生物医学研究所 | Targeting agent antibody conjugates and uses thereof |
WO2015135659A1 (en) * | 2014-03-14 | 2015-09-17 | Ontochem Gmbh | Receptor ligand linked cytotoxic molecules |
CN109081801A (en) * | 2017-06-13 | 2018-12-25 | 首都医科大学 | The indoles alcohol derivative of acidic amino acid modification, synthesis, activity and application |
CN109081803A (en) * | 2017-06-13 | 2018-12-25 | 首都医科大学 | The indoles alcohol derivative of polar amino acid modification, synthesis, activity and application |
CN109111501A (en) * | 2017-06-23 | 2019-01-01 | 首都医科大学 | The indoles alcohol derivative of fatty acid/amino acid modification, synthesis, activity and application |
Non-Patent Citations (1)
Title |
---|
PASCAL SCHLAGE 等: "Anthracycline-GnRH derivative bioconjugates with different linkages: Synthesis, in vitro drug release and cytostatic effect", 《JOURNAL OF CONTROLLED RELEASE》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112125905A (en) * | 2019-06-24 | 2020-12-25 | 首都医科大学 | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof |
CN112125905B (en) * | 2019-06-24 | 2023-04-07 | 首都医科大学 | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN112110924B (en) | 2023-01-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104277134B (en) | A kind of preparation method and applications of the dictyophora fungus polysaccharide-chelates of zinc with anti-tumor activity | |
CN112110924B (en) | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof | |
CN111995626B (en) | 6- (acetyl-AA-mercapto) purine, its synthesis, activity and use | |
CN112125905B (en) | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof | |
CN112110923B (en) | 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof | |
CN101690823B (en) | Method for preparing RGDV-containing cytosine arabinoside conjugate pharmacosome and application as antitumor agent | |
CN105198960B (en) | Imidazopyridine -6- formyl-Met-AA-OBzl, synthesis, activity and application | |
US4629627A (en) | Antiviral substance and the manufacturing method thereof | |
CN112125904B (en) | 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof | |
CN112110985B (en) | 6- (acetyl-Arg-Gly-Asp-AA-sulfhydryl) purine, synthesis, activity and application thereof | |
CN112110986B (en) | 6-acetyl RGD mercaptopurine, synthesis thereof, activity of combination of 6-acetyl RGD mercaptopurine and cisplatin and application of 6-acetyl RGD mercaptopurine | |
CN112110925B (en) | 6- (acetyl-AA-mercapto) purine, its synthesis, activity and use in combination with cisplatin | |
CN112979752B (en) | Dioxane-modified tetrahydrocarboline-3-formyl-The-EDG, preparation thereof, antitumor activity thereof and application thereof | |
CN112094322B (en) | His-Gly-Lys modified methotrexate, synthesis, antitumor activity and application thereof | |
GB2079150A (en) | Antiviral substance from Basidiomycetes | |
CN112010811B (en) | 5-fluorouracil modified by theanine and phenylalanine together, and synthesis, activity and application thereof | |
CN112094320B (en) | His-Gly-Glu modified methotrexate, synthesis, antitumor activity and application thereof | |
CN112300244B (en) | 5-fluorouracil modified by theanine alone or together with RGDS, and synthesis, activity and application thereof | |
CN112390854B (en) | 5-fluorouracil modified by theanine and RGDS together, and synthesis, activity and application thereof | |
CN112979750B (en) | Dioxohexa-ring modified tetrahydrocarboline-3-formyl-The-EDG, preparation thereof, anti-transfer activity thereof and application thereof | |
CN111995660B (en) | Glu-Asp-Gly modified methotrexate, synthesis, antitumor activity and application thereof | |
CN112110987B (en) | 5-fluorouracil modified by asparaginyl theanine and phenylalanine, synthesis, activity and application thereof | |
CN112898376B (en) | Dioxane-modified tetrahydrocarboline-3-formyl-The-HGK, preparation thereof, antitumor activity thereof and application thereof | |
CN110577518B (en) | Methyl indole and amide side chain amino acid modified diketopiperazine, synthesis and application thereof | |
CN112225779B (en) | Arg(NO 2 ) -Gly-Asp-Val-gemcitabine, synthesis, anti-tumor activity and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |