CN112125904B - 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof - Google Patents
6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof Download PDFInfo
- Publication number
- CN112125904B CN112125904B CN201910549800.1A CN201910549800A CN112125904B CN 112125904 B CN112125904 B CN 112125904B CN 201910549800 A CN201910549800 A CN 201910549800A CN 112125904 B CN112125904 B CN 112125904B
- Authority
- CN
- China
- Prior art keywords
- cisplatin
- obzl
- purine
- diacetyl
- mercapto
- 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.)
- Active
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
Abstract
The invention discloses 6-S,9-N- (diacetyl-AA-OBzl-sulfydryl) purine (AA in the formula is Met, Pro, Ser, Val and Trp residues), discloses a preparation method thereof, discloses the antitumor activity thereof, and discloses the effect of reducing the renal toxicity of cis-platinum when the compounds are combined with the cis-platinum. Therefore, the invention discloses the application of the combination of the compounds and cisplatin in the preparation of antitumor drugs.
Description
Technical Field
The present invention relates to 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purines of the formula, to a process for their preparation, and to their use in combination with cisplatin to reduce the nephrotoxicity of cisplatin. The invention thus relates to their use in combination with cisplatin in the preparation of anti-neoplastic medicaments. 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 exploration 2 CO-AA-OBzl (AA in the formula is Met, Pro, Ser, Val and Trp residue) modifies 6-SH and 9-N of 6-mercaptopurine, and can eliminate myelosuppression of 6-mercaptopurine, prolong half-life and reduce dosage. Cisplatin is a broad-spectrum anticancer drug, and has good therapeutic effects on various solid tumors. Cisplatin can accumulate in the body in the form of platinum, resulting in a number of toxicities, such as nephrotoxicity. Although there have been numerous studies attempting to overcome the nephrotoxicity of cisplatin over the past decades, there has been no significant success. The inventor finds that CH is used after years of exploration 2 CO-AA-OBzl (AA in the formula is Met, Pro, Ser, Val and Trp residue) modifies 6-SH and 9-N of 6-mercaptopurine, and can eliminate myelosuppression of 6-mercaptopurine, prolong half-life and reduce dosage. The inventors further found that CH 2 CO-AA-OBzl (wherein AA is Met, Pro, Ser, Val and Trp residue) modified 6-sulfydrylThe combined use of the derivative obtained from the 6-SH and 9-N of purine and cisplatin can further reduce the side effects of cisplatin, such as renal toxicity and the like. 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-AA-OBzl-mercapto) purine, wherein AA is Met, Pro, Ser, Val and Trp residue.
In a second aspect, the present invention provides a process for the preparation of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine (wherein AA is the Met, Pro, Ser, Val or Trp residue), which comprises:
in a second aspect, the invention provides a process for the preparation of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, wherein AA is a Met, Pro, Ser, Val or Trp residue, which process comprises:
1. synthesizing 6-S, 9-N-diacetyl-O-ethylmercaptopurine;
2. synthesizing 6-S, 9-N-dicarboxymethylmercaptopurine;
3. a liquid phase method using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst is adopted to condense 6-S,9-N- (dicarboxymethylmercapto) purine with AA-OBzl to prepare 6-S, 9-N-diacetyl-AA-OBzl-mercaptopurine, wherein AA is Met, Pro, Ser, Val and Trp residues.
The fourth aspect of the present invention is to evaluate the antitumor effect of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine in combination with cisplatin.
Drawings
FIG. 1. Synthesis of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine I) ethyl bromoacetate, dimethylformamide, K 2 CO 3 ,65℃；ii)CH 3 OH,2N NaOH aqueous solution; iii) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine, dimethylformamide. AA in 3a-e is Met residue, Pro residue, Ser residue, Val residue and Trp residue, respectively.
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 K are added 2 CO 3 As a catalyst, the reaction mixture was activated for 30min, 6.60mL (59.20mmol) of ethyl bromoacetate was added, and the reaction was continued at 65 ℃. After 48h of reaction TLC (petroleum ether/ethyl acetate-1/1) showed disappearance of 6-mercaptopurine, 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] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ/ppm＝8.692(s,1H),8.489(s,1H),5.214(s,2H),4.260(s,2H),4.215～4.098(dq,J 1 ＝6.9Hz,J 2 ＝7.2Hz,4H),1.238～1.165(dt,J 1 ＝7.2Hz,J 2 ＝11.0Hz,6H)； 13 C-NMR(75MHz,DMSO-d 6 ):δ/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 solution was adjusted to pH 13 at 0 ℃ with 2N aqueous NaOH, stirred for 4h at 0 ℃ and monitored by TLC (petroleum ether/ethyl acetate 1/2) for completion of the reaction. Saturated KHSO is used for reaction liquid 4 The 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.C 4 The aqueous solution was adjusted to pH 2. The mixture was 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] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ/ppm＝13.011(s,2H),8.501(s,1H),8.078(s,1H),4.799(s,2H),4.026(s,2H)； 13 C-NMR(75MHz,DMSO-d 6 ):δ/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-Met-OBzl-mercapto) purine (3a)
0.496g (1.85mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, 0.498g (3.70mmol) of 1-hydroxybenzotriazole was added at 0 ℃ and stirred for 10min, and then 1.140g (7.40mmol) of dicyclohexylcarbodiimide was added and stirred for 30 min. 2.300g (7.40mmol) Met-OBzl was added to the reaction mixture at 0 deg.C, the reaction mixture was adjusted to pH 9 with N-methylmorpholine, stirred at room temperature for 12h and monitored for completion by TLC (petroleum ether/ethyl acetate-1/3). 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 NaHCO 3 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution 3 The 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 (petroleum ether/ethyl acetate 1/3) to give 1.310g (49%) of the title compound. FT-MS (M/e) 709.20[ M-H] - ； 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm＝8.994～8.969(d,J＝7.5Hz,1H),8.784～8.759(d,J＝7.5Hz,1H),8.619(s,1H),8.434(s,1H),7.343(m,10H),5.173～5.079(dd,J 1 ＝13.2Hz,J 2 ＝2.4Hz,4H),5.058(s,2H),4.513～4.444(dd,J 1 ＝7.8Hz,J 2 ＝5.4Hz,2H),4.235～4.120(dd,J 1 ＝15.0Hz,J 2 ＝4.2Hz,2H),2.539～2.411(m,4H),2.242～1.834(m,10H)； 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm＝171.79,171.64,168.05,166.79,158.76,151.67,149.22,146.15,136.33,136.26,130.63,128.87,128.55,128.49,128.30,128.23,66.64,66.52,51.92,51.80,45.54,32.23,31.09,31.04,29.87,29.83,15.00。
EXAMPLE 4 preparation of 6-S,9-N- (diacetyl-Pro-OBzl-mercapto) purine (3b)
0.400g (1.49mmol)6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, and 0.808g (2.98mmol) of 1-hydroxybenzotriazole was added thereto at 0 ℃ and stirred for 10min, and then 1.230g (5.97mmol) of dicyclohexylcarbodiimide was added thereto and stirred for 30 min. 2.270g (5.97mmol) Pro-OBzl were added to the reaction mixture at 0 deg.C, the reaction mixture was adjusted to pH 9 with N-methylmorpholine, stirred at room temperature for 12h and monitored for completion by TLC (dichloromethane/methanol-40/1). The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 50mL of ethyl acetate, insoluble materials were filtered off, and the filtrate was washed with saturated NaHCO 3 Aqueous washing (30 mL. times.3), saturated aqueous NaCl washing (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution 3 The 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 ═ 90/1) to give 0.400g (41%) of the title compound. FT-MS (M/e) 641.58[ M-H] - ； 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm＝8.662(s,1H),8.366(s,1H),7.441～7.322(m,10H),5.297～5.211(m,2H),5.102～5.035(m,4H),4.422～4.394(m,2H),3.785～3.764(m,2H),3.427～3.342(m,4H),2.346～2.234(m,2H),2.008～1.897(m,6H)； 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm＝172.35,171.78,166.66,165.36,158.78,151.76,149.37,136.44,130.55,128.93,128.46,67.37,66.38,59.70,59.35,47.49,47.02,45.23,32.19,29.32,24.99,22.68。
EXAMPLE 5 preparation of 6-S,9-N- (diacetyl-Ser-OBzl-mercapto) purine (3c)
0.070g (0.26mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 5mL of anhydrous N, N-dimethylformamide, 0.070g (0.52mmol) of 1-hydroxybenzotriazole was added at 0 ℃ and stirred for 10min, then 0.414g (1.04mmol) of dicyclohexylcarbodiimide was added and stirred for 30 min. 0.386g (1.04mmol) of Ser-OBzl was added to the reaction mixture 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 mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 20mL of ethyl acetate, filtered, the residue was washed with dichloromethane and methanol, and dried to give 0.112g (71%) of the titled compoundA compound (I) is provided. FT-MS (M/e) 621.18[ M-H] - ； 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm＝8.928～8.902(d,J＝7.8Hz,1H),8.662～8.632(m,2H),8.430～8.420(m,1H),7.368～7.296(m,10H),5.225～5.189(t,J＝5.4Hz,1H),5.142～5.119(m,5H),5.085(s,2H),4.486～4.405(m,2H),4.210～4.205(d,J＝1.5Hz,2H),3.811～3.648(m,4H)； 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm＝170.65,170.54,168.12,166.78,158.64,151.75,146.25,136.37,136.33,130.55,128.84,128.80,128.43,128.36,128.07,127.98,66.49,66.38,61.67,55.57,55.47,45.49,32.05。
EXAMPLE 6 preparation of 6-S,9-N- (diacetyl-Val-OBzl-mercapto) purine (3d)
0.500g (1.86mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, 1.060g (7.46mmol) of 1-hydroxybenzotriazole was added thereto at 0 ℃ and stirred for 10min, and then 1.530g (7.46mmol) of dicyclohexylcarbodiimide was added thereto and stirred for 30 min. 2.850g (7.46mmol) Val-OBzl were added to the reaction mixture 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 30/1) 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, insoluble materials were filtered off, and the filtrate was taken with saturated NaHCO 3 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution 3 The 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 (petroleum ether/ethyl acetate 1/2) to give 0.940g (78%) of the title compound. FT-MS (M/e) 645.26[ M-H] - ； 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm＝8.818～8.791(d,J＝8.1Hz,1H),8.625(s,1H),8.599～8.572(d,J＝8.1Hz,1H),8.424(s,1H),7.375～7.310(m,10H),5.191～5.125(m,4H),5.088(s,2H),4.284～4.236(m,2H),4.262～4.146(dd,J 1 ＝15.3Hz,J 2 ＝7.8Hz,4H),2.131～2.048(m,2H),0.915～0.851(m,12H)； 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm＝171.57,171.46,168.18,166.88,158.84,151.69,149.22,146.27,136.30,136.24,130.58,128.88,128.85,128.59,128.53,128.45,66.52,66.40,58.26,58.17,45.44,32.26,30.61,30.55,19.34,18.50,18.46。
EXAMPLE 7 preparation of 6-S,9-N- (diacetyl-Trp-OBzl-mercapto) purine (3e)
0.050g (0.19mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, 0.050g (0.37mmol) of 1-hydroxybenzotriazole was added thereto at 0 ℃ and stirred for 10min, and then 0.154g (0.74mmol) of dicyclohexylcarbodiimide was added thereto and stirred for 30 min. 0.247g (0.74mmol) of Trp-OBzl was added to the reaction mixture 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-30/1) 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 NaHCO 3 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution 3 The 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 0.124g (81%) of the title compound. FT-MS (M/e) 819.28[ M-H] - ； 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.917(s,1H),10.838(s,1H),9.012～8.989(d,J＝6.9Hz,1H),8.729～8.704(d,J＝7.5Hz,1H),8.526(s,1H),8.352(s,1H),7.609～6.933(m,20H),5.077～4.962(m,6H),4.653～4.585(dd,J 1 ＝6.9Hz,J 2 ＝6.6Hz,2H),4.146(m,2H),3.254～3.132(m,4H)； 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm＝171.88,171.79,168.01,166.68,158.55,151.66,149.16,146.11,136.62,136.56,136.09,136.02,130.48,128.78,128.46,128.40,128.13,128.07,127.49,124.32,124.15,121.53,121.48,119.04,118.96,118.40,111.95,111.89,109.48,109.39,66.58 66.47,54.11,45.47,32.06,27.66,27.51。
Example 8 evaluation of the antitumor Effect of 3a, c, e in combination with cisplatin
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 compounds 3a, c, e was 32. mu. mol/kg, the dose of positive control 6-mercaptopurine was 164. mu. mol/kg, the dose of cisplatin was 5.7mol/kg, 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 10 7 one/mL. The living cells were suspended in cooled physiological saline to a cell density of 2X 10 7 one/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, the antitumor activity of the combined use of 3a, c and e and cisplatin is obviously superior to that of the cisplatin used alone. Moreover, the antitumor activity of the compound used in combination with cisplatin is equivalent to that of the compound used in combination with cisplatin under the condition that the dose of the compound is reduced by 4 times compared with that of 6-mercaptopurine. This is the unexpected technical effect of this case.
TABLE 13S 180 antitumor Activity of a, c, e in combination with cisplatin
| Compound (dose, μmol/kg) | Tumor weight (mean + -SD g) |
| CMCNa(—) | 3.06±0.20 |
| Cis-platinum (5.7) | 1.95±0.32 a |
| 6-mercaptopurine (164) + cisplatin (5.7) | 1.49±0.45 c |
| 3a (32) + cisplatin (5.7) | 1.42±0.48 b |
| 3c (32) + cisplatin (5.7) | 1.12±0.50 b |
| 3e (32) + cisplatin (5.7) | 1.13±0.45 b |
a) P <0.05 to CMCNa; b) p <0.05 to CMCNa and p <0.01 to cisplatin; c) p <0.05 to CMCNa and p <0.05 to cisplatin; n is 12.
Example 9 evaluation of hepatotoxicity of 3a, c, e in combination with cisplatin
Mice treated for 10 days by continuous administration are operated, blood is taken from eyeballs before sacrifice, centrifugation is carried out for 15min at 1000rpm at 4 ℃ within 30min, and detection is carried out by a glutamic-pyruvic transaminase/ALT/GPT kit after serum is taken. 3a, c, e are representatives of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, the control is CMCNa, and the sham group is normal mice.
Results table 2 shows that serum glutamate pyruvate transaminase activity of mice in the compound 3a, c, e combined cisplatin group is significantly lower than that of mice in the cisplatin group or 6-mercaptopurine combined cisplatin group (p <0.05), i.e. the 3a, c, e combined cisplatin administration at a dose of 32 μmol/kg can reduce the hepatotoxicity of cisplatin to some extent.
TABLE 23 serum glutamate pyruvate transaminase Activity of mice in combination with cisplatin
| Compound (I) | Serum glutamic-pyruvic transaminase activity (mean + -SD IU/L) |
| Artificial operation group | 15.95±5.76 |
| Cis-platinum | 81.29±23.39 a |
| 6-mercaptopurine + cisplatin | 80.17±17.30 a |
| 3a + cisplatin | 46.55±11.77 b |
| 3c + cisplatin | 53.39±13.74 b |
| 3e + cisplatin | 29.82±11.87 c |
a) P <0.05 compared to sham group; b) p <0.05 compared to cisplatin; c) p <0.01 to cisplatin; n is 6.
Example 10 evaluation of renal toxicity of 3a, c, e in combination with cisplatin
Mice treated with continuous administration for 10 days were operated, and blood was collected from the eyeballs before sacrifice, centrifuged at 1000rpm at 4 ℃ for 15min within 30min, and serum was collected and tested with creatinine (Cr) kit. 3a, c, e are representatives of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, the control is CMCNa, and the sham group is normal mice.
Results table 3 shows that serum creatinine levels in mice of the compound 3a, c, e in combination with cisplatin were significantly lower than those in mice of the cisplatin group or 6-mercaptopurine in combination with cisplatin (p <0.05), i.e. 3a, c, e in combination with cisplatin at a dose of 32 μmol/kg reduced the nephrotoxicity of cisplatin to some extent.
TABLE 33 serum creatinine levels in mice with cisplatin combination
| Compound (I) | Serum creatinine levels (mean. + -. SD. mu. mol/L) |
| Artificial operation group | 218.5±31.1 |
| Cis-platinum | 565.8±158.2 a |
| 6-mercaptopurine+ cis-platinum | 328.6±72.5 b |
| 3a + cisplatin | 401.5±52.8 c |
| 3c + cisplatin | 167.2±112.5 b |
| 3e + cisplatin | 179.6±25.7 c |
a) P <0.05 compared to sham group; b) p <0.05 compared to cisplatin; c) p <0.01 to cisplatin; n is 6.
Example 11 evaluation of myelosuppressive toxicity of 3a, c, e in combination with cisplatin
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. 3a, c, e are representatives of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, control CMCNa.
Results table 4 shows that the number of leukocytes was significantly reduced in cisplatin group mice compared to CMCNa group mice, and there was no significant reduction in platelet and red blood cell numbers. This suggests that the myelosuppressive toxicity caused by cisplatin is mainly manifested as a suppression of the number of leukocytes. The blood platelet number of the mice in the group of 6-mercaptopurine combined with cis-platinum is obviously lower than that of the mice in the group of CMCNa. The white blood cell count and the platelet count of the mice of the 3a, c, e combined cis-platinum group are obviously higher than those of the mice of the cis-platinum group, namely the combination of the 3a, c, e and cis-platinum can reduce the myelosuppression side effect of the cis-platinum. This is the unexpected technical effect of this case.
TABLE 43 mouse blood routine results in combination with cisplatin
a) P <0.05 to CMCNa; b) p <0.05 to CMCNa and p <0.05 to cisplatin; c) p <0.05 to CMCNa and p <0.01 to cisplatin; n is 8.
Claims (1)
1. The application of the combination of 6-S, 9-N-diacetyl-AA-OBzl-mercaptopurine and cisplatin in the preparation of antitumor drugs,
wherein AA is Met, Pro, Ser, Val and Trp residue.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910549800.1A CN112125904B (en) | 2019-06-24 | 2019-06-24 | 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910549800.1A CN112125904B (en) | 2019-06-24 | 2019-06-24 | 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112125904A CN112125904A (en) | 2020-12-25 |
| CN112125904B true CN112125904B (en) | 2022-09-02 |
Family
ID=73850065
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910549800.1A Active CN112125904B (en) | 2019-06-24 | 2019-06-24 | 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112125904B (en) |
Citations (3)
| 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 |
| 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
- 2019-06-24 CN CN201910549800.1A patent/CN112125904B/en active Active
Patent Citations (3)
| 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 |
| 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 |
|---|
| 《Anthracycline-GnRH derivative bioconjugates with different linkages:Synthesis, in vitro drug release and cytostatic effect》;Pascal Schlage等;《Journal of Controlled Release》;20110812;第156卷;第170-178页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112125904A (en) | 2020-12-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5036103A (en) | Method of treating cancer cells in humans | |
| CN112125904B (en) | 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof | |
| CN112110924B (en) | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof | |
| CN105796587B (en) | Caulis bambusae in taenian polysaccharide immunological regulation, it is antitumor in application | |
| CN112110923B (en) | 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof | |
| CN112125905B (en) | 6-S,9-N- (diacetyl-Lys-OBzl-mercapto) purine, synthesis, activity and application thereof | |
| CN106631957A (en) | Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof | |
| CN111995626B (en) | 6- (acetyl-AA-mercapto) purine, its synthesis, activity and use | |
| CN108727583A (en) | Multi-arm target anticancer conjugate | |
| US4629627A (en) | Antiviral substance and the manufacturing method 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 | |
| CN112110985B (en) | 6- (acetyl-Arg-Gly-Asp-AA-sulfhydryl) purine, synthesis, activity and application thereof | |
| CN113185582A (en) | Cyclic pentapeptide Galaxamide, preparation method thereof and application thereof in preparation of antitumor drugs | |
| CN112010811B (en) | 5-fluorouracil modified by theanine and phenylalanine together, and synthesis, activity and application thereof | |
| CN112300245B (en) | RGDS and theanine co-modified 5-fluorouracil, and synthesis, activity and application thereof | |
| GB2079150A (en) | Antiviral substance from Basidiomycetes | |
| 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 | |
| CN112094320B (en) | His-Gly-Glu modified methotrexate, synthesis, antitumor activity and application thereof | |
| CN112094322B (en) | His-Gly-Lys modified methotrexate, synthesis, antitumor activity and application thereof | |
| Schurig et al. | Experimental antitumor activity of BMY-28090, a new antitumor antibiotic | |
| CN111995660B (en) | Glu-Asp-Gly modified methotrexate, synthesis, antitumor activity and application thereof | |
| ES2205226T3 (en) | COMPLEX OF CARBOHYDRATES EXTRACTED FROM MYCOBACTERIUM TUBERCULOSIS AND PROCEDURE FOR THE PREPARATION OF THE SAME. | |
| CN110357881B (en) | Extraction process and application of beta-carbolinyl alkaloid in quassia tree |
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 |